MXPA06007322A - Improved gastrin releasing peptide compounds - Google Patents

Abstract

New and improved compounds for use in diagnostic imaging or therapy having the formula M-N-O-P-G, wherein M is an optical label or a metal chelator (in the form complexed with a metal radionuclide or not), N-O-P is the linker, and G is the GRP receptor targeting peptide. Methods for imaging a patient and/or providing radiotherapy or phototherapy to a patient using the compounds of the invention are also provided. Methods and kits for preparing a diagnostic imaging agent from the compound is further provided. Methods and kits for preparing a radiotherapeutic agent are further provided.

Description

IMPROVED GASTRINE RELEASE PEPTIDE COMPOUNDS CROSS REFERENCE WITH RELATED APPLICATIONS This application claims the benefit of the North American Application No. 10 / 828,925 filed on April 20, 2004, which is a continuation in part of the International Application PCT / US03 / 041328, filed on December 24 of 2003, which claims the priority of the North American Application No. 10 / 341,577 filed on January 13, 2003. All of these applications are incorporated in their entirety to the present invention as a reference. Field of the Invention The present invention relates to novel gastrin-releasing peptide (GRP) compounds, which are useful as diagnostic imaging agents or radiotherapeutic agents. These GRP compounds are labeled with radionuclides or detectable labels by light imaging in vivo, and include the use of novel linkers between the label and the targeting peptide, which form improved pharmacokinetics.

BACKGROUND OF THE INVENTION The use of radiopharmaceuticals (eg, radiotherapeutic diagnostic imaging agents) to detect and treat cancer is well known. In recent years, the discovery of radiopharmaceuticals directed to the site for cancer detection and / or treatment has gained great popularity and continues to grow as the medical profession better appreciates the specificity, efficacy and usefulness of said compounds. These newer radiopharmaceuticals typically consist of a targeting agent connected to a metal chelator, which can be chelated to (e.g. made in compound with) a diagnostic metal radionuclide, such as, for example, technetium or indium. , or a metal radionuclide such as, for example, lutetium, yttrium, or rhenium. The role of the chelator is to hold (for example, chelation) the metal radionuclide as the radiopharmaceutical agent that is delivered to the desired site. A metal chelator that does not bind strongly to the metal radionuclide could render the radiopharmaceutical ineffective for its intended use, since the metal radionuclide may not reach its desired site. Therefore, additional research and development led to the discovery of metal chelators, such as those reported in US Patent No.

No. 5,662,885 to Pollak et al., Incorporated herein by reference, which exhibits strong binding affinity to metal radionuclides and the ability to conjugate with the targeting agent. Subsequently, the concept of using a "spacer" to create a physical separation between the metal chelator and the steering agent was introduced additionally, for example in the North American Patent NO. No. 5,976,495 to Pollak et al., Incorporated herein by reference. The role of the targeting agent, by virtue of its affinity for certain binding sites, is to direct the diagnostic agent, such as a radiopharmaceutical containing the metal radionuclide, to the desired site for detection or treatment. Typically, the targeting agent may include a protein, a peptide, or another molecule that exhibits a specific affinity for a particular receptor. Other known targeting agents include monoclonal antibodies (MAbs), antibody fragments (Fab'S and (Fab) 2'S), and receptor-avid peptides. Donald J. Buchsbaum, "Cancer Therapy with Radiolabeled Antibodies, Pharmacokinetics of Antibodies and Their Radiolabels, Experimental Radioimmunotherapy and Methods to Increase Therapeutic Efficacy," CRC Press, Boca Raton, Chapter 10, p. 115-140, (1995); Fischman, and associates "A Ticket to Ride: Peptide Radiopharmaceuticals," The Journal of Nuclear Medicine, vol. 34, No. 12 (Dec. 1993). These references are incorporated in their entirety to the present invention as a reference. In recent years, it has been learned that some cancer cells contain gastrin-releasing peptide (GRP) receptors (GRP-R) of which there are a number of subtypes. In particular, it has been shown that several types of cancer cells have expressed or only expressed GRP receptors. For this reason, a lot of research and studies have been carried out on GRP analogues and GRP analogs that link to the GRP receptor family. One of said analogs is bombesin (BBN), a 14 amino acid peptide (for example tetradecapeptide) isolated from toad skin, which is an analogue of human GRP and which binds GRP receptors with high specificity and with an affinity similar to GRP. . Bombesin and GRP analogs can take the form of agonists or antagonists. The binding of GRP or BBN agonists to the GRP receptor increases the range of cell division of these cancer cells and said agonists are interned by the cell, whereas the binding of GRP or BBN antagonists generally does not result in either internationalization through the cell or increased ranges of cell division. Sayings Antagonists are designed to competitively inhibit endogenous GRP that binds to GRP receptors and reduce the proliferation range of cancer cells. See, for example, Hoffken, K., Peptides in Oncology II, Somatostatin Analogues and Bombesin Antagonists (1993), pp. 87-112. For this reason, a great deal of work has been done, and it has been considered to develop BBN or GRP analogs that are antagonistic. See, for example, the publication by Davis and associates., Metabolic Stability and Tumor Inhibition of Bombesin / GRP Receptor Antagonists, Peptides, vol. 13, p. 401-407, 1992. In the design of an effective compound to be used as a diagnostic or therapeutic agent for cancer, it is important that the drug have in vivo direction and adequate pharmacokinetic properties. For example, it is preferable for a radiopharmaceutical, the radiolabelled peptide has high specific uptake through the cancer cells (eg, through GRP receptors). In addition, it is also preferred that once the radionuclide is located at the cancer site, it remains there for a desired amount of time to deliver a radiation dose highly localized to the site. In addition, the development of radiolabelled peptides that are cleared efficiently from tissues normal, is also an important factor for radiopharmaceutical agents. When biomolecules (eg MAb, Fab or peptides) labeled with metal radionuclides (via a chelation conjugation) are administered in an animal such as human, a large percentage of the metal radionuclide (in some chemical form) is "trapped" either in the kidney or liver parenchyma (that is, it is not excreted in the urine or bile). Dunca et al., Lndium-111-Diethylenetriaminepentaacetic Acid-Octreotide Is Delivered in Vivo to Pancreatic, Tumor Cell, Renal, and Hepatocyte Lysosomes, Cancer Research 57, p, 659-671, (Feb. 15, 1997). For smaller radiolabeled molecules (eg peptides or Fb) the important route of activity clearance through the kidneys, which also retain high levels of radioactive metal (usually> 10-15% of the injected dose). The retention of metal radionuclides in the kidney or liver is clearly undesirable. In an adverse way, the radiopharmaceutical's clearing of the bloodstream too quickly through the kidney is also not desirable if a longer diagnostic imaging or high tumor uptake for radiotherapy is needed. Subsequent work, such as that of U.S. Patent No. 6,200,546 and 2002/0054855 of Hoffman and associates., incorporated in its entirety to the present invention as a reference, has attempted to overcome this problem by forming a compound having the general formula XYB wherein X is a group with the ability to make compounds of a metal, and is a covalent bond. in a spacer group and B is a bombesin agonist binding portion. These compounds were reported to have high binding affinities to GRP receptors, and radioactivity was retained within the cells for extended periods of time. Furthermore, in in vivo studies in normal mice it has been shown that the retention of the radioactive metal in the kidneys was also less than that known in the art, with most of the radioactivity being excreted in the urine. New and improved radiopharmaceuticals and other diagnostic compounds that have improved pharmacokinetic improvements and kidney excretion (eg, less retention of radioactive metal in the kidney, have recently been discovered for diagnostic imaging and therapeutic uses. For diagnostic purposes, rapid renal excretion and low levels of retained radioactivity are important for improved imaging.For radiotherapeutic uses, a slower blood clearance is important to allow greater tumor uptake and better direction of the tumor. tumor with low retention in the kidney. Summary of the Invention In one embodiment of the present invention, new and improved compounds are provided for use in diagnostic imaging and radiotherapy. The compounds include a chemical moiety capable of complexing a medically useful metal ion or radionuclide (metal chelator) adhered to a GRP receptor targeting peptide through a linker or spacer group. In another embodiment, these compounds include an optical label (for example, a photomarker or other detectable mark by generating images with light, generation of optoacoustic images and photoluminescence) adhered to a GRP receptor that direct the peptide through a linker or spacer group. In general, the compounds of the present invention may have the formula: MNOPG wherein M is the metal chelator (in a compound form with a metal radionuclide or not), or the optical label NOP, is the linker, and G is the direction peptide of the GRP receptor. The metal chelator M can be any of the metal chelators known in the art to be compounds with a medically useful metal ion or radionuclide. Preferred chelators include DTPA, DOTA, DO3A, HP-DO3A, EDTA, TETA, EGP, HBED, NOTE, DOTMA, TETMA, PDTA, TTHA, LICAM, MECAM, or peptide chelators, such as, for example, those that are describe in the present invention. The metal chelator may or may not be in compound with a metal radionuclide, and may include an optional spacer such as a simple amino acid. Preferred metal radionuclides for scintigraphy or radiotherapy include 99mTc, 51Cr, 67Ga, 68 Ga, 47 S, e, bnCr, 116b7'Tm, 1 14411C, e, 111 l In, 168? B, 1 / sYb, 14ULa, aüY, 88 153 97 And, Sm, 166 Ho, 165? 166? Dy, Dy, "Cu, b4Cu, b / Cu, Ru, 103 'R? u, 11806üR. e, 118080R. e, 2 ¿0U30P? b, 211 Bi, 212 Bi, 225 Ac, 105 Rh, 10S 'DPdJ, 117m Sc "n, 149' P 1 m, 161 Tb, 177 Lu, 98Au and 199Au. The choice of metal will be determined based on the desired therapeutic or diagnostic application. For example, for diagnostic purposes, preferred radionuclides include 64Cu, 67Ga, 68Ga, 99mTc, and 111ln, with 99mTc, and 111ln being particularly preferred. For therapeutic purposes, preferred radionuclides include 64Cu, 90Y, 105Rh, 111ln, 117mSn, 1 9Pm, 153Sm, 161Tb, 66Dy, 166Ho, 175? B j 177LU j 186 / 188Rej and 199Au g e n d Q 177, _u and 90? ] QS particularly preferred. A more preferred chelator used in the present invention is 4,7,10-tricarboxymethyl-1,4,7,10-tetraazacyclodocane triacetic acid substituted-1 (DO3A). The optical mark M can be of several optical marks known in the art. Preferred brands include, without limitation, optical inks, chromophores or organic fluorophores, such as light absorption compounds of cyanine inks, reflection and light screening compounds and bioluminescent molecules. In one embodiment, the linker N-O-P contains at least one non-alpha amino acid. In another embodiment, the linker N-O-P contains at least one substituted biary acid. In yet another embodiment, the linker N-O-P contains at least one non-alpha amino acid with a cyclic group. The GRP receptor that targets the peptide can be GRP, .bombesin or any derivatives or analogs thereof. In a preferred embodiment, the GRP receptor that directs the peptide is a GRP analog or bombesin that acts as an agonist. In a particularly preferred embodiment, the GRP receptor targeting peptide is a binding portion of the bombesin agonist which is described in US Patent No. 6,200,546 and in Publication No. 2002/0054855, incorporated herein by reference. A novel method for generating images using the compounds of the present invention is also provided invention. A single-vial multi-bottle kit containing all the necessary components for preparing the diagnostic or therapeutic agents of the present invention is provided., in an example mode thereof. A novel method is also provided for preparing a diagnostic imaging agent comprising the step of adding to a means for generating an injectable image a substance containing the compounds of the present invention. A novel method of radiotherapy utilizing the compounds of the present invention is also provided, which is a novel method for preparing a radiotherapeutic agent comprising the step of adding to a injectable therapeutic medium a substance comprising a compound of the present invention. Brief Description of the Drawings Figure 1A is a graphical representation of a series of chemical reactions for the synthesis of intermediate C ((3ß, 5ß) -3- (9H-Fluoren-9-ylmethoxy) aminocolan-24oic acid), starting from of A (Methyl- (3β, 5β) -3-aminocolan-24-ate) and B ((3β, 5β) -3-aminocolan-24-oico), as described in Example I. Figure 1B , is a graphic representation of the reaction in sequences of the synthesis of N - [(3ß, 5ß) -3 - [[[[[4,7,10-Tris (carboxymethyl) -1,4,7,1 O-tetraazaci I cl ododec- 1 - il] acetyl] amino] acetyl] amino] colan-24-yl] -L-glutaminyl-L-tryptopyl-L-alanyl-L-valyl-glycyl-L-histidyl-L-leucyl-L-methioninamide (L62), as described in Example I. Figure 2A is a graphical representation of the sequence reaction of the synthesis of N- [4 - [[[[[4,7,10-Tris (carboxymethyl) -1,4] 7.1 O-tetraazacylclodode c-1-yl] acetyl] amino] acetyl] amino] benzoyl] -L-gIutaminyl-L-tryptopyl-L-alanyl-L-valyl-glycyl-L-histidyl-L-leucyl-L methioninamide (L70tal as described in Example II) Figure 2B is a general graphical representation of the sequence reaction of N- [4- [2 - [[[4,7,10-Tris (carboxymethyl)] synthesis -1,4,7,1 O-tetraazaci I clododec-1 -il3acetil] amino] ethoxy] benzoyl] -L-glutaminyl-L-tryptopyl-L-alanyl-L-valyl-glycyl-L-histidyl-L-leucyl -L-methioninamide (L73), N- [3 - [[[[4, 7,10 -Tris (carboxymethyl) -1, 4,7,1 O-tetraazaci I clod or dec- 1 -yl] acetyl] amino] methyl] benzoyl] -L-glutaminyl-L-tryptopyl-L-alanyl-L-valyl-glycyl-L-histidyl-L-leucyl-L-methioninamide (L115), and N- [ 4 - [[[[4,7,10-Tris (carboxymethyl) -1,4,7,1 O-tetraazaci I clod odec-1-yl] acetyl] amino] methyl] phenylacetyl] -L-glutaminyl-L- tryptopyl-L-alanyl-L-valyl-glycyl-L-histidyl-L-leucyl-L-methioninamide (L116), as described in Example II. Figure 2C is a chemical structure of the linker used in the synthesis reaction of N- [4- [2 - [[[4,7,10- Tris (carboxymethyl) -1,4,7,1 O-tetraazaci I clod or dec-1 -yl] acetyl] amino] ethoxy] benzoyl] -L-glutaminyl-L-triptofinl-L-alanyl-L-valyl-glycyl -L-histidyl-L-leucyl-L-methioninamide (L73), as described in Example II. Figure 2D is a chemical structure of the linker used in the reaction of Figure 2B for the synthesis of N- [3 - [[[[4,7,10-Tris (carboxymethyl) -1,4,7,10- tetraazacylclododec-1-yl] acetyl] amino] methyl] benzoyl] -L-glutaminyl-L-tryptopyl-L-alanyl-L-valyl-glycyl-L-histidyl-L-leucyl-L-methioninamide (L115) as described in Example II. Figure 2E is a chemical structure of the linker used in the synthesis reaction of Figure 2B for the synthesis of N- [4 - [[[[4,7,10-Tris (carboxymethyl) -1,4,7 , 10-tetraazacylclododec-1-yl] acetyl] amino] methyl] phenylacetyl] -L-glutaminyl-L-tryptopyl-L-alanyl-L-valyl-glycyl-L-histidyl-L-leucyl-L-methioninamide (L116) , as described in the Example Figure 2F is a graphical representation of the sequence reaction for the synthesis of N - [[4,7,10-Tris (carboxymethyl) -1,4,7,10-tetraazacyclododec-1-yl] acetyl] glycyl- 4-piperidinecarbonyl-L-glutaminyl-L-tryptopyl-L-alanyl-L-valyl-glycyl-L-histidyl-L-leucyl-L-methioninamide (L74), as described in Example II. Figure 3A is a graphic representation of a series of chemical reactions for the synthesis of the intermediary of (3ß, 5ß) -3 - [[(9H-Fluoren-9-ylmethoxy) amino] acetyl] amino-12-oxocolan-24-oic acid (C), as described in Example lll. Figure 3B is a graphical representation of the sequence reaction for the synthesis of N - [(3ß, 5ß) -3 - [[[[[4,7,10-Tris (carboxymethyl) -1,4,7, 10-tetraazacylclododec-1-yl] acetyl] amino] acetyl] amino] -12,24-dixocolan-24-yl] -L-glutaminyl-L-tryptopyl-L-alanyl-L-valyl-glycyl-L-histidyl- L-leucyl-L-methioninamide (L67), as described in Example III. Figure 3C is a chemical structure of (3β, 5β) -3-Amino-12-oxocolan-24-oic acid (B), as described in Example III. Figure 3D, is a chemical structure of acid (3β, 5β) -3 - [[(9H-Fluoren-9-ylmethoxy) amino] acetyl] amino-12-oxocolan-24-oico (C), as described in Example III. Figure 3E, is a chemical structure of N - [(3ß, 5ß) -3 - [[[[[4, 7, 10-Tris (carboxymethyl) -1, 4,7,1 O-tetraazaci I clod odec-1-yl] acetyl] amino] acetyl] amino] -12,24-dixocolan-24-yl] -L-glutaminyl-L-tryptopyl-L-alanyl-L-valyl-glycyl-L-histidyl-L- leucyl-L-methioninamide (L67), as described in Example III. Figure 4A is a graphic representation of a sequence of the reactions to obtain the intermediates acid (3ß, 5ß) -3 - [[(9H-Fluoren-9-ylmethoxy) amino] acetyl] amino-12-oxocolan-24-oico (3a), and (3ß, 5ß, 7a, 12a) -3 - [[ (9H-Fluoren-9-ylmethoxy) amino] acetyl] amino-7,12-dihydroxycolan-24-oico (3b), as described in Example IV. Figure 4B is a graphical representation of the sequence reaction for the synthesis of N - [(3β, 5β) -3 - [[[[[4, 7,10 -Tris (carb oxymethyl) -1, 4,7 , 10 -tetra azacilclodode e-lilla cet il] amino] to cetil] amino] -12-hydroxy -24 -oxo-tail n-24-l] -L-glutaminyl-L-triptophyl-L-alanyl-L-valil -glycyl-L-histidyl-L-leucyl-L-methioninamide (L63), as described in Example IV. Figure 4C is a graphical representation of the sequence reaction for the synthesis of N - [(3β, 5β, 7a, 12a) -3 - [[[[[4,7,10-Tris (carboxymethyl) -1, 4,7,10-tetraazacylclododec-1-yl] acetyl] amino] acetyl] amino] -7,12-dihydroxy-24-oxocolan-24-yl] -L-glutaminyl-L-triptophoyl-L-alanyl-L- valil-glycyl-L-histidyl-L-leucyl-L-methioninamide (L64), as described in Example IV. Figure 4D is a chemical structure of acid (3β, 5β, 7a, 12a) -3-amino-7,12-dihydroxycolan-24-oico (2b), as described in Example IV. Figure 4E is a chemical structure of (3β, 5β, 12a) -3 - [[(9H-Fluoren-9-ylmethoxy) amino] acetyl] amino-12-hydroxycolan-24-oic acid (3a), such as is described in Example IV; Figure 4F is a chemical structure of (3β, 5β, 12a) -3 - [[(9H-Fluoren-9-ylmethoxy) amino] acetyl] amino-12-hydroxycolan-24-oic acid (3b), as described in Example IV; Figure 4G is a chemical structure of N - [(3β, 5β, 12a) -3 - [[[[[4,7,10-Tris (carboxymethyl) -1,4,7,10-tetraazacylcodedec-1-] il] acetyl] amino] acetyl] amino-12-hydroxy-24-oxocolan-24-yl] - L-glutaminyl-L-tryptopyl-L-alanyl-L-valyl-glycyl-L-histidyl-L-leucyl- L-methioninamide (L63), as described in Example IV. Figure 4H is a chemical structure of N - [(3ß, 5ß, 7a, 12a) -3 - [[[[[4,7,10-Tris (carboxymethyl) -1,4,7,10-tetraazacyclododec] -1-yl] acetyl] amino] acetyl] amino-7,12-dihydroxy-24-oxocolan-24-yl] - L-glutaminyl-L-triptophyl-L-alanyl-L-valyl-glycyl-L-histidyl -L-leucyl-L-methioninamide (L64), as described in Example IV. Figure 5A is a general graphical representation of the sequence reaction for the synthesis of 4 - [[[[4.7, 10-Tris (ca rboxi meti I) -1, 4,7,1 O-tetraazaci cl ododec - 1-yl] acetyl] amino] methyl] benzoyl-L-glutaminyl-L-tryptopyl-L-alanyl-L-valyl-glycyl-L-histidyl-L-leucyl-L-methionimane (L71); and Trans-4 - [[[[4,7,10-tris (carboxymethyl) -1,4,7,10-tetraazacyclododec-1-yl] acetyl] amino] methyl] cyclohexylcarbonyl-L-glutaminyl-L-triptophyl- L-alanyl-L-valyl-glycyl-L-histidyl-L- leucyl-L-methioninamide (L72) as described in Example V, wherein the linker is of Figure 5B and Figure 5C, respectively. Figure 5B is a chemical structure of the linker used in compound L71 as shown in Figure 5A and as described in Example V. Figure 5C is a chemical structure of the linker used in compound L72 such as is shown in Figure 5A and as described in Example V. Figure 5D is a chemical structure of a Rink amide resin functionalized with bombesin [7,14] (B), as described in Example V Figure 5E is a chemical structure of Trans-4 - [[[(9H-fluoren-9-ylmethoxy) carbonyl] amino] methyl] cyclohexanecarboxylic acid (D), as described in Example V; Figure 6A is a graphical representation of a sequence of reactions for the synthesis of the intermediate linker of 2 - [[[9H-Fluoren-9-ylmethoxy) carbonyl] amino] methyl] benzoic acid (E), as described in Example VI. Figure 6B is a graphical representation of a sequence of reactions for the synthesis of the intermediate linker of 4 - [[[9H-Fluoren-9-ylmethoxy) carbonyl] amino] methyl] -3-nitrobenzoic acid (H), such as it is described in Example VI. Figure 6C is a graphic representation of the synthesis of N- [2 - [[[[4,7,10-Tris (carboxymethyl) -1,4,7,10-tetraazacyclododec-1-yl] acetyl] amino] methyl ] benzoyl] -L-glutaminyl-L-tryptopyl-L-alanyl-L-valyl-glycyl-L-histidyl-L-leucyl-L-methionamide (L75), as described in example VI.

Figure 6D is a graphical representation for the synthesis of N- [4 - [[[[4,7,10-Tris (carboxymethyl) -1,4,7,10-tetraazacyclododec-1-yl] acetyl] amino] methyl] -3-nitrobenzoyl] -L-glutaminyl-L-tryptopyl-L-alanyl-L-valyl-glycyl-L-histidyl-L-leucyl-L-methionamide (L76), as described in Example VI.

Figure 7A is a graphical representation of a sequence of reactions for the synthesis of the intermediate linker [4 - [[[[9H-Fluoren-9-ylmethoxy) carbonyl] amino] methyl] phenoxy] acetic acid (E), such as described in Example VII. Figure 7B is a graphic representation of the synthesis of N - [[4 - [[[[4,7,10-Tris (carboxymethyl) -1,4,7,10-tetraazacyclododec-1-yl] acetyl] amino ] methyl] phenoxy] acetyl] -L-glutaminyl-L-tryptopyl-L-alanyl-L-valyl-glycyl-L-histidyl-L-leucyl-L-methionamide (L124), as described in example VII. Figure 7C is a chemical structure of N - [[4 - [[[[4,7,10-Tris (carboxymethyl) -1,4,7,10-tetraazacyclododec-1-yl] acetyl-amino] methyl] phenoxy ] acetyl] -L-glutaminyl-L-triptophyl-L- alanyl-L-valyl-glycyl-L-histidyl-L-leucyl-L-m-ethionamide (L124), as described in example VII. Figure 8A is a graphical representation of a sequence of reactions for the synthesis of the intermediate 4 - [[[9H-Fluoren-9-ylmethoxy) carbonyl] amino] methyl] -3-methoxybenzoic acid (E), as described in Example VIII.

Figure 8B is a graphic representation of the synthesis of N- [4 - [[[[4,7,10-Tris (carboxymethyl) -1,4,7,10-tetraazacyclic ododec- 1 -yl] acetyl] am No] methyl] -3-methoxybenzoyl] -L-glutaminyl-L-tryptopyl-L-alanyl-L-valyl-glycyl-L-histidyl-L-leucyl-L-methionamide (L125), as described in example VIII. Figure 8C is a chemical structure of N- [4 - [[[[4,7,10-Tris (carboxymethyl) -1,4,17,1-tetraazacyl-clododec-1-yl] acetyl] amino] methyl] -3-methoxybenzoyl] -L-glutaminyl-L-tryptopyl-L-alanyl-L-valyl-glycyl-L-histidyl-L-leucyl-L-methionamide (L125), as described in example VIII. Figure 9A is a graphical representation of a reaction for the synthesis of 3 - [[[(9H-Fluoren-9-ylmethoxy) carbonyl] amino] acetyl] aminobenzoic acid, (B), as described in Example IX . Figure 9B is a graphical representation of a reaction for the synthesis of 6 - [[[(9H-Fluoren-9-ylmethoxy) carbonyl] amino] acetyl] aminonaphthoic acid (C), such as it is described in example IX. Figure 9C is a graphical representation of a reaction for the synthesis of 4 - [[[[(9H-Fluoren-9-ylmethoxy) carbonyl] amino] acetyl] methylamino] benzoic acid, (D), as described in FIG. Example IX Figure 9D is a graphical representation of a reaction for the synthesis of N- [4 - [[[[[4,7,10- Tris (carboxymethyl) -1,4,7,10-tetraazacylclododec-1-yl] acetyl] amino] acetyl] amino] phenylacetyl] -L-glutaminyl-L-tryptopyl-L-alanyl-L-valyl-glycyl-L-histidyl-L-leucyl-L-methioninamide (L146), N- [3- [ [[[[[4,7,1 O-Tris (carboxymethyl) -1,4,7,10-tetraazacylclododec-1-yl] acetyl] amino] acetyl] amino] benzoyl] -L-glutaminyl-L-triptophoyl-L -alanyl-L-valyl-glycyl-L-histidyl-L-leucyl-L-methioninamide (L233), and N- [6 - [[[[4.7, 10-Tris (carboxymethyl) -1,4,7] , 10-tetraazacylclododec-1-yl] acetyl] amino] acetyl] amino] naphthoylphenylacetyl] -L-glutaminyl-L-tryptopyl-L-alanyl-L-valyl-glycyl-L-histidyl-L-leucyl-L-methioninamide ( L234), and N- [4 - [[[[[4,7, 10-Tris (carboxymethyl) -1,4,7,10-tetraazacyclododec-1-yl] acetyl] amino] Acetyl] methylamino] benzoyl] - L-glutaminyl-L-tryptopyl-L-alanyl-L-valyl-glycyl-L-histidyl-L-leucyl-L-methioninamide (L235), as described in Example IX. Figure 10A is a graphic representation of a reaction for the synthesis of 4, 10-bis (1,1-dimethylethyl) ester of 7 - [[Bis (1,1-dimethylethoxy) phosphinyl] methyl] -1,4,7,1 O-tetraazacyldecanodecane- 1, 4, 1 O-triacetic H, as described in Example X. Figure 10B is a graphical representation of a reaction for the synthesis of N- [4 - [[[[[4, 1 O-Bis ( carboxymethyl) -7- (dihydroxyphosphinyl) methyl-1,4,7,10-tetraazacyclododec-1-yl] amino] acetyl] amino] benzoyl] -L-glutaminyl-L-tryptopyl-L-alanyl-L-valyl-glycyl -L-histidyl-L-leucyl-L-methioninamide (L237), as described in Example X. Figure 11A is a graphic representation of a reaction for the synthesis of N, N-Dimethylglycyl-L-serinyl- [ S - [(acetylamino) methyl]] - L-cysteinyl-glycyl-4-aminobenzoyl-L-glutaminyl-L-tryptopyl-L-alanyl-L-valyl-glycyl-L-histidyl-L-leucyl-L-methioninamide ( L238), as described in example XI. Figure 11B is a graphical representation of a reaction for the synthesis of N, N-Dimethylglycyl-L-serinyl- [S - [(acetylamino) methyl]] - L-cysteinyl-glycyl- (3ß, 5ß, 7a, 12a) -3-amino-7-12-dihydroxy-24-oxocolan-24-yl-L-glutaminyl-L-tryptopyl-L-alanyl-L-valyl-glycyl-L-histidyl-L-leucyl-L-methioninamide (L239), as described in example XI. Figure 12A is a graphical representation of a reaction for the synthesis of 4 - [[[(9H-Fluoren-9- ilmethoxy) carbonyl] amino] acetyl] amino-3-methoxybenzoic acid (A), as described in example Xll. Figure 12B is a graphic representation of a reaction for the synthesis of 4 - [[[(9H-Fluoren-9-ylmethoxy) carbonyl] amino] acetyl] amino-3-chlorobenzoic acid, (D), as described in example Xll. Figure 12C is a graphical representation of a reaction for the synthesis of 4 - [[[(9H-Fluoren-9-ylmethoxy) carbonyl] amino] acetyl] amino-3-methylbenzoic acid (E), as described in the example Xll. Figure 12D is a chemical structure of N- [4 - [[[[4,7,10-Tris (carboxymethyl) -1,4,7,10-tetraazacyclododec-1-yl] acetyl] glycyl] amino] -3 -methoxybenzoyl] -L-glutaminyl-L-tryptopyl-L-alanyl-L-valyl-glycyl-L-histidyl-L-leucyl-L-methioninamide (L240), as described in example Xll. Figure 12E is a chemical structure of a compound N- [4 - [[[[4,7,10-Tris (carboxymethyl) -1,4,7,10-tetraazacyclododec-1-yl] -acetyl] glycyl] amino] 3 -chlorobenzoyl] L-glutaminyl-L-tryptopyl-L-alanyl-L-valyl-glycyl-L-histidyl-L-leucyl-L-methioninamide (L241), as described in example Xll. Figure 12F is a chemical structure of N- [4 - [[[[4,7,10-Tris (carboxymethyl) -1,4,7,10-tetraazacyclododec-1-yl] -acetyl] glycyl] amino] 3-methyIbenzoyl ] L-glutaminyl-L-triptophoyl-L- alanyl-L-valyl-glycyl-L-histidyl-L-leucyl-L-methioninamide (L242), as described in example Xll. Figure 13A is a graphical representation of a reaction for the synthesis of 4- [N, N'-Bis [(9-H-fluoren-9-ylmethoxy) carbonyl] aminoethyl] amino] -4-oxobutanoic acid; (D), as described in Example Xlll. Figure 13B is a graphical representation of a reaction for the synthesis of N- [4 - [[4- [Bis [2 - [[[4,7,10-tris (carboxymethyl) -1,4,7,10 -tetraazacyclododec-1 -yl] acetyl] amino] ethyl] amino-1,4-dioxobutyl] amino] benzoyl] -L-glutaminyl-L-tryptopyl-L-alanyl-L-valyl-glycyl-L-histidyl-L- leucyl-L-methioninamide (L244), as described in the example 'Xlll. Figure 13C is a chemical structure of compound L244, as described in Example Xlll. Figure 14A and Figure 14B are graphical representations of the link and competition curves that are described in Example XLIII. Figure 15A is a graphical representation of the results of radiotherapy experiments described in example LV. Figure 15B is a graphical representation of the results of radiotherapy experiments described in example LV. Figure 16 is a chemical structure of N- [4 - [[[[4,7,10- Tris (carboxymethyl) -1,4,7,10-tetraazacyclododec-1-yl] acetyl] glycyl] amino] -L-Lisinyl- (3,6,9) -trioxaundecane-1,11-dicarboxylic acid-3,7- dideoxy-3-aminocolic acid-L-arginyl-L-glutaminyl-L-tryptopyl-L-alanyl-L-valyl-glycyl-L-histidyl-L-leucyl-L-methioninamide (L65). Figure 17 is a chemical structure of N- [2-S- [[[[[12a-Hydroxy-17a- (1-methyl-3-carboxypropyl) etiocolan-3β-carbamoylmethoxyethoxyethoxyacetyl] -amino-6- [4, 7,10-tris (carboxymethyl) -1,4,7,1 O-tetraazacyl ododec-1 -yl] acetyl] amino] acetyl] amino] hexanoyl.L-glutaminyl-L-triptophyl-L-alanyl-L- valil-glycyl-L-histidyl-L-leucyl-L-methioninamide (L66). Figure 18A is a chemical structure of N- [4- [[[[4,7,10-Tris (carboxymethyl) -1,4,7,10-tetraazacyclododec-1-yl] acetyl] amino] acetyl] amino] benzoyl] -L-glutaminyl-L-tryptopyl-L-alanyl-L-valyl-glycyl-L-histidyl-L-leucyl-L-methioninamide (L70) Figure 18B is a chemical structure of N- [4- [[[[4,7,10-Tris (carboxymethyl) -1,4,7,10-tetraazacyclododec-1-yl] -3-carboxypropionyl] amino] acetyl] amino] benzoyl] -L-glutaminyl-L-tryptopyl-L-alanyl-L-valyl-glycyl-L-histidyl-L-leucyl-L-methioninamide (L114). Figure 18C is a chemical structure of N- [4- [[4,7,10-Tris (carboxymethyl) -1,4,7,10-tetraazacyclododec-1-yl] -2-hydroxy-3-propoxy] benzoyl ] -L-glutaminyl-L-triptofiI-L-alanyl- L-valyl-glycyl-L-histidyl-L-leucyl-L-methioninamide (L144). Figure 18D is a chemical structure of N - [(3ß, 5ß, 7a, 12a) -3 - [[[[[[4,7,10-Tris (carboxymethyl) -1,4,7,10-tetraazacyclododec] -1-yl] acetyl] amino] ethoxy] acetyl] amino] -7,12-dihydroxycolan-24-yl] -L-glutaminiI-L-tryptopyl-L-alanyl-L-valyl-glycyl-L-histidyl-L -leucyl-L-methioninamide (L69). Figure 18E is a chemical structure of N- [4 - [[[[[4,7,10-Tris (carboxymethyl) -1,4,7,10-tetraazacyclododec-1-yl] acetyl] amino] acetyl] amino ] phenylacetyl] -L-glutaminyl-L-tryptopyl-L-alanyl-L-valyl-glycyl-L-histidyl-L-leucyl-L-methioninamide (L146). Figure 19 describes chemical structures of intermediates that can be used to prepare compounds L64 and L70 as described in example LVI. Figure 20 is a graphical representation of the preparation of L64 using segment coupling, as described in example LVI. Figure 21 is a graphical representation of the preparation of (1 R) -1 - (Bis. {2- [bis (carboxymethyl) amino] ethyl} amino) propane-3-carboxylic acid-1-carboxyl- glycyl-4-aminobenzoyl-L-glutaminyl-L-tryptopyl-L-alanyl-L-valyl-glycyl-L-histidyl-L-leucyl-L-methioninamide (L201). Figure 22A is a graphic representation of the Chemical structure of chemical intermediates used to prepare L202. Figure 22B is a graphic representation of the preparation of N - [(3ß, 5β, 12a) -3 - [[[[[4,7,10-Tris (carboxymethyl) -1,4,7,10-tetraazacyclododec] -1-yl] acetyl] amino] acetyl] amino] -4-hydrazinobenzoyl-L-glutaminyl-L-tryptopyl-L-alanyl-L-valyl-glycyl-L-histidyl-L-leucyl-L-methioninamide (L202) . Figure 23A, is a graphic representation of the chemical structure of chemical intermediates used to prepare L203. Figure 23B is a graphical representation of the preparation of N - [(3ß, 5β, 12a) -3 - [[[(4,7,10- Tris (carboxymethyl) -1,4,7,1 O-tetraazacyclododec -1-yl] acetyl] amino] -4-aminobenzoyl-L-glutaminyl-L-tr-phenyl-L-alanyl-L-valyl-glycyl-L-histidyl-L-leucyl-L-methioninamide (L203). Figure 24 is a graphical representation of the preparation of N - [(3ß, 5ß, 12a) -3 - [[[4.7, 1 O-Tris (carboxymethyl) -1,4,7,1 O-tetraazacyclodode c -1 -yl] acetyl] amino] -4-aminobenzoyl-glycyl-L-glutaminyl-L-tryptopyl-L-alanyl-L-valyl-glycyl-L-histidyl-L-leucyl-L-methioninamide (L204). Figure 25 is a graphical representation of the preparation of N - [(3β, 5β, 12a) -3 - [[[4,7,1 O-Tris (carboxymethyl) -1,4,7,1 O-tetraazacyclodode c -1-yl] acetyl] amino] -4 ~ aminobenzoyl-glycyl-L-glutaminyl-L-tryptopyl-L-alanyl-L-valyl-glycyl-L-histidyl-L-leucyl-L-methioninamide (L205). Figure 26A is a graphic representation of the chemical structures of chemical intermediates used to prepare L206. Figure 26B is a graphical representation of the preparation of N - [(3β, 5β, 12a) -3 - [[[[[4.7, 10-Tris (carboxymethyl) -1,4,7,1-O) tetraazaci clod odec-1 -yl] a cet il] amino] a cet il] amino] - [4 '-Amino-2'-methyl biphenyl-4-carboxyl] -L-glutaminyl-L-triptofil-L-alanil - L-valyl-glycyl-L-histidyl-L-leucyl-L-methioninamide (L206). Figure 27A is a graphic representation of the chemical structure of chemical intermediates used to prepare L207. Figure 27B is a graphical representation of the preparation of N - [(3ß, 5β, 12a) -3 - [[[[[4.7, 1-Tris (carboxymethyl) -1,4,7,1 -tetraazacyclic ododec-1 -yl] acetyl] amino] acetyl amine] - [3'-amino-biphenyl-3-carboxyl] -L-glutaminyl-L-tryptopyl-L-alanyl-L-valyl-glycyl-L- histidyl-L-leucyl-L-methioninamide (L207). Figure 28 is a graphic representation of the preparation of N - [(3β, 5β, 12a) -3 - [[[[[4,7,10-Tris (carboxymethyl) -1,4,7,11- tetraazacyclododec-1 -yl] acetyl] amino] acetyl] amino] - [1,2-diaminoethyl-terephthalyl] -L-glutaminyl-L-tryptopyl-L-alanyl-L-vaylyl-glycyl-L-histidyl-L-leucyl -L-methioninamide (L208). Figure 29A is a graphic representation of the chemical structures of chemical intermediaries used to prepare L209. Figure 29B is a graphic representation of the preparation of L209. Figure 30A is a graphical representation of the chemical structures of chemical intermediates used to prepare L21 0. Figure 30B is a chemical structure of L21 0. Figure 31 is a chemical structure of N - [(3ß , 5β, 12a) -3 - [[[4,7, 10-Tris (carboxymethyl) -1,4,7,10-tetraazacyclododec-1-yl] acetyl] amino] -glycyl-glycyl-4-aminobenzoyl- L-glutaminyl-L-tryptopyl-L-alanyl-L-valyl-glycyl-L-histidyl-L-leucyl-L-methioninamide L21 1. Figure 32 is a chemical structure of N - [(3ß, 5β, 12a) -3 - [[[4,7,10-Tris (carboxymethyl) -1,4,7,10-tetraazacyclododec-1-yl] acetyl] amino] -glycyl-4-aminobenzoyl-glycyl-L-glutaminyl-L-tryptopyl-L-alanyl-L-valyl-glycyl-L-histidyl-L-leucyl-L-methioninamide L212. Figure 33 is a carboxylate chemical structure of N - [(3β, 5β, 12a) -3 - [[[4.7, 1-Tris (carboxymethyl) -1,4,7,10-tetraazacyclododec-1] -yl] acetyl] amino] -glycyl-4-aminobenzoyl-L-glutaminyl-L-tryptopyl-L-alanyl-L-valyl-glycyl-L-histidyl-L-leucyl-L-methioninamide L213. Figure 34 is a chemical structure of N - [(3ß, 5ß, 12a) -3 - [[[4.7, 1-Tris (carboxymethyl) -1,4,7,10-tetraazacyclododec-1-yl ] acetyl] amino] -glycyl-4-aminobenzoyl-D-phenylalanyl-L-glutaminyl- L-tryptopyl-L-alanyl-L-valyl-glycyl-L-histidyl-L-leucyl-L-methioninamide L214. Figure 35 is a chemical structure of N- [(3ß, 5ß, 12a) -3- [p4,7,10-Tris (carboxymethyl) -1,4,7,10-tetraazacyclododec-1-yl] acetyl] amino] -glycyl-4-aminobenzoyl-L-glutaminyl-L-arginyl-L-leucyl-glycyl-L-asparginyl-L-glutaminyl-L-tryptopyl-L-alanyl-L-valyl-glycyl-L-histidyl-L -leucyl-L-methioninamide L215. Figure 36 is a chemical structure of N - [(3ß, 5ß, 12a) -3 - [[[4,7,10-Tris (carboxymethyl) -1,4,7,10-tetraazacyclod odec-1-yl ] acetyl] amino] -glycyl-4-aminobenzoyl-L-glutaminyl-L-arginyl-L-leucyl-glycyl-L-asparginyl-L-glutaminyl-L-tryptopyl-L-alanyl-L-valyl-glycyl-L- histidyl-L-leucyl-L-methioninamide L216. Figure 37 is a chemical structure of N - [(3ß, 5ß, 12a) -3 - [[[4,7,10-Tris (carboxymethyl) -1,4,7,10-tetraazacyclod odec-1-y ] acetyl] amino] -glycyl-4-aminobenzoyl-L-glutaminyl-L-lysyl-L-tyrosinyl-glycyl-L-glutaminyl-L-tryptopyl-L-alanyl-L-valyl-glycyl-L-histidyl-L- leucyl-L-methioninamide L217. Figure 38 is a chemical structure of L218. Figure 39 is a chemical structure of N - [(3ß, 5ß, 12a) - 3 - [[[4,7,10-Tris (carboxymethyl) -1,4,7,10-tetraazacyclod odec-1-y ] acetyl] amino] -glycyl-4-aminobenzoyl-D-phenylalanyl-L-glutaminyl-L-tryptopyl-L-alanyl-L-valyl-glycyl-L-histidyl-L-leucyl-L-methioninamide L219. Figure 40 is a chemical structure of N - [(3ß, 5ß, 12a) - 3 - [[[4,7,10-Tris (carboxymethyl) -1,4,7,1 O-tetraazacyclod odec-1-yl] acetyl] amino] -glycyl-4-aminobenzoyl-L-glutaminyl-L-triptophilil -L-alanyl-L-serinyl-L-valyl-D-alanyl-L-histidyl-L-leucyl-L-methioninamide L220. Figure 41 is a chemical structure of N - [(3ß, 5ß, 12a) - 3 - [[[4, 7, 10-T ris (carboxymethyl) -1, 4, 7,1 O-tetraazaciclod odec -1-ii] acetyl] amino] -glycyl-4-aminobenzoyl-D-phenylalanyl-L-glutaminyl-L-tryptopyl-L-alanyl-L-valyl-glycyl-L-histidyl-L-leucyl-L-leucinamide L221 . Figure 42 is a structure of N - [(3ß, 5ß, 12a) -3- [[[4,7,10-Tris (carboxymethyl) -1,4,7,10-tetra azacyclododec-1-yl] acetyl] amino] -glycyl-4-aminobenzoyl-D-tyrosyl-L-glutaminyl-L-tryptopyl-L-alanyl-L-valyl-beta-alanyl-L-histidyl-L-phenylalanyl-L-norleucinamide L222. Figure 43 is a chemical structure of N - [(3ß, 5ß, 12a) - 3 - [[[4, 7, 10-Tris (carboxymethyl) -1,4,7,10-tetraazacyclododec-1-] il] acetyl] amino] -glycyl-4-aminobenzoyl-L-phenylalanyl-L-glutamyl-L-triptophyl-L-alanyl-L-valyl-beta-alanyl-L-histidyl-L-phenylalanyl-L-norleucinamide L223. Figure 44 is a chemical structure of N - [(3β, 5β, 12a) - 3 - [[[4,7,10-Tris (carboxymethyl) -1,4,17,1-tetraazacyclod odec-1 - il] acetyl] amino] -glycyl-4-aminobenzoyl-L-glutaminyl-L-tryptopyl-L-alanyl-L-glycyl-L-histidyl-L-phenylalanyl-L-leucinamide L224. Figure 45 is a chemical structure of N - [(3ß, 5ß, 12a) -3 - [[[4,7,10-Tris (carboxymethyl) -1,4,7,10-tetraazacyclododec-1- il] acetyl] amino] -glycyl-4-aminobenzoyl-L-leucyl-L-tryptopyl-L-alanyl-L-valinyl-glycyl-L-serinyl-L-phenylalanyl-L-methioninamide L225. Figure 46 is a chemical structure of N - [(3ß, 5ß, 12a) - 3 - [[[4,7,10-Tris (carboxymethyl) -1,4,7,7,10-tetraazacyclododec-1-yl] acetyl] amino] -glycyl-4-aminobenzoyl-L-histidyl-L-triptofyl-L-alanyl-L-valyl-glycyl-L-histidyl-L-leucyl-L-methioninamide L226. Figure 47 is a chemical structure of N - [(3ß, 5ß, 12a) -3 - [[[4,7,10-Tris (carboxymethyl) -1,4,7,1-tetraazacyclododec-1-y] ] acetyl] amino] -glycyl-4-aminobenzoyl-L-leucyl-L-tryptopyl-L-alanyl-L-valyl-glycyl-L-serinyl-L-phenylalanyl-L-methioninamide L227. Figure 48 is a chemical structure of N - [(3ß, 5β, 12a) -3 - [[[4,7,10-Tris (carboxymethyl) -1,4,7,1-O-tetraazacyclod odec-1 -yl] acetyl] amino] -glycyl-4-aminobenzoyl-L-glutaminyl-L-tryptopyl-L-alanyl-L-valyl-glycyl-L-histidyl-L-phenylalanyl-L-methioninamide L228. Figure 49A is a graphical representation of a reaction for the synthesis of (3ß, 5ß, 7a, 12a) -3- (9H-Fluoren-9-ylmethoxy) amino-7, 12-dihydroxycolan-24-oic acid (B ) as described in the example LVI I. Figure 49B is a graphical representation of a reaction for the synthesis of N- [3β, 5β, 7a, 12a) -3 - [[[2- [2 - [[[4.7, 10-Tris (carboxymethyl)] I) -1, 4, 7, 1 O-tetraazacyclododec-1 -yl] acetyl] amino] ethoxy] ethoxy] acetyl] amino] -7, 12-dihydroxy-24-oxocolan-24-yl] -L-glutaminyl- L-tryptopyl-L-alanyl-L-valyl-glycyl-Lh isidyl-L-leucyl-L-methioninamide, (L69), as described in example LVI I.

Figure 50 is a graphical representation of a reaction of the synthesis of N- [4- [2-Hydroxy-3- [4,7,10-tris (carboxy-methy1) -1,4,7,10-tetraazacyclodod ec-1-yl] propoxy] benzoyl] -L-glutaminyl-L-tryptopyl-L-alanyl-L-valyl-glycyl-L-histidyl-L-leucyl-L-methioninamide (L144), as described in example LVIII. Figure 51 is a chemical structure of L300. Figure 52 is a TOCSY spectrum of Lu-L70 in DMSO-d6 at a temperature of 25 ° C. Figure 53 is a COZY spectrum of Lu-L70 in DMSO-d6 at a temperature of 25 ° C. Figure 54 is a NOESY spectrum of Lu-L70 in DMSO-de at a temperature of 25 ° C. Figure 55 is a gHSQC spectrum of Lu-L70 in DMSO-d6 at a temperature of 25 ° C. Figure 56 is a gHMBC specimen of Lu-L70 in DMSO-d6a at a temperature of 25 ° C. Figure 57 is a gHSQCTOCSY spectrum of Lu-L70 in DMSO-de at a temperature of 25 ° C. Figure 58 is a regular 1H-NMR (bottom) spectrum and selective homo-decoupling of the water peak at 3.5 ppm of Lu-L70 in DMSO-d6 at a temperature of 15 ° C. Figure 59 is a TOCSY Spectrum of 175Lu-DO3A-monosamide-Aoc-QWAVGHLM-NH2 in DMSO-de at a temperature of 25 ° C.

Figure 60 is a chemical structure of L70. Figure 61 is a chemical structure of 175Lu-DO3A-monosamide-Aoc-QWAVGHLM-NH2. Figure 62 is a chemical structure of 175Lu-L70 with a water molecule bound. Figure 63 is a chemical structure of L301. Abbreviations Used in the Application Detailed Description of the Invention In the following description, various aspects of the present invention are further elaborated. For purposes of explanation, specific configurations and details are set forth in order to provide a thorough understanding of the present invention. However, it will also be appreciated by those skilled in the art, that the present invention can be practiced without specific details. In addition, well-known characteristics can be omitted or simplified in order not to obscure the present invention. In one embodiment of the present invention, new and improved compounds are provided for use in diagnostic imaging or radiotherapy. The compounds include an optical label or a chemical moiety with the ability to make complexes of a medically useful metal ion or radionuclide (metal chelator) ion adhered to a peptide that targets the GRP receptor through a linker or spacer group. In general, the compounds of the present invention can have the formula: MNOPG wherein M is the metal chelator (in a compound form with a metal radionuclide or not), or the NOP optical label, is the linker, and G is the peptide that Directs the GRP receiver. Each of the metal chelator, optical label, linker and peptide that is directed to the GRP receptor is described in the description that follows. In another embodiment of the present invention, a novel and improved linker or spacer group is provided which has the ability to bind an optical label or metal chelator to a peptide that targets the GRP receptor. In general, the linkers of the present invention may have the formula: N-O-P wherein each N, O and P are defined throughout the specification. Compounds that meet the criteria defined in the present invention were discovered to have improved pharmacokinetic properties compared to other GRP receptor targeting peptides known in the art. For example, the compounds containing the linkers of the present invention were retained longer in the bloodstream, and therefore had a longer average life than previously known compounds. The longer average life was medically beneficial because it allowed a better direction to the tumor which is useful for diagnostic imaging, and especially for therapeutic uses, wherein the cancerous cells and tumors receive greater amounts of radiolabelled peptides. In addition, the compounds of the present invention had improved tissue receptor specificity compared to the prior art compounds. 1 A. Metal Chelator The term "metal chelator" refers to a molecule that forms a complex with a metal atom, wherein the complex is stable under physiological conditions. That is, the metal will remain complexed with the skeleton of the chelator in vivo. More particularly, the metal chelator is a molecule that makes complexes with a radionuclide metal to form a metal complex that is stable under physiological conditions and that also has at least one reactive functional group for conjugation with the N-O-P linker. The metal chelator M can be any of the metal chelators known in the art to make medically useful ion-metal or radionuclide complexes. The metal chelator may or may not be made in complex with a metal radionuclide. In addition, the chelator may include an optional spacer, such as, for example, a simple amino acid (for example, Gly) that does not make a compound with the metal, but that creates a physical separation between the metal chelator and the metal chelator. linker. Metal chelators of the present invention may include, for example, linear macrocyclic chelators of terpyridine and N3S, N2S2, or N4 (also see U.S. Patent No. 5,367,080, U.S. Pat.

No. 5,364,613, US Patent No. 5,021,556, US Patent No. 5,075,099, US Patent No. 5,886,142, the disclosures of which are incorporated in their entirety by reference) and other chelators known in the art, including but not limited to HYNIC, DTPA, EDTA, DOTA, TETA, and bisamino bistiol chelators (BAT) (also see US Patent No. 5,720,934). For example, N chelators are described in U.S. Patent Nos. 6,143,274; 6,093,382; 5,608,110; 5,665,329; 5,656,254; and 5,688,487, the disclosures of which are incorporated in their entirety by reference to the present invention. Certain N3S chelators are described in Publications PCT / CA94 / 00395, PCT / CA94 / 00479, PCT / CA95 / 00249, and in U.S. Patent Nos. 5,662,885; 5,976,495; and 5,780,006, the disclosures of which are incorporated in their entirety by reference to the present invention. The chelator may also include mercapto-acetyl-glycyl-glycine-glycine (MAG3) derivatives of the chelating ligand, which contains N3S, and N2S2 systems such as MAMA (monoamidamonoaminadithiols), DADS (N2S diaminadithiols), CODADS and the like. These ligand systems and a variety of others are described in Liu and Edwards, Chem. Rev. 1999, 99, 2235-2268 and references therein, the descriptions of which are incorporated herein by reference. The metal chelator may also include complexes containing ligand atoms that are not donated to the metal in a tetra-dentate formation. These include boronic acid adducts of dioxins of technetium and rhenium, such as those described in US Pat. Nos. 5,183,653; 5,387,409; and 5,118,797, the descriptions of which are incorporated in their entirety by reference to the present invention. Examples of preferred chelators include, but are not limited to, diethylenetriaminepentaacetic acid (DTPA), 1, 4,7,10-tetra-azacyclotetradecan-1, 4,7, 10-tetraacetic acid (DOTA), acid triamethacic 1, 4,7-tricarboxymethyl-1, 4,7,1-tetraacezacyclododecane 1 -substituted, ethylenediaminetetraacetic acid (EDTA), 4-carbonylmethyl-10-phosphonomethyl-1,4,7,10- tetra-azacyclododecan-1,7-diacetic (Cm4pm10d2a); and 1, 4,8,11-tetra-azacyclododecan-1, 4,8, 11-tetraacetic acid (TETA). Additional chelating ligands are ethylenebis- (2-hydroxy-phenylglycine) (EHPG), and derivatives thereof, including 5-CI-EHPG, 5-Br- EHPG, 5-Me-EHPG, 5-t-Bu-EHPG, and 5-sec-Bu-EHPG; pentaacetic acid of benzodiethylenetriamine (benzo-DTPA) and derivatives thereof, including dibenzo-DTPA, phenyl-DTPA, diphenyl-DTPA, benzyl-DTPA, and dibenzyl-DTPA; bis-2- (hydroxybenzyl) -ethylene diamine diacetic acid (HBED), and derivatives thereof; the class of macrocyclic compounds containing at least 3 carbon atoms, more preferably at least 6 and at least 2 heteroatoms (O and / or N), whose macrocyclic compounds may consist of a ring, or two or three rings joined together in the hetero ring elements, for example, benzo-DOTA, dibenzo-DOTA, and benzo-NOTE, where NOTE is N, N ', N "-triacetic acid of 1,4,7-triazacyclononane, benzo-TETA, benzo-DOTMA , wherein DOTMA is 1, 4,7, 10-tetra-azaciclotetradecan-1,4,7,10-tetra (methyl-tetra-acetic acid), and benzo-TETMA, where TETMA is 1, 4,8, 11-tetra-aza ciclo te tradecan-1, 4.8, 11- (methyl-tetra-acetic acid); 1,3-propylenediaminetetraacetic acid (PDTA) derivatives and triethylenetetra-aminehexaacetic acid (TTHA); derivatives of 1,5,10-N, N ', N "-tris- (2,3-dihydroxybenzoyl) -tripetecholate (LICAM), and 1,3,5-N, N ', N "-tris (2,3-dihydroxybenzoyl) -aminomethylbenzene (MECAM) Examples of representative chelators and chelation groups are contemplated by the present invention and are described in Publications WO 98/18496, WO 86/06605, WO 91/03200, WO 95/28179, WO 96/23526, WO 97/36619, PCT / US98 / 01473, PCT / US98 / 20182, and in U.S. Patent No. 4,899,755, U.S. Patent No. 5,474,756, U.S. Patent No. 5,846,519, and U.S. Patent No. 6,143,274, each of which is incorporated in its entirety to the present invention as a reference. Particularly preferred metal chelators include those of formula 1, 2, and 3 (for radioactive 111 and Lanthanides, such as, for example, 177Lu, 90Y, 153Sm, and 166Ho) and those of formula 4, 5, and 6 (for 99mTc, 186Re, and radioactive 188Re) set forth below. These and other chelating groups are described in U.S. Patent Nos. 6,093,382 and 5,608,110, which are incorporated in their entirety by reference to the present invention. In addition, the chelation group of formula 3 is described, for example, in U.S. Patent No. 6,143,274; the chelation group of formula 5 is described, for example, in U.S. Patent Nos. 5,627,286 and 6,093,382, and the chelation group of formula 6 is described, for example, in U.S. Patent Nos. 5,662,885; 5,780,006; and 5,976,495, which are all incorporated herein by reference. The specific metal chelators of formula 6 include N, N-dimethylGly- Ser-Cys; N, N-dimethylGly-Thr-Cys; N, N-diethylGly-Ser-Cys; N, N-dibenzylGly-Ser-Cys; and other variations thereof. For example, spacers that do not actually make compounds with the metal radionuclide, such as an extra simple amino acid Gly, can adhere to these metal chelators (e.g. N, N-dimethylGly-Ser-Cys-Gly; N, N- dimethy! Gly-Thr-Cys-Gly; N, N-diethylGly-Ser-Cys-Gly, N, N-dibenzylGly-Ser-Cys-Gly). Other useful metal chelators, such as all those described in US Pat. No. 6,334,996, are also incorporated by reference (for example, dimethylgly-Lt-butylgly-L-Cys-Gly; dimethylgly-Dt-butylgly-L-Cys) -Gly, dimethylgly-Lt-butylgly-L-Cys, etc.). In addition, sulfur protection groups such as Acm (acetamidomethyl), trityl or other alkyl, aryl, acyl, alkanoyl, aryloyl, mercaptoacyl, and organotiol groups can adhere to the cysteine amino acid of these metal chelators. In addition, other useful metal chelators include: (1) HOOC- -COOH (5a) (5b) (6) (7) In formulas 1 and 2 above, R is alkyl, preferably methyl. In the above formulas 5a and 5b, X is either CH2 or O; And it is C? -C10 alkyl branched or not branched aryloxy, arylamino, arylaminoacyl; arylalkyl - wherein the alkyl group or groups adhered to the aryl group are branched or unbranched C1-C-10 alkyl groups, branched or unbranched C?-C10 hydroxy or polyhydroxyalkyl groups or polyalkoxyalkyl or polyhydroxy-polyalkoxyalkyl groups; J is optional, although if found it is C (= O), OC (= O) -, SO2-, NC (= O) -, NC (= S) -, N (Y), NC (= NCH3) - , NC (= NH) -, N = N-, homopolyamides or heteropolyamines derived from naturally occurring or synthetic amino acids; all when n is from 1 to 100. Other variants of these structures are described, for example, in U.S. Patent No. 6,093,382. In formula 6, the S-NHCOCH3 group can be replaced with SH or S-Z, where Z is any of the known sulfur protection groups such as those described above. Formula 7 illustrates a mode of t-butyl compounds useful as a metal chelator. The descriptions of each of the above patents, applications and references are incorporated in their entirety to the present invention as a reference. In a preferred embodiment, the metal chelator includes cyclic or acyclic polyaminocarboxylic acids, such as DOTA (1, 4,7,10-tetra-azacyclododecan-1, 4,7, 10-tetraacetic acid), DTPA (diethylenetriaminepentacid) -acetic), DTPA-bismethylamide, DTPA-bismorfolinamide, Cm4pm10d2a (1,4-carbonylmethyl-10-phosphonomethyl-1,4,7,10-tetra-azacyclododecan-1,7-diacetic acid), DO3A N - [[4,7,10-tris (carboxymethyl) -1, 4,7,10-tetra-azacyclododecan-1-yl] acetyl], HP-DO3A, DO3A-monoamide and derivatives thereof. Preferred metal radionuclides for therapy scintigraphy include 99mTc, 51Cr, 67Ga, 68Ga, 47Sc, 51Cr, 167Tm, 141Ce, 1 1n, 168Yb, 175Yb, 1 0La, 90Y, 88Y, 153Sm, 166? Ho, 165 'iDy, 116t560 iDy, 6"2Cu, 67,' Cu, Cu, 9 a7 ', Ru, 103 Ru, 186 Re, 188 i Re, Pb, 2 -1111 Bi, - 2112_ - 21133 and 214? 105 i 109 i 117m Bi, Bi, 'Bi, lusRh, i ua Pd, Sn, 149Pm, 16Tb, 177Lu, 198Au, and 199Au, and oxides or nitrides thereof. The choice of metal will be determined based on the desired therapeutic or diagnostic application. For example, for diagnostic purposes (for example to diagnose and monitor therapeutic progress in primary tumors and metastases), subsequent radionuclides include 64Cu, 67Ga, 68Ga, 99mTc, and 111ln, with 99mTc and 111ln as especially preferred. For therapeutic purposes (for example, to provide radiotherapy for primary tumors and metastases related to cancers of the prostate such as breast, lung, etc.), preferred radionuclides include 6 Cu, 90Y, 105Rh, 111ln, 117mSn, 1 9Pm, 153Sm, 161Tb, 166Dy, 166Ho, 175Yb, 177Lu, 186 188Re, and 199Au, with 177Lu and 90Y being the particularly preferred. 99 Tc is particularly useful and it is preferred for diagnostic radionuclides due to its low cost, availability, image generation properties and high specific activity. The nuclear and radioactive properties of 99mTc, towards this isotope an ideal scintigraphic imaging agent. This isotope has a single photon energy of 140 keV and a radioactive average life of approximately 6 hours, and is readily available from a 99Mo-99mTc generator. For example, the peptide labeled with 99 Tc can be used to diagnose and monitor therapeutic progress in primary tumors and metastases. Peptides labeled with 177Lu, 90Y, or other therapeutic radionuclides, can be used to provide radiotherapy for primary tumors and metastases related to cancers of the prostate, lung, breast, etc. 1 B. Optical Labels In an exemplary embodiment, the compounds of the present invention can be conjugated with photo-labels, such as optical inks, including organic chromophores and fluorophores, which have extensive delocalized ring systems and have a maximum emission absorption within the Range of 400-1,500 nm. The compounds of the present invention can be derivatized alternatively with a bioluminescent molecule. The maximum of the preferred absorption range for photo-labels is between 600 and 1,000 nm, to minimize interference with the signal from hemoglobin. Preferably, the photoabsorption labels have large molar absorption capacities, for example > 105 cm "1M" 1, while the fluorescent optical inks will have higher quantum productions. Examples of optical inks include, but are not limited to, those described in Publications WO 98/18497, WO 98/18496, WO 98/18495, WO 98/18498, WO 98/53857, WO 96/17628, WO 97/18841, WO 96/23524, WO 98/47538, and the references mentioned therein. For example, photolabels can be covalently linked directly to compounds of the present invention, such as, for example, compounds containing GRP receptor targeting peptides and linkers of the present invention. Several inks that absorb and emit light in the visible and near infrared region of the electromagnetic spectrum are normally used for various biomedical applications due to their biocompatibility, high molar absorption capacity and / or high fluorescence quantum yields. The high sensitivity of the optical modality in conjunction with inks as contrast agents, is comparable to that of nuclear medicine and allows the visualization of organs and tissues without the undesirable effect of radiation by ionization. Cyanide inks with absorption and intense emission in the Near-infrared region (NIR) are particularly useful because the biological tissues are optically transparent in this region. For example, the green color of indocyanine, which absorbs and emits in the NIR region, has been used to monitor cardiac outcomes, liver functions, and blood flow of the liver and its functionalized derivatives have been used to conjugate biomolecules for diagnostic purposes (RB). Mujumdar, LA Ernst, SR Mujumdar and Associates, Cyanine dye labeling reagents: Sulfoindocyanine succinimidyl esters Bioconjugate Chemistry, 1993, 4 (2), 105-111; Linda G. Lee and Sam L. Woo. "N-heteroaromatic ion and iminium ion substituted cyanine dyes for use as fluorescent labels", U.S. Patent No. 5,453,505; Eric Hohenschuh and Associates, "Light imaging contrast agents", Publication WO 98/48846; Jonathan Turner and Associates, "Optical diagnostic agents for the diagnostic of neurodegenerative diseases by means of near infra-red radiation", Publication WO 98/22146; Kai Licha and Associates, "In vivo diagnostic process by near infrared radiation", Publication WO 96/17628; Robert A. Snow and Associates, Compounds, Publication 98/48838. Various imaging techniques and reagents have been described in US Pat. Nos. 6,663,847; 6,656,451; 6,641,798; 6,485,704; 6,423,547; 6,395,257; 6,280,703; 6,277,841; 6,264,920; 6,264,919; 6,228,344; 6,217,848; 6,190,641; 6,183,726; 6,180,087; 6,180,086; 6,180,085; 6,013,243, and in the published U.S. Patent Applications Nos. 2003185756, 20031656432, 2003158127, 2003152577, 2003143159, 2003105300, 2003105299, 2003072763, 2003036538, 2003031627, 2003017164, 2002169107, 2002164287, and 2002156117. All the above references are incorporated in their entirety to the present invention as reference. 2A. Linkers containing at least one non-alpha amino acid In one embodiment of the present invention, the linker N-O-P contains at least one non-alpha amino acid. Therefore, in this embodiment the linker N-O-P, N is 0 (where 0 means that it is absent), an alpha or non-alpha amino acid or another linking group; O is an alpha or non-alpha amino acid; and P is 0, an alpha or non-alpha amino acid or another linking group, wherein at least one of N, O, or P is a non-alpha amino acid. Therefore, in one example, N = Gly, O = a non-alpha amino acid, and P = 0. Alpha amino acids are well known in the art and include naturally occurring amino acids and synthetic Non-alpha amino acids are also known in the art and include those that occur naturally or synthetics. Preferred non-alpha amino acids include: 8-amino-3,6-dioxaoctanoic acid; N-4-aminoethyl-N-1-acetic acid; and polyethylene glycol derivatives having the formula NH2- (CH2CH2O) n -CH2CO2H or -NH2- (CH2CH2O) n -CH2CH2CO2H, wherein n = 2 to 100. Examples of compounds having the formula M-NOPG containing linkers with at least one non-alpha amino acid is described in Table 1. These compounds can be prepared using the methods described herein, particularly in the examples, as well as through similar methods known to those skilled in the art. TABLE 1 * BBN (7-14) is [SEQ ID NO: 1]. 1 HPLC method refers to 10 minutes time for the HPLC gradient. 2HPLC RT refers to the retention time of the compound in HPLC. 3MS refers to the mass spectrum when the molecular weight is calculated from the mass / unit charge (m / e). 4IC50 refers to the concentration of the compound to inhibit 50% iodine bombesin binding to a GRP receptor in cells. 2B. Linkers containing at least one substituted bile acid In another embodiment of the present invention, the linker N-O-P contains at least one substituted biary acid. Therefore, in this embodiment of the linker N-O-P, N is 0 (where 0 means that it is absent), an alpha amino acid, a substituted biary acid or another linking group; O is an alpha amino acid or a substituted bile acid; P is O, an alpha amino acid, a substituted biary acid or another linking group, wherein at least one of N, O, or P is a substituted acid. Bile acids are found in the bile (a secretion of the liver) and are steroids that have a hydroxyl group and a side chain of 5 carbon atoms ending in a carboxyl group. In substituted bile acids, at least one atom such as a hydrogen atom of bile acid, is substituted with another atom, molecule or chemical group. For example, substituted biary acids include those having the 3-amino, 24-carboxyl function optionally substituted at positions 7 and 12 with hydrogen, hydroxyl or keto functionality. Other substituted bile acids useful herein Invention, include substituted colic acids and derivatives thereof. Specific substituted cholic acid derivatives include: (3β, 5β) -3-aminocolan-24-oic acid; (3ß, 5β, 12a) -3-amino-12-hydroxycolan-24-oic acid; (3β, 5β, 7a, 12a) -3-amino-7,12-dihydroxycolan-24-oic acid; Lys- (3,6,9) -trioxaundecan-1,11-dicarbonyl-3,7-dideoxy-3-aminocolic acid; (3ß, 5ß, 7a) -3-amino-7-hydroxy-12-oxocolan-24- acid oico and (3β, 5β, 7a) -3-amino-7-hydroxycolan-24-oic acid. Examples of compounds having the formula MNOPG containing linkers with at least one substituted biary acid are described in Table 2. These compounds can be prepared using the methods described herein, particularly in the examples, as well as through known similar methods by those skilled in the art. TABLE 2 * BBN (7-14) is [SEQ ID NO: 1] 1 HPLC method refers to 10 minutes time for the HPLC gradient. 2HPLC RT refers to the retention time of the compound in HPLC. 3MS refers to the mass spectrum when the molecular weight is calculated from the mass / unit charge (m / e). IC 50 refers to the concentration of the compound to inhibit 50% iodine bombesin binding to a GRP receptor in cells. 2 C. Linkers containing at least one non-alpha amino acid with a cyclic group In yet another embodiment of the present invention, the linker N-O-P contains at least one non-alpha amino acid with a cyclic group. Therefore, in this embodiment the linker N-O-P, N is 0 (where 0 means that it is absent) an alpha amino acid, a non-alpha amino acid with a cyclic group or another linking group; O is an alpha amino acid or a non-alpha amino acid with a cyclic group; and P is 0, an alpha amino acid, a non-alpha amino acid with a cyclic group or other linking group, wherein at least one of N, O, or P is a non-alpha amino acid with a cyclic group.

Non-alpha amino acids with a cyclic group include phenyl, biphenyl, substituted cyclohexyl or other amines and carboxyl containing cyclic or heterocyclic aliphatic portions. Examples include: 4-aminobenzoic acid (hereinafter referred to as "Abz4 in the specification"), 3-aminobenzoic acid, 4-aminomethyl-benzoic acid, 8-aminooctanoic acid, trans-4-aminomethylcyclohexane-carboxylic acid, 4- (2-aminoethoxy) -benzoic acid, isonipecotic acid, -aminomethylbenzoic acid, 4-amino-3-nitrobenzoic acid, 6- (piperazin-1 -yl) -4- (3H) -quinazolinone-3-acetic acid 4- (3-carboxymethyl-2-keto-1-benzimidazole-1-piperidine, (2S, 5S) -5-amino-1, 2,4,5,6,7-hexahydro-azepine [3,21-] hi] indole-4-on-2-carboxylic acid, (4S, 7R) -4-amino-6-aza-5-oxo-9-thiabicyclo- [4.3.0] -nonan-7-carboxylic acid, N1 acid piperazine-acetic acid 3-carboxymethyl-1-phenyl-1,3,8-triazaspiro- [4,5] -decan-4-one, N-4-aminoethyl-N-1-piperazine-acetic acid, (3S) - 3-amino-1-carboxymethylcaprolactam, 3-amino-3-deoxycholic acid (2S, 6S, 9) -6-amino-2- carboxymethyl-3,8-diazabicyclo- [4,3,0] -nonan-1,4-dione, 4-hydroxybenzoic acid, 4-aminophenylacetic acid, 3-hydroxy-4-aminobenzoic acid, 3-methyl-4-acid aminobenzoic acid, 3-chloro-4-aminobenzoic acid, 3-methoxy-4-aminobenzoic acid, 6-aminonaphthoic acid, N, N'-bis (2-aminoethyl) -succinnamic acid. Examples of compounds having the formula M-NOPG, which contain linkers with at least one alpha amino acid with a cyclic group are described in Table 3. These compounds can be prepared using the methods described herein, particularly in the examples, as well as through similar methods known to those skilled in the art.

TABLE 3 * BBN (7-14) is [SEQ ID NO: 1] ** NT is defined as "not tested. *** BOA is defined as acid (1 R) -1 - (bis { 2- [bis ( carboxymethyl) amino] ethyl.}. amino) propane-1,3-dicarboxylic acid. 1 HPLC method refers to 10 minutes time for the HPLC gradient. 2HPLC RT refers to the retention time of the compound in HPLC. 3MS refers to the mass spectrum when the molecular weight is calculated from the mass / unit charge (me). 4IC50 refers to the concentration of the compound to inhibit 50% iodine bombesin binding to a GRP receptor in cells. A subset of compounds containing preferred linkers and various targeting peptides of the GRP receptor are set forth in Table 4. These compounds can be prepared using the methods described herein, particularly in the examples, as well as through similar methods known to those skilled in the art. in the technique.

TABLE 4 2D Other linkage groups Other linkage groups which can be used within the NOP linker, include a ical group which serves to attach the targeting peptide to the GRP receptor to the metal ator or optical label, and at the same time does not adversely affect either the direction function of the peptide directing the GRP receptor or the metal ator metal making function or the detection ability of the optical label. Other suitable linking groups include peptides (e.g., amino acids linked together) alone, a group without a peptide (e.g., hydrocarbon chain) or a combination of an amino acid sequence and a spacer without peptide. In one embodiment, other linking groups for use within the N-O-P linker include L-glutamine and hydrocarbon chains or a combination thereof. In another embodiment, other linking groups to be used within the NOP linker, include a pure peptide linking group consisting of a series of amino acids (eg, diglycine, triglycine, gly-gly-glu, gly-ser-gly, etc.), wherein the total number of atoms between the N-terminal residue of the GRP receptor targeting peptide and the metal ator or the optical label in the polymer chain is < _ 12 atoms. In a still further embodiment, other linking groups to be used within the NOP linker may also include a hydrocarbon chain [eg, Ri- (CH2) n-R2], wherein n is from 0 to 10, preferably n = 3 to 9, Ri is a group (e.g., H2N-, HS-, -COOH) that can be used as a site to covalently link the previously formed metal ator backbone or ator backbone or the backbone metal compounds or optical label; and R2 is a group that is used for covalent coupling to the N-terminal NH2 group of the GRP receptor targeting peptide (for example, R2 is an activated COOH group). Several ical methods have been described in the literature to conjugate ligands (eg ators) or metal ates that are preferred to biomolecules [Wilburn, 1992; Parker, 1990; Hermanson, 1996; Frizberg and Associates, 1995]. One or more of these methods can be used to bind any non-compound ligand (ator) or radiometal ate or optical label to the linker or to link the linker to the GRP receptor targeting peptides. These methods include the formation of anhydrides, aldehydes, acid arylisothiocyanates, activated esters or N-hydroxysuccinimides [Wilburn, 1992; Parker, 1990; Hermanson, 1996; Frizberg and Associates, 1995]. In a preferred embodiment, other linking groups can be formed for use within the NOP linker from the linker precursors having electrophiles or nucleophiles as set forth below: LP1: a linker precursor having at least two locations of the linker the same electrophile E1 or the same nucleophile Nu1; LP2: a linking precursor having an E1 electrophile and a different E2 electrophile elsewhere in the linker; LP3: a linking precursor having a nucleophile Nu1 and elsewhere in the linker a different nucleophile Nu2; or LP4: a binding precursor having one end functionalized with an E1 electrophile and another with a Nu1 nucleophile. Preferred nucleophiles Nu1 / Nu2 include -OH, -NH, -NR, -SH, -HN-NH2, -RN-NH2, and -RN-NHR ', wherein R' and R are independently selected from the definitions of R previously determined, but for R 'it is not H. Preferred electrophiles E1 / E2 include -COOH, -CH = O (aldehyde), -CR = OR' (ketone), -RN-C = S, -RN-C = O, - SS-2-pyridyl, -SO2-Y, -CH2C (= O) Y; Y where Y can be selected from the following groups: \ - + N-N = N Cl, Br. F 3. GRP receptor targeting peptide The GRP receptor targeting peptide (e.g., G in the formula M-N-O-P-G) is any peptide, equivalent, derivative or analogue thereof which has binding affinity to the GRP receptor family. The GRP receptor targeting peptide may take the form of an agonist or an antagonist. It is known that a GRP receptor targeting peptide agonist "activates" the cell after binding with high affinity, and can be internalized by the cell. In an adverse manner, GRP receptor targeting peptide antagonists are known to bind only the GRP receptor in the cells without being internalized by the cell and without "activating" the cell. In a preferred embodiment, the GRP receptor targeting peptide is an agonist. In a more preferred embodiment of the present invention, the GRP agonist is a bombesin analogue (BBN) and / or a derivative thereof. The BBN derivative or analogue thereof preferably contains either the same primary structure of the binding region BBN (for example BBN (7-14) [SEQ ID NO: 1]) or similar primary structures, with specific amino acid substitutions that will link specifically, GRP receptors with better or similar binding affinities than BBN alone (for example, Kd <25nM). Suitable compounds include peptides, peptidomimetics and analogs and derivatives thereof. The presence of L-methionine (Met) in the BBN-14 position generally confers agonist properties whereas the absence of this residue in BBN-14, generally confers antagonistic properties [Hoffken, 1994]. Some useful bombesin analogs are described in U.S. Patent Publication No. 2003/0224998, incorporated herein by reference in its entirety. It is well documented in the art that there is a small and selective number of substitutions of specific amino acids in the binding region BBN (8-14) (for example, D-Ala11 for L-Gly11 or D-Trp8 for L-Trp8), which can be elaborated without diminishing the link affinity [Leban and Associates, 1994; Qin and Associates, 1994; Jensen and Associates, 1993]. In addition, the adhesion of some chains of amino acid or other groups to the N-terminal amine group at the BBN-8 position (eg, the Trp8 residue) can dramatically decrease the binding affinity of BBN analogs to the GRP receptors [Davis and Associates, 1992; Hoffken, 1994; Moody and Associates, 1996; Coy and Associates, 1988; Cai and Associates, 1994]. In some cases, it is possible to attach additional amino acids or chemical portions without decreasing the binding affinity. Analogs of the BBN receptor targeting peptides include molecules that direct GRP receptors with an avidity greater than or equal to that of BBN, as well as GRP or BBN muteins, retropeptides and retro-inverso-peptides. Those skilled in the art will appreciate that these analogs may also contain modifications that include substitutions and / or deletions and / or additions of one or more amino acids, provided that these modifications do not adversely alter the biological activity of the peptides described herein. These substitutions can be carried out by replacing one or more amino acids with their synonymous amino acids. Synonymous amino acids within a group are defined as amino acids that have sufficient physicochemical properties that allow substitution between members of a group in order to preserve the biological function of the molecule. The eliminations or insertions of amino acids they can also be introduced into the defined sequences as long as they do not alter the biological functions of the sequences. Preferably said insertions or deletions should be limited to 1, 2, 3, 4, or 5 amino acids and should not remove or disturb in physical form or displace amino acids that are important for functional conformation. The muteins of the GRP receptor targeting peptides described herein may have a sequence homologous to the sequence described in the present specification, wherein the substitutions, deletions or insertions of amino acids are found at one or more amino acid positions. The muteins may have biological activity that is at least 40%, preferably at least 50%, or more preferably 60-70%, most preferably 80-90% of the peptides described herein. However, they may also have a biological activity greater than that of the specifically exemplified peptides, and therefore do not necessarily have to be identical to the biological function of the exemplified peptides. Analogs of the GRP receptor targeting peptides also include peptidomimetics or pseudo-peptides that incorporate changes to the amide bonds of the peptide backbone, including thioamides, methylene amides, and E-olefins. Also the skeleton-based peptides include thioamides, methyleneamines and E- olefins. Also the peptides based on the structure of GEP, BBN or their peptide analogs with amino acids replaced by N-substituted hydrazine carbonyl compounds (also known as aza amino acids), are included in the term analogs used herein. The GRP receptor targeting peptide can be prepared by various methods depending on the selected chelator. The peptide can generally be prepared in the most convenient manner by techniques generally established and known in the art of peptide synthesis, such as the solid phase peptide synthesis method (SPPS). Solid phase peptide synthesis (SPPS) comprises the stepwise addition of amino acid residues to a growth peptide chain that is linked to an insoluble matrix support, such as polystyrene. The C-terminal residue of the peptide is first attached to a commercially available support with its amino group protected with a protecting agent N, such as a t-butyloxycarbonyl group (Boc) or a fluorenylmethoxycarbonyl group (Fmoc). The amino protecting group is removed with suitable deprotection agents, such as TFA in the case of Boc or piperidine for Fmoc and the next amino acid residue (in N-protected form), is added with a coupling agent such as N , N'-dicyclohexylcarbodi- Measure (DCC), or N, N'-diisopropylcarbodiimide (DIC), or 2- (1 H-benzotriazol-1-yl) -1, 1, 3,3-tetramethyluronium hexafluorophosphate (HBTU). At the time of formation of the peptide linkage, the reagents are washed from the support. After the addition of the final residue, the residue is dissociated from the support with a suitable reagent such as trifluoroacetic acid (TFA) or hydrogen fluoride (HF). The linker can subsequently be coupled to form a conjugate by reacting the free amino group of the Trp8 residue of the GRP receptor targeting peptide with a suitable functional group of the linker. The entire construction of the chelator, linker and address portion described above can be assembled into the resin and subsequently dissociated by the agency of suitable reagents such as trifluoroacetic acid or HF.

Bombesin (7-14) undergoes proteolytic cleavage in vivo and in vivo, which decreases the average life of the peptide. It is well known in the literature that the amide bond of the polypeptide backbone can be substituted and retain the activity, and at the same time resist the proteolytic cleavage. For example, to reduce or eliminate undesired proteolysis, or other degradation pathways that decrease the stability of the serum, which results in reduced or eliminated bioactivity, or to restrict or increase conformational flexibility, is It is common to replace amide bonds within the skeleton of the peptides with a functionality that mimics the existing conformation or alters the conformation in the desired form. Such modifications can produce increased binding affinity or improved pharmacokinetic behavior. It will be understood that those skilled in the art of peptide synthesis can subsequently make changes of the amide bond for any amide bond that connects two amino acids (eg, amide bonds in the address portion, linker, chelator, etc.). ) waiting for the resulting peptides to have the same or improved activity: insertion of skeletal alpha-N-methylamides or thioamides, removal of carbonyl to produce the secondary amines of cognate, replacement of an amino acid with an aza-amino acid to produce semicarbazone derivatives, and the use of E-olefins and substituted E-olefins in the form of an amide bond substitute. Hydrolysis can also be prevented by incorporating a D-amino acid from one of the amino acids of the labile amide linkage, or by alpha-methyl amino acid derivatives. The amide bonds of the skeleton have also been replaced by heterocycles, such as oxazoles, pyrrolidinones, imidazoles, as well as ketomethylenes and fluoro-olefins. Some specific compounds include Amide link modifications are described in Table 4a. The abbreviations used in Table 4a for various amide link modifications are exemplified below: 4. Labeling and administration of radiopharmaceuticals The incorporation of the metal within the pharmaceutical conjugates can be achieved through various methods commonly known in the art of coordination chemistry. When the metal is 99mTc, a preferred radionuclide for diagnostic imaging, the following general procedure can be used to form a technetium complex. A solution of peptide-chelator conjugate is formed by initially dissolving the conjugate in water, dilute acid, or in an aqueous solution of an alcohol, such as ethanol. Subsequently, the gases are extracted from the solution optionally, to eliminate the dissolved oxygen. When a -SH group is found in the peptide, a thiol protection group, such as Acm (acetamidomethyl), trityl or other thiol protection group can optionally be used to protect the thiol from oxidation. The thiol protecting group (s) is removed with a suitable reagent, for example with sodium hydroxide, and subsequently neutralized with an organic acid such as acetic acid (pH 6.0-6.5). Alternatively, the thiol protection group can be removed in situ during technetium chelation. In the labeling step, the sodium pertechnetate obtained from a molybdenum generator is added to a solution of the conjugate with a sufficient amount of a reducing agent, such as stannous chloride, to reduce the technetium and to be allowed to settle at room temperature or warm up The labeled conjugate can be separated from the 99mTcO "and colloidal 99mTcO2 contaminants in chromatographic form, for example with a Sep Pak C-10 cartridge [Millipore Corporation, Waters Chromatography Division, 34 Maple Street, Milford, Massachusetts 01757] or by HPLC using known methods by the person skilled in the art In an alternative method, labeling can be achieved through a transpolation reaction In this method, the technetium source is a technetium solution that is reduced and made with labile ligands before the reaction with the selected chelator, thereby facilitating the exchange of ligand with the selected chelator. Examples of suitable ligands for transquelation include tartrate, citrate, gluconate, and heptagluconate. It will be appreciated that the conjugate can be labeled using the techniques described above, or alternatively, the chelator itself can be labeled and subsequently coupled to the peptide to form the conjugate.; a process referred to as the "pre-labeled chelate" method. Re and Te are both in row VI I B of the Periodic Table and are chemical congeners. Therefore, for the most part, the chemistry of complex elaboration of these two metals with ligand structures that exhibit high stabilities in vitro and in vivo, are the same [Eckelman, 1995] and chelators and similar procedures can be used to label with Re. Many complexes 99mTc or 186 188Re, which are used to form stable radiometal complexes with peptides and proteins, chelate these metals in their oxidation state +5 [Lister-James and Associates, 1997] This oxidation state makes possible to selectively place 99 Tc or 186 / 188Re in the ligand structures either conjugated to the biomolecule, constructed from a variety of weak chelates 99mTc (V) and / or 186 188Re (V) (eg 99mTc-glucoheptonate, citrate, gluconate, etc.) [Eckelman, 1995; Lister-James and Associates, 1997; Pollak and Associates, 1996]. These references are incorporated in their entirety to the present invention as a reference. 5. Diagnostic and therapeutic uses When labeled with diagnostic and / or therapeutically useful optical labels or metals, the compounds of the present invention can be used to treat and / or detect any pathology comprising an overexpression of GRP receptor (or NMB receptors). ) through established procedures in the radiodiagnostic, radiotherapeutic and optical imaging techniques. [See, for example, Bushbaum, 1995 Fischman and Associates, 1993; Schubiger and Associates, 1996 Lowbertz and Associates, 1994; Krenning and Associates, 1994 examples of optical inks include, but are not limited to, those described in Publications WO 98/18497, WO 98/18496, WO 98/18495, WO 98/18498, WO 98/53857, WO 96/17628, WO 97/18841, WO 96/23524, WO 98/47538, and the references mentioned therein, incorporated in their entirety to the present invention as reference. The expression GRP-R is highly activated in a variety of human tumors. See, for example, Publication WO 99/62563. Therefore, the compounds of the present invention can be widely useful for treating and diagnosing cancers, including cancer of prostate (primary and metastatic), breast cancer (primary and metastatic), colon cancer, gastric cancer, pancreatic cancer, non-small cell lung cancer, small cell lung cancer, gastrinomas, melanomas, glioblastomas, neuroblastomas, tumors of leiomyosarcoma of the uterus, prosthetic intraepithelial neoplasms [PIN], and ovarian cancer. In addition, the compounds of the present invention may be useful for distinguishing between conditions in which GRP receptors are regulated and in which they are not (eg, chronic pancreatitis and ductal pancreatic carcinoma, respectively). The compounds of the present invention, which will be explained in more detail in the examples, show greater specificity and greater uptake in tumors in vivo than the compounds without the novel linkers described herein, which exhibit an improved ability to direct expressing tumors. the GRP receptor and therefore generate the image or provide radiotherapy to these tissues. In fact, as shown in the examples, radiotherapy is more effective (and the survival time is implied) using the compounds of the present invention. The diagnostic application of these compounds can be like a diagnostic screen first line with respect to the presence of neoplastic cells using gammagraphic, optical, sonoluminescence or photoacoustic imaging, as an agent for directing neoplastic tissue using manual radiation detection instrumentation in the field of radioimmuno surgery (RIGS) as a means to obtain dosimetry data to administer the matching pair of the radiotherapeutic compound; and as a means to evaluate the GRP receptor population as a function of the treatment over time. The therapeutic application of these compounds can be defined as an agent that will be used as a first line therapy in the treatment of cancer, as a combination therapy when these agents can be used together with adjuvant chemotherapy, and / or as a therapeutic agent of Matching pair The concept of matching pair refers to a single non-metallized compound that can serve both as a diagnostic and therapeutic agent, depending on the radiometal that has been selected to bind to the appropriate chelate. If the chelator can not accommodate the desired metals, suitable substitutions can be made to accommodate the different metal and maintain the pharmacology at the same time so that the behavior of the in vivo diagnostic compound can be used to predict the behavior of the radiotherapeutic compound. When used in conjunction with adjuvant chemotherapy, any suitable chemotherapeutic can be used, including for example, antineoplastic agents, such as platinum compounds (eg, spiroplatin, cisplatin, and carboplatin), methotrexate, adriamycin, mitomycin, ansamitocin, bleomycin, cytosine. , arabinoside, arabinosyl adenine, mercaptopolilisine, vincristine, busulfan, chlorambucil, melphalan (for example, PAM, a, L-PAM or phenylalanine mustard), mercaptopurine, mitotane, procarbazine hydrochloride, dactinomycin (actinomycin D), daunorubicin hydrochloride , doxorubicin hydrochloride, taxol, mitomycin, plicamycin (mithramycin), aminoglutethimide, sodium estramustine phosphate, flutamide, leuprolide acetate, magestrol acetate, tamoxifen citrate, testolactone, trilostane, amsacrine (m-AMSA), asparaginase (L -asparaginase) Erwina aparaginase, etoposide- (VP-16), interferon a-2a, interferon a-2b, teniposide (VM-26), vinblastine sulfate (VLB), and arabinosyl. In certain embodiments, the therapeutic may be a monoclonal antibody, such as a monoclonal antibody with the ability to bind to a melanoma antigen. A conjugate labeled with a radionuclide metal, such as 99mTc, can be administered to a mammal, including patients or human subjects, for example, by intravenous, subcutaneous, or intraperitoneal injection in a vehicle and / or pharmaceutically acceptable solution, such as isotonic saline solutions. The radiolabeled scintigraphic image generation agents provided by the present invention are provided having an adequate amount of radioactivity. In the formation of radioactive 99mTc complexes, it is generally preferred to form radioactive complexes in solutions containing radioactivity in concentrations from 0.01 milli-meter (mCi) to 100 mCi per ml. Generally, the dose of unit to be administered has a radioactivity of about 0.01 mCi to about 100 mCi, preferably 1 mCi to 30 mCi. The solution that will be injected in unit dose is from approximately 0.01 ml to approximately 10 ml. The amount of labeled conjugate suitable for administration depends on the possible distribution of the conjugate chosen in the sense that a conjugate that is cleared in a rapid manner to be administered in higher doses or one that clears less rapidly may be needed. The distribution and localization in vivo can be tracked by standard scintigraphic techniques in a suitable time subsequent to the administration; normally between 30 minutes and 180 minutes depending on the range of accumulation at the target site with respect to the range of clearance in non-target tissue. For example, after an injection of the diagnostic radionuclide labeled compounds of the present invention into the patient, a gamma camera calibrated for the gamma-ray energy of the nuclide incorporated in the imaging agent can be used to generate images of the agent's catchment areas and quantify the amount of radioactivity found at the site. The generation of images of the site in vivo, can take place in a few minutes. However, if the generation of images is desired, it can take place in hours or even longer, after the radiolabelled peptide is injected into a patient. In most cases, a sufficient amount of the dose administered will accumulate in the area from which the image will be generated in approximately 0.1 hours to allow taking the belts. The compounds of the present invention can be administered to a patient, alone or as part of a composition containing other components such as excipients, diluents, radical engers, stabilizers and vehicles, all of which are known in the art. The compounds can be administered to patients either intravenously or intraperitoneally.

There are numerous advantages associated with the present invention. The compounds made according to the present invention form compounds labeled with 99mTc Q i86 i88Re b defined. Similar compounds of the present invention can also be made using chelator structures suitable for the respective radiometals, to form well-defined products labeled with 10-ySm, 9 a0u? Y, 166 'H io, 105 Rh, 199 Au, 9Pm, 177Lu , 111ln or other radiometals. The radiolabelled GRP receptor targeting peptides selectively bind neoplastic cells expressing GRP receptors, and if an agonist is used, they are interned and retained in the tumor cells for prolonged periods of time. The radioactive material that does not reach (ie does not bind) to the cancer cells is preferably efficiently secreted in the urine with minimal retention of the radiometal in the kidneys. 6. Generation of optical images, sonoluminescence. Photoacoustic Imaging and Phototherapy According to the present invention, a number of optical parameters can be used to determine the location of a target with in vivo light imaging after injection to the subject with an optically labeled compound of the present invention. invention. The optical parameters that will be detected in the preparation of an image, may include transmitted radiation, absorption, fluorescent or phosphorescent emission, light reflection, changes in amplitude or maximum absorption and elastic scanning radiation. For example, biological tissue is relatively translucent to light in the near-infrared (NIR) wavelength range of 650-1000 nm. NIR radiation can penetrate tissue up to several centimeters, allowing the use of the compounds of the present invention to generate tissue images containing target in vivo. The use of visible and near infrared (NIR) light in clinical practice is growing rapidly. Compounds that absorb or emit in the region of visible, NIR, or long wavelength (UV-A,> 350 nm) of the electromagnetic spectrum, are potentially useful for the generation of optical tomographic images, endoscopic visualization and phototherapy. An important advantage of biomedical optics lies in their therapeutic potential. Phototherapy has proven to be a safe and effective procedure for the treatment of several surface lesions, both external and internal. Inks are important to improve signal detection and / or photosensitize tissues in optical image generation and phototherapy. Previous studies have shown that certain inks can be localized in tumors and serve as a powerful probe for the detection and treatment of small cancers 8D. A. Bellnier et al., Murine pharmacokinetics and antitumor efficacy of the photodynamic sensitizer 2- [1-hexyloxyethyl] -2-devinyl pyropheophorbide-a, J. Photochem. Photobiol., 1993, 20, pages 55-61; G. A. Wagnieres and Associates, In vivo fluorescence spectroscopy and imaging for oncological applications, Photochem. Photobiol., 1998, 68, pages 603-632; J. S. Reynolds and Associates, Imaging of spontaneous canine mammarytumors using fluorescent contrast agents, Photochem. Photobiol., 1999, 70 p. 87-94). All of these described references are incorporated in their entirety to the present invention. However, these inks are not preferably located in malignant tissues.

In an exemplary embodiment, the compounds of the present invention can be conjugated with photo-labels, such as optical inks, including chromophores or organic fluorophores and having extensive non-localized ring systems and having a maximum of absorption and emission within the range of 400-1500 nm. The compounds of the present invention can be derivatized alternatively with a bioluminescent molecule. The preferred range of maximum absorption for photolabels is between 600 and 1,000 nm to minimize interference with the signal from hemoglobin. Preferably, the photoabsorption labels have high molar absorption capacities, for example, > 105 cm "1M" 1, while the fluorescent optical inks will have high quantum productions. Examples of optical inks include, but are not limited to, those included in U.S. Patent No. 6,641,798, and in Publications Nos. WO 98/18497, WO 98/18496, WO 98/18495, WO 98/18498, WO 98/53857, WO 96/17628, WO 97/18841, WO 96/23524, WO 98/47538, and the references mentioned therein, which are all incorporated herein by reference in their entirety. For example, the photolabels may be covalently linked directly to the compounds of the present invention, such as, for example, compounds comprising GRP receptor targeting peptides and linkers of the present invention. Several inks that absorb and emit light in the visible and near infrared region of the electromagnetic spectrum, are being used normally for various biomedical applications due to their compatibility, high molar capacity, and / or high quantum fluorescence productions. The high optical sensitivity together with the inks, such as contrast agents parallel to those of nuclear medicine, allow the visualization of organs and tissues without the undesirable effect of ionization radiation. The cyanine inks with absorption and intense emission in the almost Infrared (NIR) are particularly useful because biological tissues are optically transparent in this region (B.C. Wilson, Optical Properties of Tissues, Encyclopedia of Human Biology, 1991, 5, 587-597). For example, indocyanine green, which absorbs and emits in the NIR region, was used to monitor cardiac outcomes, liver function and liver blood flow (YL He, H. Tanigami, H. Ueyana, T. Mashimo, and I. Yoshiya, Measurement of blood volume using indocyanine green measured with pulse-spectrometry: Its reproducibility and reliability, Critical Care Medicine, 1998, 26 (8), 1446-1451, J. Caesar, S. Shaldon, L. Chiandussi, and associates. , The use of Indocyanine green in the measurement of hepatic blood flow and the test of hepatic function, Clin. Sci. 1961, 21, 43-57) and its functionalized derivatives have been used to conjugate biomolecules for diagnostic purposes (RB Mujumbar , LA Ernst, SR Mujumbar, and associates, Cyanine dye labeling reagents: Sulfoindocyanine succinimidyl esters Bioconjugate Chemistry, 1993, 4 (2), 105-111; Linda G. Lee and Sam L. Woo. "N-Heteroaromatic ion and iminium on replaced cyanine dyes for use as fluorescent label s ", U.S. Patent No. 5,453,505; Eric Hohenschuh, and associates "Light imaging contrast agents", Publication WO 98/48846; Jonathan Turner and associates. "Optical diagnostic agents for the diagnosis of neurodegenerative designs by means of near-infrared radiation ", Publication WO 98/22146, Kai Licha and associates," In-vivo diagnostic process by near infrared radiation ", Publication WO 96/17628, Robert A. Snow and associates, Compounds, Publication WO 98/48838, Patent North American No. 6,641,798. Where all of these described references are incorporated in their entirety to the present invention as a reference. After injection of the labeled compound in optical form, the patient is scanned with one or more light sources (for example a laser) in the wavelength range suitable for the photo-label employed in the agent. The light used can be monochromatic, polychromatic and continuous or pulsed. The transmitted, scattered or reflected light is detected through a photodetector tuned to one or multiple wavelengths to determine the location of the tissue containing the target (eg, tissue containing GRP) in the subject. Changes in the optical parameter can be monitored over time to detect the accumulation of the labeled reagent in optical form at the address site (eg the tumor or other site with GRP receptors). Standard image processing and detection apparatus can be used in conjunction with the optical image generation reagents of the present invention.

The optical imaging reagents described above can also be used for acousto-optic or sonoluminescent imaging with optically labeled imaging agents (see U.S. Patent No. 5,171,298, WO Publication 98/57666, and the references mentioned there). In the generation of acousto-optic images, ultrasound radiation is applied to the subject and the optical parameters of the transmitted, emitted or reflected light are affected. In the generation of sonoluminescent image, the applied ultrasound actually generates the detected light. Suitable image generation methods using said, and techniques are described in Publication WO 98/57666. In US Patent Nos. 6,663,847, 6,56,451, 6,641,798, 6,485,704, 6,423,547, 6,395,257, 6,280,703, 6,277,841, 6,264,920, 6,264,919, 6,228,344, 6,217,848, 6,190,641, 6,183,726, 6,180,087, 6,180,086, 6,180,085, 6,013,243, and in US Published Patent Applications No. 2003185756, 20031656432, 20033158127, 20033152577, 20033143159, 2003105300, 2003105299, 2003072763, 2003036538, 2003031627, 2003017164, 2002169107, 2002164287 and 2002156117, all of which are incorporated by reference to the present invention as a reference, describe various techniques and reagents of image generation. 7. Radiotherapy Radioisotope therapy comprises the administration of a radiolabelled compound in an amount sufficient to damage or destroy the tissue to which it is directed. After administration of the compound (for example, by intravenous, subcutaneous, intraperitoneal injection), the radiolabelled pharmacist is preferably located at the site of the disease (in this case, tumor tissue or other tissue expressing the relevant GRP receptor). Once localized, the radiolabelled compound damages or destroys the diseased tissue with the energy that is released during the radioactive decay of the isotope that is administered. As described in the present invention, the present invention also comprises the use of radiotherapy in combination with adjuvant chemotherapy (or in combination with any other suitable therapeutic agent). The design of a successful radiation therapy comprises several critical factors: 1. selection of an appropriate management group to deliver the radioactivity to the diseased site; 2.- selection of a suitable radionuclide that releases enough energy to damage the diseased site, without damaging it substantially adjacent normal tissues; 3.- selection of an appropriate combination of the steering group and radionuclide without adversely affecting the ability of this conjugate to be located in the diseased site. For radiometals, this often comprises a chelation group that coordinates adequately with the radionuclide, combined with a linker that couples the chelate to the targeting group, and that affects the overall biodistribution of the compound to maximize uptake in target tissues and minimize uptake in normal, non-objective organs. The present invention provides radiotherapeutic agents that meet the above three criteria, through the appropriate selection of the targeting group, radionuclide, metal chelate and linker. The radiotherapeutic agents may contain a chelated 3+ metal ion of the class of elements known as the lanthanides (elements with atomic number 57-71) and their analogues (for example M3 + metals, such as yttrium and indium). Typical radioactive metals in this class include the isotopes 90-Yttrium, 111-lndium, 149-Prometheus, 153-Samarium, 166-Disprosium, 166-Holmium, 175-lterbium, and 177-Lutetium. All these metals (and others of the lanthanide series) have very similar chemistries, since they remain in the oxidation state +3, and prefer chelating ligands containing hard donor (oxygen / nitrogen) atoms, as typified by the DTPA derivatives of chelate (diethylenetriaminepentaacetic acid) and known polycarboxylate macrocycles such as DOTA (1,4,7,10-tetrazacyclododecane-N, N'.N ".N '" - tetraacetic and its close analogues The structures of these chelating ligands, in their completely deprotonated form are shown below.

These chelating ligands encapsulate the radiometal by binding to it through multiple nitrogen and oxygen atoms, thus preventing the release of free radiometal (unbound) within the body. This is important, since the in vivo dissociation of the 3+ radiometals from their chelate can result in the uptake of radiometal in the liver, bone and blood [Brechbiel MW, Gansow OA, "Backbone-substituted DTPA ligands for 90 Y radioimmunotherapy ", Bioconj. Chem. 1991; 2: 187-194; Li, WP, Ma DS, Higginbotham C, Hoffman T, Ketring AR, Cutler CS, Jurisson, SS, "Development of an in vitro model for assesing the in vivo stability of lanthanide chelates". Nucí Med. Biol. 2001; 28 (2): 145-154; Kasokat T, Urich K, Arzneim. -Forsch, "Quantification of dechelation of gadopentetate dimeglumine in rats". 1992; 42 (6): 869-76]. Unless directed specifically to these organs, such non-specific uptake is highly undesirable, since it leads to non-specific irradiation of non-target tissues, which can lead to problems such as hematopoietic suppression due to bone marrow irritation. . For radiotherapy applications, any of the therapeutic radionuclide chelators described herein can be used. However, the forms of the chelated DOTA [Tweedle MF, Gaughan GT, Hagan JT, "1-Substituted-1,4,7-triscarboxymethyl-1,4,7,10-tetraazacyclododecane and analogs" U.S. Patent No. 4,885,363, Dec 5, 1989] are particularly preferred, since chelated DOTA is expected to eliminate chelate to a lesser degree than in the body than DTPA or other linear chelates. Compounds L64 and L70 (when labeled with a suitable therapeutic radionuclide) are particularly preferred for radiotherapy. The general methods for coupling the macrocycles DOTA type to address groups through a linker (e.g., by activation of one of the DOTA carboxylates to form an ester, which is subsequently reacted with an amino group in the linker to form a stable amide bond) , are known to those skilled in the art (see, for example, the publication of Tweedle et al., US Patent No. 4,885,363). The coupling can also be carried out in DOTA macrocycles that are modified in the skeleton of the polyaza ring. The selection of a suitable nuclide for use in a particular radiotherapeutic application depends on many factors, including: a. Physical average life - This should be long enough to allow the synthesis and purification of the radiotherapeutic construction from the radiometal and conjugate, and the supply of the construction to the injection site, without a significant decrease of the radioactive before the injection. Preferably, the radionuclide should have a physical average life of between about 0.5 and 8 days. b. Energy of radionuclide emission (s) - Radionuclides that are emitters of particles (such as alpha emitters, beta emitters, and Auger electron emitters) are particularly useful, since they emit particles highly energetic that deposit their energy in short distances, thus producing highly localized damage. Beta emission radionuclides are particularly preferred, since the energy of the beta particle emissions of these isotopes is deposited in diameters from 5 to about 150 cells. Radiation therapy agents prepared from these nuclides have the ability to kill diseased cells that are relatively close to their localization sites, but that can not travel long distances to damage adjacent normal tissue, such as bone marrow. c. Specific activity (for example radioactivity by mass of the radionuclide) Radionuclides that have high specific activity (for example, generator produced 90-Y, 111-ln, 177-Lu) are particularly preferred. The specific activity of a radionuclide is determined through its production method, the particular purpose that is used to produce it, and the properties of the isotope in question. Many of the lanthanides and lanthanoids include radioisotopes that have nuclear properties that make them suitable for use as radiotherapeutic agents, since they emit beta particles. Some of these are described in the table that is continuation.

Pm: Promised, S: Samarium, Dy: Disproslo, Ho: Holmio, Yb: Iterbio, Lu ± utetio, Y: Itrio, ln: lndio.

Methods for the preparation of radiometals such as beta-emitting lanthanide radioisotopes, are known to those skilled in the art, and have been described [e.g., Cutler CS, Smith CJ, Ehrhardt GJ; Tyler TT, Jurisson SS, Deutsch E. "Current and potential therapeutic uses of lanthanide radioisotopes". Cancer Biother. Radiopharm. 2000; 15 (6): 531-545]. Many of these isotopes can be produced in high production at a relatively low cost, and many (eg, 90-Y, 149-Pm, 177-Lu) can be produced with activities close to specific vehicle-free activities (eg , the vast majority of atoms are radioactive). Since non-radioactive atoms can compete with their radioactive analogs to bind receptors in the target tissue, the use of high-level specific activity radioisotopes is important. allow the supply of radioactivity doses to the target tissue as high as possible. The radiotherapeutic derivatives of the present invention containing rhenium beta emission isotopes (186-Re and 88-Re) are also particularly preferred. 8. Doses and Additives Suitable dose schedules for the compounds of the present invention are known to those skilled in the art. The compounds can be administered using many methods including, but not limited to, multiple IV or IP injections. For radiopharmaceuticals, a quantity of radioactivity is administered which is sufficient to allow the generation of images, or in the case of radiotherapy, to cause damage or removal of tissue containing targeted GRP-R, but not so as to cause damage substantial to non-objective tissue (normal tissue). The amount and dose required for scintigraphic image generation is described supra. The amount of dose required for radiotherapy is also different for different constructions, depending on the energy and average life of the isotope used, the degree of uptake and clearance of the body agent and the mass of the tumor. In general, doses can range from a single dose of about 30-50 mCi to a cumulative dose of up to about 3 Curies.

For optical imaging compounds, sufficient doses to achieve improvement of the desired image are known to those skilled in the art and can vary widely depending on the ink or other compound used, the organ or tissue from which the image will be generated. , the image generation equipment, etc. The compositions of the present invention may include physiologically acceptable regulators, and may require radiation stabilizers to prevent radiolytic damage to the compound prior to injection. Radiation stabilizers are known to those skilled in the art, and may include para-aminobenzoic acid, ascorbic acid, gentistic acid, and the like. A single vial multiple bottle kit containing all the components necessary to prepare the diagnostic or therapeutic agents of the present invention is an integral part thereof. In the case of radiopharmaceuticals, such equipment will often include all the necessary ingredients except the radionuclide. For example, a single-bottle kit for preparing a radiopharmaceutical of the present invention preferably contains a chelator / linker / targeting peptide conjugate of the formula M-N-O-P-G, a source of stannous salt (if reduction is required, for example, when using tecnetium), or other pharmaceutically acceptable reducing agent, and is suitably regulated with a pharmaceutically acceptable acid or base to adjust the pH to a value of about 3 to about 9. The amount and type of reducing agent used It will depend highly on the nature of the exchange complex that will be formed. Suitable conditions are well known to those skilled in the art. It is preferred that the contents of the equipment are in lyophilized form. Such a single-bottle kit may optionally contain ligands such as glucoheptonate, gluconate, mannitol, malate, citric or tartaric acid and may also contain reaction modifiers such as diethylenetriamine pentaacetic acid (DPTA), ethylene diamine tetraacetic acid (EDTA) or a cyclodextrin-β or? which serves to improve the radiochemical purity and stability of the final product. The equipment may also contain stabilizers, bulking agents such as mannitol, which are designed to aid in the freeze-drying process, and other additives known to those skilled in the art. A multi-vial kit preferably contains the same general components, but employs more than one bottle to reconstitute the radiopharmaceutical. For example, a bottle can contain all the ingredients that are required to form a labile complex Tc (V) in addition to the pertechnetate (e.g., the stannous source or other reducing agent). The pertechnetate is added to this bottle, and after waiting for a suitable period of time, the contents of the bottle are added to a second bottle containing the chelator and steering peptide, as well as suitable regulators to adjust the pH to its optimum value. After a reaction time of approximately 5 to 60 minutes, the complexes of the present invention are formed. It is convenient that the contents of both bottles of this multi-bottle equipment are lyophilized. As described above, the reaction modifiers, exchange ligands, stabilizers, bulking agents, etc. They can be found in either or both of the jars. General Preparation of Compounds The compounds of the present invention can be prepared by various methods depending on the selected chelator. The peptide portion of the compound can be prepared in the most convenient manner by techniques generally established and known in the art of peptide synthesis, such as the solid phase peptide synthesis method (SPPS). Because it adapts to the synthesis of solid phase, the use of FMOC protection and deprotection of Alternation is the preferred method for making short peptides. Recombinant DNA technology is preferred to produce protein and long fragments thereof. Solid phase peptide synthesis (SPPS) comprises the stepwise addition of amino acid residues to a growth peptide chain that binds to an insoluble support or matrix, such as polystyrene. The C-terminal residue of the peptide is first attached to a commercially available support with its amino group protected with an N-protecting agent, such as a t-butyloxycarbonyl group (Boc) to a fluorenylmethoxycarbonyl group (Fmoc). The amino protecting group is removed with suitable deprotection agents, such as TFA in the case of Boc or piperidine for Fmoc and the next amino acid residue (in N-protected form) is added with a coupling agent such as diisopropylcarbodiimide (DIC). ). At the time of formation of a peptide linkage, the reagents are washed from the support. After addition of the final residue, the peptide is dissociated from the support with a suitable reagent such as trifluoroacetic acid (TFA) or hydrogen fluoride (HF). Alternative Preparation of the Compounds Through Segment Coupling The compounds of the present invention can also be prepared through the process known in the art. as segment coupling or fragment condensation (Barios, K. Cats; 2002"Convergent Peptide Synthesis" in Fmoc Solid Phase Synthesis - A Practical Approach; Eds. Chan, WC and White, PD, Oxford University Press, New York; Chap. 9 pp. 215-228). In this method the segments of the peptide normally in side-chain protected form, are prepared separately either by solution phase synthesis or solid phase synthesis or a combination of the two methods. The choice of segments is crucial and is made using a division strategy that can provide a manageable number of segments, whose C-terminal residues and N-terminal residues are projected to provide the cleanest coupling in peptide synthesis. The C-terminal residues of the best segments are devoid of chiral alpha carbons (glycine or other aquilalic portions in the carbon oc for the carboxyl group to be activated in the coupling step) or compromised of amino acids whose propensity to racemize during the activation and coupling is the lowest of the possible selections. The choice of the N-terminal amino acid for each segment is based on the ease of coupling of an activated acyl intermediate to the amino group. Once the division strategy is selected, the method of coupling of each of the segments based on the synthetic access capacity of the required intermediaries and the ease of handling and relative purification of the resulting products (if necessary). The segments are then coupled together, either in solution, or one in solid phase and another in solution to prepare the final structure in a fully or partially protected form. The subsequently protected target compound is subjected to removal of the protecting groups, purified and isolated to produce the final desired compound. The advantages of the segment coupling method are that each segment can be purified separately, allowing the elimination of side products such as elimination sequences that result from incomplete couplings or those that are derived from reactions such as dehydration of side chain amide during the coupling steps, or internal cycling of side chains (such as Gln) to the alpha amino group during deprotection of the Fmoc groups. Said side products could all be present in the final product of a "direct" peptide chain assembly based on conventional resin, where the elimination of these materials can be carried out, if necessary, in many stages, in a strategy of segment coupling. Another important advantage of the segment coupling strategy is that different solvents, reagents and conditions can be applied to optimize the synthesis of each of the segments at the purity and superior production which results in improved purity and production of the final product. Other advantages considered are the decreased consumption of reagents and lower costs. EXAMPLES The examples set forth below are provided as examples of different methods that can be used to prepare various compounds of the present invention. Within each example, there are compounds identified with uppercase letters (for example, A, B, C), which are correlated with the same corresponding compounds labeled in the identified drawings. General Experiments A. Definitions of Additional Abbreviations Used Here are the common abbreviations that are used throughout this specification: 1, 1-dimethylethoxycarbonyl (Boc or Boc); 9-fluorenylmethyloxycarbonyl (Fmoc); Allyloxycarbonyl (Aloe); 1-hydroxybenoxotriazole (HOBt or HOBT); N, N'-diisopro pilca rbodiimide (DIC); N-methylpyrrolidinone (NMP); Acetic anhydride (AC2O); (4,4-dimethyl-2,6-dioxocyclohex-1-ylidene) -3-methylbutyl (iv-Dde); Trifluoroacetic acid (TFA); Reagent B (TFA: H2O: phenol: triisopropylsilane, 88: 5: 5: 2); Diisopropylethylamine (DIEA); Hexafluorophosphate O- (1 H-benzotriazole-1-yl) -N, N, N ', N', - tetramethyluronium (HBUT); Hexafluorophosphate 0- (7-azabenzotriazol-1-iI) -1, 1,3,3-tetramethyluronium (HATU); N-hydroxysuccinimide (NHS); Synthesis of solid phase peptide (SPPS); Dimethylsulfoxide (DMSO); Dichloromethane (DCM); Dimethylformamide (DMF); Dimethylacetamide (DMA); 1,4,7,10 -tetra azacid or tetra decan o-1, 4,7,10-tetraacetic acid (DOTA); Triisopropylsilane (TIPS); 1,4,7,10-tetraazacyclotetradecane-1,4,7,10-tetraacetic acid (DOTA) (1R) -1- [1,4,7,10-tetraaza-4,7,10-tris (carboxymethyl) cyclododecyl] ethane-1,2-dicarboxylic acid (CMDOTA); Fetal bovine serum (FBS); Human serum albumin (HSA); Human prostate cancer cell line (PC3); Isobutylchloroformate (IBCF); Tributyl amine (TBA); Radiochemical purity (RCP); and High Performance Liquid Chromatography (HPLC). B. Materials The amino acids protected with Fmoc used were purchased from Nova-Biochem (San Diego, CA, USA), Advanced Chem Tech (Lousville, KY, USA), Chem-lmpex International (Wood Dale ILL., USA), and Multiple Peptide Systems (San Diego, CA, USA). Other chemicals, reagents and absorbents required for the synthesis were procured from Aldrich Chemical Co. (Milwaukee, WI, USA) and VWR Scientific Products (Bridgeport, NJ., USA). Solvents for peptide synthesis were obtained from Pharmco Co.

(Brookfield CT., USA). Columns for HPLC analysis and purification were obtained from Waters Co. (Milford, MA., USA). Below are experimental details for those that were not commercially available.

C. Instrumentation for Peptide Synthesis The peptides were prepared using an Advanced Chem Tech 496 O MOS synthesizer, an Advanced Chem Tech 357 FBS synthesizer and / or by manual peptide synthesis. However, the protocols for iteractive deprotection and chain extension used were the same for everyone. D. Automatic synthesis with the Svmphonv instrument (developed by Rainin) The synthesis was run with the Symphony software (Version 3) supplied by Protein Technologies Inc. The Novagel TGR resin, with a 0.25 mmol / g substitution, was used and each deposit contained 0.2 g of the resin (50 μmol). The amino acids were dissolved in NMP and the concentration was 0.25M. A 0.25M solution of BUT and N-Methylmorpholine in DMF was prepared and used for coupling. All couplings were carried out for 2.0 hours. Dissociation was performed outside the machine by transferring the resin to another reaction container and using Reagent B as the manual synthesis. E. Instrumentation Used for Analysis and Purification. Analytical HPLC was performed using a system Analytical gradient LC of dual pump Shimadzu-LC-10A using Shimadzu-ClassVP software version 4.1 for the control of the system, data acquisition and post-run processing. Mass spectra were acquired in a Hewlett-Packard Series 1100 MSD mass spectrometer interfaced with a Hewlett-Packard Series 1100 dual pump gradient HPLC system adapted with an Agilent Technologies 1100 servo autosampler adapted for either direct flow injection or injection in a Waters Associates Xterra MS C18 column (4.6 mm x 50 mm, 5 μ particle, 120 pores). The instrument was operated through an HP Kayak workstation using 'MSD Anyione' for sample presentation and HP Chemstation software for instrument control and data acquisition. In most cases, the samples were introduced through direct injection using 5μL of an injection of sample solution in a concentration of 1 mg / mL and analyzed using positive ion electrorocium to obtain m / eym / z ions ( charged by multiple) for the confirmation of the structure. 1H-NMR spectra were obtained in a 500 MHz Varian Innova spectrometer, 13C-NMR spectra were obtained in the same instrument at 125.73 MHz. Generally, the residual 1H absorption, or in the case of 13C-NMR as the 13C absorption of the solvent used , it was used as an internal reference; in other cases, tetramethylsilane (d = 0.00 ppm) was used. The resonance values are provided in units d. The microanalysis data was obtained from Quantitative Technologies Inc., Whitehouse NJ. The HPLC preparation was carried out in a HPLC system of dual pump gradient preparation Shimadzu-LC-8A using Shimadzu-ClassVP software version 4.3 for system control, data acquisition, fraction collection and post-run processing. F. General Procedures for Peptide Synthesis The Rink Amida-Novagel HL resin (0.6 mmol / g) was used as the solid. G. Coupling Procedure In a typical experiment, the first amino acid was loaded on 0.1 g of the resin (0.06 mmol). The amino acid Adequate Fmoc in NMP (0.25M solution, 0.960 mL was added to the resin followed by N-hydroxybenzotriazole (0.5M in NMP, 0.48 mL) and the reaction block (in the case of automated peptide synthesis)) or packaging Individual reaction (in the case of manual peptide synthesis) was stirred for about 2 minutes. To the previous mixture, diisopropylcarbodiimide (0.5M in NMP; 0.48 mL) and the reaction mixture was stirred for 4 hours at room temperature. Subsequently, the reaction block or the individual reaction vessel was purged in as to reagents by applying a positive pressure of dry nitrogen. H. Washing Procedure Each deposit of the reaction block was filled with 1.2 mL of NMP and the block was stirred for 5 minutes. The solution was drained under reduced nitrogen pressure. This procedure was repeated three times. The same procedure was used, with an adequate volume of NMP, in the case of manual synthesis using individual packages. I. Removal of the Fmoc Protection Group The resin containing the amino acid protected by Fmoc was treated with 1.5 mL of 20% piperidine in DMF (v / v) and the reaction block or the individual manual synthesis package was shaken for 15 minutes. minutes The solution was drained of the resin. This procedure was repeated once and the resin was washed using the washing procedure described above. J. Final ligand coupling (DOTA v CMDOTA) The N-determined amino group of the resin bonded peptide linker construct was deblocked and the resin was washed. A 0.25M solution of the desired ligand and HBUT in NMP was made, and treated with a two-fold equivalence of DIEA. The resulting solution of the activated ligand was added to the resin (1.972 mL, 0.48 mmol) and the reaction mixture was stirred at room temperature. environment for 24 to 30 hours. The solution was drained and the resin was washed. The final wash of the resin was carried out with 1.5 mL of dichloromethane (3X). K. Deprotection and Purification of the Final Peptide A solution of Reagent B (2 mL; 88: 5: 5: 2-TFA: phenol: water: TIPS) was added to the resin and the individual reaction block or package was shaken for 4.5 hours at room temperature. The resulting solution, which contains the deprotected peptide, was drained in a flask. This procedure was repeated two more times with 1 mL of Reagent B. The combined filtrate was concentrated under reduced pressure using a Genevac HT-12 series II centrifugal concentrator. The residue in each vial was subsequently titrated with 2 mL of Et2O and the supernatant was decanted. This procedure was repeated twice to provide the peptide in the form of colorless solids. The crude peptides were dissolved in water / acetonitrile and purified using either an HPLC column of preparation WatersXTerra MS C18 (50 mm x 19 mm, particle size 5 miera, pore size 120) or a Waters-YMC C18 ODS column ( 250 mm x 30 mm id, particle size 10 microns, pore size 120). The fractions containing the product were collected and analyzed by HPLC. Fractions with > 95% purity was gathered and the peptides were isolated by lyophilization. Preparation HPLC conditions (Waters Xterra Column): Elution range: 50 mL / min Detection: UV,? = 220 nm Eluent A: 0.1% aq. TFA; Eluent B: Acetonitrile (0.1% TFA). Conditions for HPLC Analysis: Column: Waters Xterra (Waters Co, 4.6 x 50 mm, MS C18, size 5 microns, pore 120). Elution range: 3 mL / min; Detection: UV,? = 220 nm. Eluent A: 0.1% aq. TFA; Eluent B: Acetonitrile (0.1% TFA). Example I - Figures 1A-B Synthesis of L62 Summary: As shown in Figures 1A-B, L62 was prepared using the following steps: Hydrolysis of (3β, 5β) -3-aminocolan-24-oic acid methyl ester with NaOH produced the corresponding acid B, which was subsequently reacted with Fmoc-CI to produce the intermediate C. The Rink amide resin functionalized with the octapeptide Gln-Trp-Ala-Val-Gly-His-Leu-Met-NH2 (BBN [7-14] [SEQ ID NO: 1]) was reacted in sequences with C, Fmoc-glycine and tri-t-butyl ester DOTA After dissociation and deprotection with the Reagent B, the crude was purified by HPLC preparation to produce L62. Overall production: 2.5%.

More details are given below: A. Rink Amide Resin functionalized with Bombesinaf7-14l. (A) In a solid phase peptide synthesis package (see Table No. 1) the amino acid Fmoc (24 mmol), N-hydroxybenzotriazole (HOBt) (3.67 g, 24 mmol), and N, N'-diisopropylcarbodiimide (DIC) (3.75 mL, 24 mmol) were added in sequences to a suspension of Rink NovaGel ™ amide resin (10 g, 6.0 mmol) A in DMF (45 mL). The mixture was stirred for 3 hours at room temperature using a bench top stirrer, then the solution was emptied and the resin was washed with DMF (5 x 45 mL). The resin was stirred with 25% piperidine in DMF (45 mL) for 4 minutes, the solution was emptied and fresh piperidine in DMF (45 mL) was added. The suspension was stirred for 10 minutes, then the solution was emptied and the resin was washed with DMF (5 x 45 mL). This procedure was applied in sequences for the following amino acids: Na-Fmoc-L-methionine, Na-Fmoc-L-leucine, N- -Fmoc-N, m.trityl-L-histidine, Na-Fmoc-glycine, Na- Fmoc-L-valine, Na-Fmoc-L-alanine, Na-Fmoc-N? N-Boc-L-tryptophan.

In the last coupling reaction, Na-Fmoc-N-β-trityl-L-glutamine (14.6 g, 24 mmol), HOBt (3.67 g, 24 mmol), and DIC (3.75 mL, 24 mmol) were added to the resin in DMF (45 mL). The mixture was stirred for 3 hours at room temperature, the solution was emptied and the resin was washed with DMF (5 x 45 mL), CH2Cl2 (5 X 45 mL) and dried under vacuum. B. Preparation of Intermediates B and C (Fig. 1A): 1. Synthesis of (3ß, 5ß) -3-Aminocolan-24-oic acid (B) A solution of 1M NaOH (16.6 mL) was added as drops. 16.6 mmol) was added to a solution of (3β, 5β) -3-aminocolan-24-oic acid methyl ester (5.0 g, 12.8 mmol) in MeOH (65 mL) at a temperature of 45 ° C. After 3 hours stirring at a temperature of 45 ° C, the mixture was concentrated to 25 mL and H2O (40 mL) and 1M HCl (22 mL) were added. The precipitated solid was filtered, washed with H 2 O (2 x 50 mL) and dried in vacuo to yield B in the form of a white solid (5.0 g, 13.3 mmol). Performance 80%. 2. Synthesis of (3ß.5β) -3- (9H-Fluoren-9-ylmethoxy) aminocolan-24-oic acid (C) A solution of 9-fluorenylmethoxycarbonyl chloride (0.76 g; 2.93 mmol) in 1,4-dioxane (9 mL) to a suspension of (3ß, 5ß) -3- acid. aminocolan-24-oico B (1.0g, 2.66 mmol) in 10% aqueous Na2CO3 (16 mL) and 1,4-dioxane (9 mL) was stirred at a temperature of 0 ° C. After 6 hours of stirring at room temperature, H2O (90 mL) was added, the aqueous phase was washed with Et2O (2x90 mL) and then 2M HCl (15 mL) was added (final pH: 1.5). The aqueous phase was extracted with EtOAc (2 x 100 mL), the organic phase was dried over Na2SO and evaporated. The crude was purified by flash chromatography to produce C in the form of a white solid (1.2 g, 2.0 mmol). Performance 69%. C. Synthesis of L62 (N - [((3β, 5β) -3 - [[[[[4,7,10-Tris (carboxymethyl) -1,4,7,10-tetraazacyclododec-1-yl] acetyl] amino] acetyl] amino] -colan-24-yl] -L-glutaminyl-triptophyl-L-alanyl-L-valyl-glycyl-L-histidyl-L-leucyl-L-methioninamide) (Fig. IB): Resin A (0.5 g, 0.3 mmol) was stirred in a solid phase peptide synthesis flask with 50% morpholine in DMA (7 mL) for 10 minutes, the solution was emptied and fresh morpholine was added to the solution. 50% in DMA (7 mL) The suspension was stirred for 20 minutes, then the solution was emptied and the resin was washed with DMA (5 x 7 mL). (3ß, 5ß) -3- was added to the resin. (9H-Fluoren-9-ylmethoxy) aminocolan-24-oico C (0.72 g, 1.2 mmol), N-hydroxybenzotriazole (HOBt) (0.18 g, 1.2 mmol), N, N'-diisopropylcarbodiimide (DIC) (0.19 mL; 1.2 mmol) and DMA (7 mL) to the resin, the mixture was stirred for 24 hours at room temperature, and the solution was emptied and the resin was washed with DMA (5x7 mL). The resin was then stirred with 50% morpholine in DMA (7 mL) for 10 minutes, the solution was emptied, fresh 50% morpholine in DMA (7 mL) was added and the mixture was stirred for another 20 minutes. The solution was emptied and the resin was washed with DMA (5x7 mL). N-α-Fmoc-glycine (0.79 g, 1.2 mmol), HOBt (0.18 g); 1.2 mmol), DIC (0.19 mL: 1.2 mmol) and DMA (7 mL) were added to the resin. The mixture was stirred for 3 hours at room temperature, the solution was emptied and the resin was washed with DMA (5x7 mL). The resin was subsequently stirred with 50% morpholine in DMA (7 mL) for 10 minutes, the solution was emptied, fresh 50% morpholine in DMA (7 mL) was added and the mixture was stirred for another 20 minutes. The solution was emptied and the resin was washed with DMA (5xd7 mL) followed by the addition of tris (1,1-dimethylethyl) acid adduct of 1,4,7,10-tetraazacyclododecane-1,4,7,103 -Tracetic with NaCl (0.79 g, 1.2 mmol), HOBt (0.18 g, 1.2 mmol), DIC (0.19 mL: 1.2 mmol), DIEA (0.40 mL, 2.4 mmol) in DMA (7 mL) to the resin. The mixture was stirred for 24 hours at room temperature, the solution was emptied and the resin was washed with DMA (5x7 mL), CH2Cl2 (5x7 mL) and dried under vacuum. The resin was stirred in a flask with Reagent B (25 mL) for 4.5 hours. The resin was filtered and The solution was evaporated under reduced pressure to produce an oily crude which was titrated with Et2O (20 mL) which produced a precipitate. The precipitate was collected by centrifugation and washed with Et2O (3x20 mL), then analyzed by HPLC and purified by preparative HPLC. The fractions containing the product were lyophilized to yield L62 (6.6 mg, 3.8 x 10"3 mmol) in the form of a white solid, Yield 4.5% Example II - Figures 2A-F Synthesis of L70, L73, L74, L115 and L116 Summary: The products were obtained by coupling the octapeptide Gln-Trp-Ala-Val-Gly-His-Leu-Met-NH2 (BBN [7-14] [SEQ ID NO: 1]) (with adequate side chain protection ) in the Rink amide resin with different linkers, followed by functionalization with tri-t-butyl ester DOTA, after the dissociation and deprotection with Reagent B, the final products were purified by preparative HPLC, general yields 3-9%. A. Synthesis of L70 (Fio 2A) Resin A (0.5 g, 0.3 mmol) was stirred in a solid phase peptide synthesis flask with 50% morpholine in DMA (7 mL) for 10 minutes, the solution empty and 50% fresh morpholine in DMA (7 mL) was added.The suspension was stirred for 20 minutes, subsequently The solution was emptied and the resin was washed with DMA (5 x 7 mL). Fmoc-4-aminobenzoic acid (0.43 g, 1.2 mmol), HOBt (0.18 g, 1.2 mmol), DIC (0.19 mL, 1.2 mmol) and DMA (7 mL) were added to the resin, the mixture was stirred. for 3 hours at room temperature, and the solution was emptied and the resin was washed with DMA (5x7 mL). Subsequently the resin was stirred with 50% morpholine in DMA (7 mL) for 10 minutes, the solution was emptied, fresh 50% morpholine in DMA (7 mL) was added and the mixture was stirred for 20 minutes. They were stirred for 15 minutes in DMA (5x7 mL) Fmoc-glycine (0.36 g, 1.2 mmol), HOBt (0.18 g, 1.2 mmol) HATU (0.46 g, 1.2 mmol) and DIEA (0.40 mL, 2.4 mmol). Subsequently the solution was added to the resin, the mixture was stirred for 2 hours at room temperature, the solution was emptied and the resin was washed with DMA (5x7 mL). The resin was subsequently stirred with 50% morpholine in DMA (7 mL) for 10 minutes, the solution was emptied, fresh 50% morpholine in DMA (7 mL) was added and the mixture was stirred for 20 minutes. The solution was emptied and the resin was washed with DMA (5x7 mL) followed by the addition of tris (1,1-dimethyl ethyl) adduct of 1,4,7,10-tetraazacyclododecane-1, 4,7,10. -tetraacetic with NaCl (0.79 g, 1.2 mmol), HOBt (0.18 g, 1.2 mmol), DIC (0.19 mL: 1.2 mmol), DIEA (0.40 mL, 2.4 mmol) in DMA (7 mL) to the resin. The mixture was stirred for 24 hours at room temperature At room temperature, the solution was emptied and the resin was washed with DMA (5x7 mL), CH2Cl2 (5x7 mL) and dried under vacuum. The resin was stirred in a flask with Reagent B (25 mL) for 4 hours. The resin was filtered and the solution was evaporated under reduced pressure to produce an oily crude which was titrated with Et2O (5 mL). The precipitate was collected by centrifugation and washed with Et2O (5x5 mL), then analyzed by HPLC and purified by preparative HPLC. The fractions containing the product were lyophilized to produce L70 in the form of a white fluffy solid (6.8 mg, 0.005 mmol). Performance 3%. B. Synthesis of L73. L115 v L116 (Figs 2B-2E) Resin A (0.5 g, 0.3 mmol) was stirred in a solid phase peptide synthesis flask with 50% morpholine in DMA (7 mL) for 10 minutes, the solution empty and 50% fresh morpholine in DMA (7 mL) was added. The suspension was stirred for 20 minutes, then the solution was emptied and the resin was washed with DMA (5 x 7 mL). Fmoc-linker-OH (1.2 mmol), HOBt (0.18 g, 1.2 mmol) DIC (0.19 mL, 1.2 mmol) and DMA (7 mL) were added to the resin, the mixture was stirred for 3 hours at room temperature. environment, and the solution was emptied and the resin was washed with DMA (5x7 mL). Subsequently the resin was stirred with 50% morpholine in DMA (7 mL) for 10 minutes, the solution was emptied, fresh 50% morpholine in DMA (7 mL) was added and the mixture was stirred for 20 minutes. The solution was emptied and the resin was washed with DMA (5x7 mL). To the resin add tri s (1, 1-dimethyl ethyl) adduct of 1, 4,7, 10-Tetrazazacyclododecane-1, 4,7,10-tetraacetic acid with NaCl (0.79 g, 1.2 mmol), HOBt ( 0.18 g, 1.2 mmol) DIC (0.19 mL, 1.2 mmol) DIEA (0.40 mL, 2.4 mmol) and DMA (7 mL). The mixture was stirred for 24 hours at room temperature, the solution was emptied and the resin was washed with DMA (5x7 mL), CH2Cl2 (5x7 mL) and dried under vacuum. The resin was stirred in a flask with Reagent B (25 mL) for 4 hours. The resin was filtered and the solution was evaporated under reduced pressure to produce an oily crude which was titrated with Et2O (5 mL). The precipitate was collected by centrifugation and washed with Et2O (5x5 mL), then analyzed by HPLC and purified by preparative HPLC. The fractions containing the product were lyophilized. C Synthesis of L74 (Fig. 2F): Resin A (0.5 g, 0.3 mmol) was stirred in a solid phase peptide synthesis flask with 50% morpholine in DMA (7 mL) for 10 minutes, the solution empty and 50% fresh morpholine in DMA (7 mL) was added. The suspension was stirred for 20 minutes, then the solution was emptied and the resin was washed with DMA (5 x 7 mL).

Fmoc-isonipecotic acid (0.42 g, 1.2 mmol), HOBt (0.18 g, 1.2 mmol), DIC (0.19 mL, 1.2 mmol) and DMA (7 mL) were added to the resin, the mixture was stirred for 3 hours at room temperature. environment, and the solution was emptied and the resin was washed with DMA (5x7 mL). Subsequently the resin was stirred with 50% morpholine in DMA (7 mL) for 10 minutes, the solution was emptied, fresh 50% morpholine in DMA (7 mL) was added and the mixture was stirred for 20 minutes. The solution was emptied and the resin was washed with DMA (5x7 mL). Tris (1,1-dimethylethyl) ester adduct of 1,4,6,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid adduct was added to the resin with NaCl (0.79 g, 1.2 mmol), HOBt (0.18). g; 1.2 mmol), DIC (0.19 mL: 1.2 mmol), DIEA (0.40 mL, 2.4 mmol) in DMA (7 mL) to the resin. The mixture was stirred for 24 hours at room temperature, the solution was emptied and the resin was washed with DMA (5x7 mL), CH2Cl2 (5x7 mL) and dried under vacuum. The resin was stirred in a bottle with reagent B (25 ml) for 4 hours. The resin was filtered and the solution was evaporated under reduced pressure to produce an oily crude which was triturated with Et2O (5 mL). The precipitate was collected by centrifugation and washed with Et2O (5x5 ml), subsequently analyzed by HPLC and purified by HPLC. The fractions containing the product were lyophilized to produce L74 in the form of a white fluffy solid (18.0 mg, 0.012 mmol). 8% production. Example III - Figures 3A-E Synthesis of L67 Summary: The hydrolysis of methyl ester of (3ß, 5ß) -3-amino-12-oxocolan-24-oic acid with NaOH yielded the corresponding acid B, which subsequently did react with Fmoc-Glycine to produce the intermediate C. The amide resin was reacted in sequences Rink functionalized with octapeptide Gln-Trp-Ala-Val-Gly-His-Leu-Met-NH2 (BBN [7-14] [SEQ ID NO: 1]), with C and tri-t-butyl ester DOTA. After dissociation and deprotection with reagent B, the crude was purified by HPLC preparation to produce L67. Overall production: 5.2%. A. Synthesis of (3ß.5ß) -3-amino-12-oxocolan-24 acid. (B) (FIGURE 3A) A 1M solution of NaOH (6.6 ml, 6.6 mmoi) was added dropwise to a solution of (3β, 5β) -3-amino-12-oxocolan-24- methyl ester. O a (2.1 g, 5.1 mmol) in MeOH (15 ml) at a temperature of 45 ° C. After 3 hours stirring at a temperature of 45 ° C, the mixture was concentrated to 25 ml, then 1M HCl (8 ml) was added. The precipitated solid was filtered, washed with H2O (2 x 30 ml) and dried under vacuum to yield B in the form of a white solid (1.7 g, 4.4 mmol). 88% production. B. Synthesis of (3ß.5ß) -3-yl (9H-fluoren-9-ylmethoxy) amino-alkyl-amino-12-oxocolan-24-oic acid (C) (FIGURE 3A) Tributylamine (0.7 ml, 3.1 mmol) was added dropwise to a solution of N-α-Fmoc-glycine (0.9 g, 3.1 mmol) in THF (25 ml) stirred at a temperature of 0 ° C. Isobutyl chloroformate (0.4 ml, 3.1 mmol) was added in sequence and, after 10 minutes, a suspension of tributylamine (0.6 ml, 2.6 mmol) and (3ß, 5β) -3-amino acid was added as drops. 12-Oxocolan-24-Oico B (1.0 g, 2.6 mmol) in DMF (30 mL), for 1 hour in a cooled solution. The mixture was allowed to warm and after 6 hours the solution was concentrated to 40 ml, then H2O (50 ml) and 1N HCl (10 ml) were added (final pH: 1.5). The precipitated solid was filtered, washed with H2O (2 x 50 ml), dried in vacuo and purified by flash chromatography to produce C, in the form of a white solid (1.1 g, 1.7 mmol). Performance 66%. C. Synthesis of L67 (Nr (3ß.5ß) -3-F, 4.7.10-tris (carboxymethyl) -1,4,7,10-tetra-azacyclododec-1-ylacetyl-1-amino-1-acetyl-1-4,2-dioxocolan-24- il1-L-gyutamyl-L-tryptopyl-L-alanyl-L-valyl-qylil-L-histidyl-L-leucyl-L-methioninamide) (FIGURE 3B v FIGURE 3E). Resin D (0.5 g, 0.3 mmol) was stirred in a container of solid phase peptide synthesis with 50% morpholine in DMA (7 ml) for 10 minutes, the solution was emptied and 50% fresh morpholine in DMA (7 ml) was added. The suspension was stirred for 20 minutes, then the solution was emptied and the resin was washed with DMA (5 x 7 ml). Resin (3β, 5β) -3 - [[(9H-fluoren-9-ylmethoxy) amino] acetyl] amino] -12-oxocolan-24-oico C (0.80 g, 1.2 mmol), HOBt (0.18) was added g; 1.2 mmol), DIC (0.19 ml, 1.2 mmol), and DMA (7 ml), the mixture was stirred for 24 hours at room temperature, the solution was emptied and the resin was washed with DMA (5 x 7 ml) . The resin was stirred with 50% morpholine in DMA (7 ml) for 10 minutes, the solution was emptied, fresh 50% morpholine in DMA (7 ml) was added and the mixture was stirred for 20 minutes. The solution was emptied and the resin was washed with DMA (5 x 7 ml). 1,4,1,10-Tetra-azacyclododecane-1,4,7,10-tetraacetic acid adduct was added to the resin with tris (1, 1-dimethylethyl) ester with NaCl (0.79 g, 1.2 mmol) , HOBt (0.18 g, 1.2 mmol), DIC (0.19 mL, 1.2 mmol), DIEA (0.40 mL, 2.4 mmol), and DMA (7 mL). The mixture was stirred for 24 hours at room temperature, the solution was emptied and the resin was washed with DMA (5 x 7 ml), CH 2 Cl 2 (5 x 7 ml) and dried under vacuum. The resin was stirred in a flask with reagent B (25 ml) for 4.5 hours. The resin was filtered and the solution was evaporated under reduced pressure to produce an oily crude which was triturated with Et 2 O (20 ml). Example IV - Figures 4A-H Synthesis of L63 and L64 Summary: Hydrolysis of (3β, 5β, 7a, 12a) -3-amino-7,12-dihydroxycolan-24-oico 1b with the NaOH produced the intermediate 2b, which was subsequently reacted with Fmoc-glycine to produce 3b. The functionalized Rink amide resin was reacted with octapeptide Gln-Trp-Ala-Val-Gly-His-Leu-Met-NH2 (BBN [7-14] [SEQ ID NO: 1]) with 3b and subsequently with tri-ester. -t-butyl DOTA. After dissociation and deprotection with reagent B, the crude was purified by HPLC preparation to produce L64. The same procedure was repeated starting from intermediate 2a, already available, to produce L63. General returns: 9 and 4%, respectively. A. Synthesis of (3ß.5ß.7a, 12a) -3-amino-7.12-dihydroxycolan-24-oic acid. (2b) (FIGURE 4A) A 1M solution of NaOH (130 mL, 0.13 mmol) was added dropwise to a solution of (3ß, 5ß, 7a, 12a) -3-amino-7, 12 methyl ester. -dihydroxycolan-24-oico 1b (42.1 g, 0.10 mmol) in MeOH (300 ml) heated to a temperature of 45 ° C. After 3 hours stirring at a temperature of 45 ° C, the mixture was concentrated to 150 ml and H2 (350 ml) was added. After extraction with CH2CI2 (2 x 100 ml), the aqueous solution was concentrated to 200 ml and 1M HCl (150 ml) was added. The precipitated solid was filtered, washed with H 2 O (2 x 100 ml) and dried under vacuum to yield 2b in the form of a white solid (34.8 g, 0.08 mmol). Performance 80%. B. Synthesis of (3ß.5B.12a) -3-fr (9H-Fluoren-9-ylmethoxy) amino-1-acetylamino-12-hydroxylan-24-oic acid (3a) (FIGURE 4A) Tributylamine (4.8 ml, 20.2 mmol) was added dropwise to a solution of N-α-Fmoc-glycine (6.0 g, 20.2 mmol) in THF (120 ml) stirred at a temperature of 0 ° C. Subsequently, isobutyl chloroformate (2.6 ml, 20.2 mmol) was added, after 10 minutes, a suspension of tributylamine (3.9 ml, 16.8 mmol) and (3ß, 5β, 12a) -3-amino acid was added as drops. 12-hydroxycolan-24-oico-2a (6.6 g, 16.8 mmol) in DMF (120 ml) for 1 hour in the cooled solution. The mixture was allowed to warm and after 6 hours the solution was concentrated to 150 ml, then H2O (250 ml) and 1N HCl (40 ml) were added (final pH: 1.5). The precipitated solid was filtered, washed with H 2 O (2 x 100 ml), dried under vacuum and purified by means of flash chromatography to produce 3a in the form of a white solid (3.5 g, 5.2 mmol). Performance of 31%. C. Synthesis of acid (3B.5B.7a.12a) -3-rf (9H-fluoren-9-ylmethoxy!) Aminolacetylamino-7,12-dihydroxycolan-24-oico (3b) (FIGURE 4A) Tributylamine (3.2 ml, 13.5 mmol) was added dropwise to a solution of N-α-Fmoc-glycine (4.0 g, 13.5 mmol) in THF (80 ml) stirred at a temperature of 0 ° C. Subsequently, isobutyl chloroformate (1.7 ml, 13.5 mmol) was added and after 10 minutes, a suspension of tributylamine (2.6 ml, 11.2 mmol) and acid (3ß, 5ß, 7a, 12a) -3- was added as drops. amino-7,12-dihydroxycolan-24-oico 3a (4.5 g; 11.2 mmol) in DMF (80 ml), for 1 hour in a cooled solution. The mixture was allowed to warm and after 6 hours the solution was concentrated to 120 ml, then H2O (180 ml) and 1 N HCl (30 ml) were added (final pH: 1.5). The precipitated solid was filtered, washed with H 2 O (2 x 100 ml), dried in vacuo and purified by flash chromatography to yield 3a in the form of a white solid (1.9 g, 2.8 mmol). Performance 25%. In an alternative method, (3β, 5β, 7a, 12a) -3 - [[(9H-fluoren-9-ylmethoxy) amino] acetyl] amino-7,12-dihydroxycolan-24-oic acid (3b) can be prepared as follows: N-hydroxysuccinimide (1.70 g, 14.77 mmol) and DIC (1.87 g, 14.77 mmol) were added in sequence to a stirred solution of Fmoc-Gly-OH (4.0 g, 13.45 mmol) in dichloromethane ( 15 ml); the resulting mixture was stirred to room temperature for 4 hours. The N, N'-diisopropylurea was removed by filtration and the solid was washed with ether (20 ml). The volatiles were removed and the solid Fmoc-Gly-succinimidylester formed was washed with ether (3 x 20 ml). Subsequently, Fmoc-Gly-succinimidyl ester was dissolved again in dry DMF (15 ml) and 3-aminodeoxycholic acid (5.21 g, 12.78 mmol) was added to the clarified solution. The reaction mixture was stirred at room temperature for 4 hours, water (200 ml) was added and the precipitated solid was filtered, washed with water, dried and purified by silica gel chromatography (TLC (silica): (Rf = 0.50, silica gel, CH2Cl2 / CH3OH, 9: 1) (solvent extraction: CH2Cl2 / CH3OH (9: 1)) to produce (3ß, 5β, 7a, 12a) -3 - [[(9H-fluoren- 9-ylmethoxy) amino] acetyl] amino-7,12-dihydroxycolan-24-oico in the form of a colorless solid Yield: 7.46 g (85%) D. Synthesis of L63 (Nf (3ß.5ß.12a) -3-rfrff4.7.10-tris (carboxymethyl) -1, 4.7.10-tetra-azacyclododecan-1-lamethylamino-1-acetyl] amino-12-hydroxy-24-oxocolan-24-ill-L-qlutaminyl-L-triptophil -L-alanyl-L-valyl-glycyl-L-histidyl-L-leucyl-L-methioninamide) (FIGURE 4B) Resin A (0.5 g, 0.3 mmol) was stirred in a solid phase peptide synthesis container with 50% morpholine in DMA (7 ml) for 10 minutes, the solution was emptied and 50% fresh morpholine in DMA (7 ml) was added.

The suspension was stirred for 20 minutes, then the solution was emptied and the resin was washed with DMA (5 x 7 ml). Resin (3β, 5β, 12a) -3 - [[(9H-fluoren-9-ylmethoxy) amino] acetyl] amino-12-hydroxycolan-24-oico-3a (0.82 g, 1.2 mmol) was added; HOBt (0.18 g, 1.2 mmol) DIC (0.19 ml, 1.2 mmol) and DMA (7 ml), the mixture was stirred for 24 hours at room temperature, the solution was emptied and the resin was washed with DMA (5 x 7 ml ). The resin was then stirred with 50% morpholine in DMA (7 ml) for 10 minutes, the solution was emptied, fresh 50% morpholine in DMA (7 ml) was added and the mixture was stirred for 20 minutes. The solution was emptied and the resin was washed with DMA (5 x 7 ml). To the resin add tri s (1, 1-dimethylethyl) ester adduct of 1,4,4,10-tetra-azacyclododecan-1,4,7,10-tetraacetic acid with NaCl (0.79 g); 1.2 mmol), HOBt (0.18 g, 1.2 mmol), DIC (0.19 mL, 1.2 mmol), DIEA (0.40 mL, 2.4 mmol) and DMA (7 mL). The mixture was stirred for 24 hours at room temperature, the solution was emptied and the resin was washed with DMA (5 x 7 ml), CH 2 Cl 2 (5 x 7 ml) and dried under vacuum. The resin was stirred in a bottle with reagent B (25 ml) for 4 hours. The resin was filtered and the solution was evaporated under reduced pressure to produce an oily crude which after treatment with Et2O (5 ml) produced a precipitate. The precipitate was collected by centrifugation and washed with Et2O (5 x 5 ml), subsequently it was analyzed and purified by HPLC. The fractions containing the product were lyophilized to produce L63 in the form of a white fluffy solid L63 (12.8 mg, 0.0073 mmol). 9% yield. E. Synthesis of L64 (Nr (3ß.5ß.7a.12a) -3-rfrrf4.7.10-tris (carboxymethyl) -1,4,7,10-tetra-azacyclododec-1-yl-1acetiHaminoxacetypamino1-7,12- dihydroxy-24-oxocolan-24-ill-L-alutaminyl-L-tryptopyl-L-alanyl-L-valyl-glycyl-L-histidyl-L-leucyl-L-methioninamide) (FIGURE 4C) The resin was stirred (0.5 g; 0.3 mmol) in a solid phase peptide synthesis container with 50% morpholine in DMA (7 ml) for 10 minutes, the solution was emptied and 50% fresh morpholine in DMA (7 ml) was added. The suspension was stirred for 20 minutes, the solution was emptied and the resin was washed with DMA (5 x 7 ml). To the resin were added (3β, 5β, 7a, 12a) -3 - [[(9H-fluoren-9-ylmethoxy) amino] acetyl] amino-7,12-dihydroxycolan-24-oico 3b (0.81 g; 1.2 mmol), HOBt (0.18 g, 1.2 mmol), DIC (0.19 mL, 1.2 mmol), and DMA (7 mL), the mixture was stirred for 24 hours at room temperature, the solution was emptied and the resin was washed with DMA (5 x 7 ml). The resin was stirred with 50% morpholine in DMA (7 ml) for 10 minutes, the solution was emptied, fresh 50% morpholine in DMA (7 ml) was added and the mixture was stirred for 20 minutes. The solution was emptied and the resin was washed with DMA (5 x 7 ml). HE they added to the resin adduct of tri s (1,1-dimethylethyl) ester of 1, 4,7, 10-tetra-azacyclododecan-1, 4,7, 10-tetraacetic acid with NaCl (0.79 g, 1.2 mmol) , HOBt (0.18 g, 1.2 mmol), DIC (0.19 mL, 1.2 mmol), DIEA (0.40 mL, 2.4 mmol) and DMA (7 mL). The mixture was stirred for 24 hours at room temperature, the solution was emptied and the resin was washed with DMA (5x7 ml), CH2Cl2 (5 x 7 ml), and dried under vacuum. The resin was stirred in a bottle with reagent B (25 ml) for 4 hours. The resin was filtered and the solution was evaporated under reduced pressure to produce an oily crude which was titrated with Et 2 O (5 ml). The precipitate was collected by centrifugation and washed with Et2O (5 x 5 ml). Subsequently, it was dissolved in H2O (20 ml), and Na2CO3 (0.10 g, 0.70 mmol) was added; The resulting mixture was stirred 4 hours at room temperature. This solution was purified by HPLC, fractions containing the product were lyophilized to produce L64 in the form of a white fluffy solid (3.6 mg, 0.0021 mmol). 4% yield. Example V - Figures 5A-E Synthesis of L71 and L72 Summary: The products were obtained in two steps. The first step was octapeptide solid phase synthesis Gln-Trp-Ala-Val-Gly-His-Leu-Met-NH2 (BBN [7-14] [SEQ ID NO: 1]) (with natural chain protection groups suitable) in the Rink amide resin described above. The second step was the coupling with different linkers followed by functionalization with tri-t-butyl ester DOTA. After dissociation and deprotection with reagent B, the final products were purified by preparative HPLC. General returns 3-9%. A. Bombesin Functionalization and Dissociation Procedure, 7-141 (FIGURES 5A AND 5D) Resin B (0.5 g, 0.3 mmol) was stirred in a solid phase peptide synthesis container with 50% morpholine in DMA (7). ml) for 10 minutes, the solution was emptied and 50% fresh morpholine in DMA (7 ml) was added. The suspension was stirred for 20 minutes, then the solution was emptied and the resin was washed with DMA (5 x 7 ml). Fmoc-linker-OH (1.2 mmol), HOBt (0.18 g, 1.2 mmol), DIC (0.19 mL, 1.2 mmol), and DMA (7 mL) were added to the resin. The mixture was stirred for 3 hours at room temperature, the solution was emptied and the resin was washed with DMA (5 x 7 ml). The resin was then stirred with 50% morpholine in DMA (7 ml) for 10 minutes, the solution was emptied, fresh 50% morpholine in DMA (7 ml) was added and the mixture was stirred for 20 minutes. The solution was emptied and the resin was washed with DMA (5 x 7 ml). Tris (1,1-dimethylethyl) 1,4,7,10- acid ester adduct was added to the resin. tetra-aza-cyclododecan-1, 4,7, 10-tetraacetic with NaCl C (0.79 g, 1.2 mmol), HOBt (0.18 g, 1.2 mmol), DIC (0.19 mL, 1.2 mmol), DIEA (0.40 mL) 2.4 mmol) and DMA (7 ml). The mixture was stirred for 24 hours at room temperature. The solution was emptied and the resin was washed with DMA (5 x 7 ml), CH 2 Cl 2 (5 x 7 ml) and dried under vacuum. The resin was stirred in a bottle with reagent B (25 ml) for 4 hours. The resin was filtered and the filtrate was evaporated under reduced pressure to yield an oily crude which was triturated with ether (5 ml). The precipitate was collected by centrifugation and washed with ether (5 x 5 ml), then analyzed by means of Analytical HPLC and purified by preparative HPLC.

The fractions containing the product were lyophilized.

B. Products 1. L71 (4 - [[[[4,7,10-tris (carboxymethyl) -1,4,7,10-tetra-azacyclododec-1-yl] acetyl] amino] methyl] benzoyl-L- glutaminyl-L-tryptopyl-L-alanyl-L-valyl-glycyl-L-histidyl-L-leucyl-L-methioninamide) The product was obtained in the form of a white fluffy solid (7.3 mg, 0.05 mmol). Production 7.5%. 2. L72 (trans-4 - [[[[4,7,10-tris (carboxymethyl) -1,4,7,10-tetra-azacyclododec-1-yl] acetyl] amino] methyl] cyclohexylcarbonyl-L-glutamine LL-tryptopyl-L-alanyl-L-valyl-glycyl-L-histidyl-L-leucyl-L- methioninamide). The product was obtained in the form of a white fluffy solid (7.0 mg, 0.005 mmol). Performance 4.8%. C. Trans-4-rrí (9H-fluoren-9-ylmethoxy) carbonillaminolmethyl 1-cyclohexanecarboxylic acid, (D) (FIGURE 5E) A solution of N- (9-fluorenylmethoxycarbonyloxy) succinimide (4.4 g, 14.0 mmol) in 1,4-dioxane (40 ml) was added dropwise to a solution of trans-4- (aminomethyl) cyclohexanecarboxylic acid (2.0 g, 12.7 mmol) in % Na2CO3 (30 ml) cooled to a temperature of 0 ° C.

Subsequently the mixture was allowed to warm to room temperature and after 1 hour stirring at room temperature, it was treated with 1N HCl (32 ml) until the final pH was 2. The resulting solution was extracted with n-BuOH (100 ml); the volatiles were removed and the crude residue was purified by flash chromatography to produce D, in the form of a solid (1.6 g, 4.2 mmol). Performance 33%. Example VI - Figures 6A-F Synthesis of L75 and L76 Summary: the two products were obtained by coupling the octapeptide Gln-Trp-Aia-Val-Gly-His-Leu-Met-NH2 (BBN [7-14] [SEQ ID NO: 1]) (A) in the resin of Rink amide with the two linkers E and H, followed by functionalization with tri-t-butyl ester DOTA. After dissociation and deprotection with reagent B, the final products were purified by preparative HPLC. Overall returns: 8.5% (L75) and 5.6% (L76). A. 2-f acid (1,3-dydro-1,3-dioxo-2H-isoindol-2-dimethylbenzoic acid. (C) (FIGURE 6A) The product was synthesized following the procedure reported in the literature (Bornstein, J; Drummon, PE; Bedell, SF Org. Synth., Coll. Vol. IV, 1963, 810-812) B. 2- (aminomethyl) benzoic acid (D) (FIG. 6A) A 40% solution of methylamine was added ( 6.14 ml, 7.1 mmol) to 2 - [(1,3-d ih idro- 1, 3-dioxo-2H-isoindol-2-yl) methyl] benzoic acid C (2 g, 7.1 mmol) and subsequently EtOH was added. (30 ml) After 5 minutes stirring at room temperature, the reaction mixture was heated to a temperature of 50 ° C. After 2.5 hours, the mixture was cooled and the solvent was evaporated under reduced pressure. suspended in 50 ml of absolute ethanol and the suspension was stirred at room temperature for 1 hour.The solid was filtered and washed with EtOH to yield 2- (aminomethyl) benzoic acid (0.87 g, 5.8 mmol) Yield 81%. Acid 2-riT9H-fluoren-9- lmetoxi) carbon¡l] amino1metillbenzoico, (E) (FIGURE 6A) The product was synthesized following the procedure reported in the literature 8Sun, J-H .; Deneker, W. F. Synth. Commun. 1998, 28, 4525-4530). D. 4- (Aminomethyl) -3-nitrobenzoic acid (G) (FIGURE 6B) 4- (Bromomethyl) -3-nltrobenzoic acid (3.2 g, 12.3 mmol) was dissolved in 8% NH3 in EtOH (300 mL) and The resulting solution was stirred at room temperature. After 22 hours the solution was evaporated and the residue was suspended in H2O (70 ml). The suspension was stirred for 15 minutes and filtered. The collected solid was suspended in H2O (40 ml) and dissolved by the addition of a few drops of 25% aqueous NH4OH (pH 12), the pH of the solution was subsequently adjusted to 6 by the addition of 6 N HCl. The precipitated solid was filtered, and washed in sequences with MeOH (3 x 5 ml), and Et2O (10 ml) and dried under vacuum (1.3 kPa); P2O5) to produce 4- (aminomethyl) -3-nitrobenzoic acid in the form of a pale brown solid (1.65 g, 8.4 mmol). Performance 68%. E. 4-rrr9H-Fluoren-9-ylmethoxy) carbonyl-amino-1-methyl-3-nitrobenzoic acid, 8H) (FIGURE 6Bi 4-8-Aminomethyl) -3-nitrobenzoic acid G (0.8 g, 4 mmol) was dissolved in 10% aqueous Na2CO3 825 ml) and 1,4-dioxane (10 ml) and the solution was cooled to a temperature of 0 ° C. A solution of 9-fluorenylmethyl chloroformate (Fmoc-CI) (1.06 g, 4 mmol) in 1,4-dioxane (10 ml) was added dropwise over 20 minutes. After 2 hours at a temperature of 0 to 5 ° C and 1 hour at a temperature of 10 ° C, the reaction mixture was filtered and the solution acidified to a pH of 5 by the addition of 1N HCl. The precipitate was filtered, washed with H2O (2 x 2 ml), dried under vacuum (1.3 kPa, P2O5) to yield 4 - [[[9H-fluoren-9-ylmethoxy) carbonyl] amino] methyl] -3 acid. -nitrobenzoic acid in the form of a white solid (1.6 g, 3.7 mmol). Yield 92%. F. L75 (N-f2-rrfí4, 7,1 O-tris (carboxymethyl) - 1.4.7.1 O-tetraazacyclododec-1-ipacetyl-amino-1-methyl-1-benzoyl-1-L-glutaminyl-L-triptophoyl-L-alanyl-L-valyl-glycyl-L -histidyl-L-leucyl-L-methioninamide) (FIGURE 6C) Resin A (0.5 g, 0.3 mmol) was stirred in a solid phase peptide synthesis container with 50% morpholine in DMA (7 ml) for 10 minutes. minutes, the solution was emptied and fresh 50% morpholine in DMA (7 ml) was added. The suspension was stirred for 20 minutes, then it was drained and the resin was washed with DMA (5 x 7 ml). 2 - [[[9H-Fluoren-9-ylmethoxy) carbonyl] amino] methyl] benzoic acid, E (0.45 g, 1.2 mmol), N-hydroxybenzotriazole (HOBt) (0.18 g, 1.2 mmol) was added to the resin, N, N'-diisopropylcarbodie (DIC) (0.19 ml, 1.2 mmol) and DMA (7 ml), the mixture was stirred for 24 hours at room temperature, the solution was emptied and the resin was washed with DMA (7 ml). The resin was subsequently stirred with 50% morpholine in DMA (7 ml) for 10 minutes, the solution was emptied, fresh morpholine 50% in DMA (7 ml) was added and the mixture was stirred for 20 minutes. The solution was emptied and the resin was washed with DMA (5 x 7 ml). Tris (1,1-dimethylethyl) ester adduct of 1, 4,7, 10-tetra-azacyclododecan-1, 4,7,10-tetraacetic acid adduct was added to the resin with NaCl (tri-t-butyl ester) DOTA) (0.79 g, 1.2 mmol), HOBt (0.18 g, 1.2 mmol), DIC (0.19 mL, 1.2 mmol), DIEA (0.40 mL, 2.4 mmol), and DMA (7 mL). The mixture was stirred for 24 hours at room temperature, the solution was emptied and the resin was washed with DMA (5 x 7 ml), CH 2 Cl 2 (5 x 7 ml) and dried under vacuum. The resin was stirred in a flask with reagent B (25 ml) for 4.5 hours. The resin was filtered and the filtrate was evaporated under reduced pressure to produce an oily crude which after treatment with Et2O (20 ml) produced a precipitate. The resulting precipitate was collected by centrifugation and washed with Et2O (3 x 20 ml) to yield L75 (190 mg, 0.13 mmol) in the form of a white solid. Performance 44%. G. L76 (N-r4-rrrr4.7.10-trisf carboxy methi h- 1.4.7.10-tetra-azacyclododec-1-yl1acetylHamino-1-methyl-3-nitrobenzoic-L-q-glutaminyl-L-triptophoyl-L-alanyl-L-iallyl -alicil-L-histidyl-L- leucyl-L-methioninamide) (FIGURE 6D) Resin A (0.5 g, 0.3 mmol) was stirred in a solid phase peptide synthesis container with 50% morpholine in DMA (7 ml) for 10 minutes, the solution empty and 50% fresh morpholine in DMA (7 ml) was added. The suspension was stirred for 20 minutes, then it was drained and the resin was washed with DMA (5 x 7 ml). 4 - [[[9H-Fluoren-9-ylmethoxy) carbonyl] amino] methyl] -3-nitrobenzoic acid, H (0.50 g, 1.2 mmol), HOBt (0.18 g, 1.2 mmol), DIC ( 0.19 ml, 1.2 mmol) and DMA (7 ml), the mixture was stirred for 24 hours at room temperature, the solution was emptied and the resin was washed with DMA (5 x 7 ml). The resin was then stirred with 50% morpholine in DMA (7 ml) for 10 minutes, the solution was emptied, fresh 50% morpholine in DMA (7 ml) was added and the mixture was stirred for 20 minutes. The solution was emptied and the resin was washed with DMA (5 x 7 ml). DOTA tri-t-butyl ester (0.79 g, 1.2 mmol), HOBt (0.18 g, 1.2 mmol), DIC (0.19 mL, 1.2 mmol), DIEA (0.40 mL, 2.4 mmol), and DMA were added to the resin. 7 ml). The mixture was stirred for 24 hours at room temperature, the solution was emptied and the resin was washed with DMA (5 x 7 ml), CH 2 Cl 2 (5 x 7 ml) and dried under vacuum. The resin was stirred in a flask with reagent B (25 ml) for 4.5 hours. The resin was filtered and the solution was evaporated under reduced pressure to produce a Oily crude that was titrated with Et2O (20 ml). The precipitate was collected by centrifugation and washed with Et2O (3 x 20 ml) to yield a solid (141 mg) which was analyzed by HPLC. A 37 mg portion of the crude was purified by preparative HPLC. The fractions containing the product were lyophilized to yield L76 (10.8 mg, 7.2 x 10"3 mmol) in the form of a white solid, Yield 9%, Example VII - Figures 7A-C Synthesis of L124 Summary: Reacted 4-cyanophenol A with ethyl bromoacetate and K2CO3 in acetone to produce an intermediate B, which was hydrolyzed with NaOH to the corresponding acid C. Successive hydrogenation of C with H2 and PtO2 at 355 kPa in EtOH / CHCl3 produced the corresponding amino acid D , which was directly protected with FmocOSu to produce E. The functionalized Rink amide resin was reacted with the octapeptide Gln-Trp-Ala-Val-Gly-His-Leu-Met-NH2 (BBN [7-14] [SEQ ID NO: 1]) with E and subsequently with tri-t-butyl ester DOTA After dissociation and deprotection with reagent B, the crude was purified by HPLC preparation to produce L124. Overall yield: 1.3% A. Synthesis of ethyl (4-cyanophenoxy) acetic acid ester (B) (FIGURE 7A) The product was synthesized after the procedure reported in the literature (Archimbault, P., LeClerc, G., Strosberg, A.D., Pietri-Rouxel, F. PCT International Application WO 980005, 1998). B. Synthesis of (4-cyanophenoxy) acetic acid (C) (FIGURE 7A) A 1N solution of NaOH (7.6 mL, 7.6 mmol) was added dropwise to a solution of (4-cyano-phenoxy) -acetic acid ethyl ester B (1.55 g, 7.6 mmol) in MeOH (15 mL) . After 1 hour, the solution was acidified with 1N HCl (7.6 ml, 7.6 mmol) and evaporated. The residue was taken with water (20 ml) and extracted with CHCl3 (2 x 30 ml). The organic phases were evaporated and the crude was purified by flash chromatography to yield (4-cyanophenoxy) acetic acid C (0.97 g, 5.5 mmol) in the form of a white solid. Performance 72%. C. Synthesis of r4-frr9H-Fluoren-9-lmetoxy) -carmoylamino-methyl-phenoxylacetic acid (E) (FIGURE Z? 1 PtO2 (150 mg) was added to a solution of (4-cyanophenoxy) acetic acid C (1.05 g, 5.9 mmol) in EtOH (147 mL) and CHCl3 (3 mL). The suspension was stirred for 30 hours under a hydrogen atmosphere (355 kPa, 20 ° C). The mixture was filtered through a pad of Celite® and the solution was evaporated under vacuum. The residue was purified by instant chromatography to produce acid D (0.7 g) which was dissolved in H2O (10 ml), MeCN (2 ml) and Et3N (0.6 ml) at a temperature of 0 ° C, then a solution was added as drops of N- (9-fluorenylmethoxycarbonyloxy) succinimide (1.3 g, 3.9 mmol) in MeCN (22 ml). After stirring 16 hours at room temperature, the reaction mixture was filtered and the volatiles were removed under vacuum. The residues were treated with 1N HCf (10 ml) and the precipitated solid was filtered and purified by flash chromatography to yield [4 - [[[9H-fIuoren-9-ylmethoxy) carbonyl] amino] methyl] phenoxy] acetic acid. (0.56 g, 1.4 mmol) in the form of a white solid. Overall performance 24%. D. Synthesis of L124 (N-R4-frir4.7.10-tris (carboxymethyl) -1.4,7.10-tetra-azacyclodode c-1-yl-acetyl-amino] meth1-phenoxylacetyl-L-q-glutaminyl-L-triptophyl- L-alanyl-L-valyl-glycyl-L-histidyl-L-leucyl-L-methioninamide) (FIGURE 7B) Resin A (480 mg, 0.29 mmol) was stirred in a solid phase peptide synthesis package with morpholine 50% in DMA (7 ml) for 10 minutes, the solution was emptied and 50% fresh morpholine in DMA (7 ml) was added. The suspension was stirred for 20 minutes, the solution was emptied and the resin was washed with DMA (5 x 7 ml). They were added to the resin [4 - [[[9H-fluoren-9- ilmethoxy) carbonyl] amino] methyl] phenoxy] acetic E (480 mg, 1.19 mmol), N-hydroxybenzotriazole (HOBt) (182 mg, 1.19 mmol), N. N'-diisopropylcarbodiimide (DIC) (185 μl, 1.19 mmol) and DMA (7ml), the mixture was stirred for 24 hours at room temperature, the solution was emptied and the resin was washed with DMA (5 x 7 ml). The resin was subsequently stirred with 50% morpholine in DMA (6 ml) for 10 minutes, the solution was emptied, fresh 50% morpholine in DMA (6 ml) was added and the mixture was stirred for 20 minutes. The solution was emptied and the resin was washed with DMA (5 x 7 ml). To the resin add tri-1- (1-dimethylethyl) ester adduct of 1, 4,7, 10-tetra-azacyclododecan-1, 4,7,10-tetraacetic acid with NaCl (750 mg; 1.19 mmol), HOBt (182 mg, 1.19 mmol), DIEA (404 μL, 2.36 mmol), DIC (185 μL, 1.19 mmol) and DMA (6 mL). The mixture was stirred for 24 hours at room temperature, the solution was emptied, the resin was washed with DMA (2 x 7 ml), CH 2 Cl 2 (5 x 7 ml) and dried under vacuum. The resin was stirred in a bottle with reagent B (25 ml) for 4 hours. The resin was filtered and the filtrate was evaporated under reduced pressure to yield an oily crude which was triturated with Et2O (5 ml). The precipitate was collected by centrifugation and washed with Et2O (5 x 5 ml) to yield a solid (148 mg) which was analyzed by HPLC. A 65 mg portion of the crude was purified by preparative HPLC. The fractions that containing the product were lyophilized to produce L124 (FIGURE 7C) in the form of a white solid (15 mg, 0.01 mmol). Performance 7.9%. Example VIII - Figures 8A-C Synthesis of L125 Summary: 4- (Bromomethyl) -3-methoxybenzoic acid methyl ester was reacted with NaN3 in DMF to produce intermediate azide B, which was subsequently reduced with Ph3P and H2O to amine C. Hydrolysis of C with NaOH produced acid D, which was directly protected with FmocOsu to produce E. The functionalized Rink amide resin was reacted with the octapeptic Gln-Trp-Ala-Val-Gly-His- Leu-Met-NH2 (BBN [7-14] [SEQ ID NO: 1] (A) with E and subsequently with tri-t-butyl ester DOTA After dissociation and deprotection with reagent B, the crude was purified by Preparation HPLC to produce L125.General yield: 0.2% A. Synthesis of 4- (azidomethyl) -3-methoxybenzoic acid methyl ester (B) (FIGURE 8A) An ester solution was stirred overnight at room temperature. 4- (Bromomethyl) -3-methoxybenzoic acid methyl ester (8 g, 31 mmol) and NaN 3 (2 g, 31 mmol) in DMF (90 mL). Volatiles were removed under vacuum and the crude product was dissolved in EtOAc (50 mL). The solution was washed with water (2 x 50 ml) and dried. The volatiles are evaporated to yield 4- (azidomethyl) -3-methoxybenzoic acid methyl ester (6.68 g, 30 mmol). Performance 97%. B. 4- (Aminomethyl) -3-methoxybenzoic acid methyl ester. (C) (FIGURE 8A) Triphenylphosphine (6.06 g, 23 mmol) was added to a solution of (4-azidomethyl) -3-methoxybenzoic acid methyl ester (5 g, 22 mmol) in THF (50 mL): observed evolution of hydrogen and formation of a white solid. The mixture was stirred under nitrogen at room temperature. After 24 hours more triphenylphosphine (0.6 g, 2.3 mmol) was added. After 24 hours the azide was consumed and H2O (10 ml) was added. After 4 hours the white solid disappeared. The mixture was heated to a temperature of 45 ° C for 3 hours and stirred overnight at room temperature. The solution was evaporated to dryness and the crude was purified by flash chromatography to yield 4- (aminomethyl) -3-methoxy-benzoic acid methyl ester (1.2 g, 6.1 mmol). Performance 28%. C. 4-rrr9H-Fluoren-9-ylmethoxy) carbonyl-amino] methyl-3-methoxybenzoic acid. J X (FIGURE 8A) A 1N solution of NaOH (6.15 ml, 6.14 mmol) was added dropwise to a solution of methyl ester of NaOH. 4- (Aminomethyl) -3-methoxybenzoic acid C (1.2 g; 6.14 mmol) in MeOH (25 mL) heated to a temperature of 40 ° C. After stirring 8 hours at a temperature of 45 ° C, the solution was stirred overnight at room temperature. A 1N NaOH solution (0.6 ml, 0.6 mmol) was added and the mixture was heated to a temperature of 40 ° C for 4 hours. The solution was concentrated, acidified with 1N HCl (8 ml, 8 mmol), extracted with EtOAc (2 x 10 ml), then the aqueous layer was concentrated to 15 ml. This solution (pH 4.5) was cooled to a temperature of 0 ° C and Et3N (936 μL, 6.75 mmol) was added and added (pH 11). A solution of N- (9-fluorenylmethoxycarbonyloxy) succinimide (3.04 g, 9 mmol) in MeCN (30 ml) was added dropwise (final pH 9) and a white solid precipitated. After stirring 1 hour at room temperature, the solid was filtered, suspended in 1N HCl (15 ml) and the suspension was stirred for 30 minutes. The solid was filtered to give 4 - [[[9H-fluoren-9-ylmethoxy) carbonyl] amino] methyl] -3-methoxybenzoic acid E in the form of a white solid (275 mg, 0.7 mmol). The filtrate was evaporated under vacuum and the resulting white residue was suspended in 1N HCl (20 ml) and stirred for 30 minutes. The solid was filtered and purified by flash chromatography to yield more acid E (198 mg, 0.5 mmol). Overall performance 20%.

D. L125 (N-G4-GGGG4.7.10-tris (carboxymethyl-1,4,7,10-tetra-azacyclododec-1-yl-acetylamino-1-methyl-3-methoxybenzoyl-L-glutaminyl-L-triptophyl-L-alanyl-L-valyl) glycyl-L-histidyl-L-leucyl-L-methioninamide) (FIGURE 8B) Resin A (410 mg) was stirred; 0.24 mmol) in a solid phase peptide synthesis pack with 50% morpholine in DMA (7 ml) for 10 minutes, the solution was emptied and 50% fresh morpholine in DMA (7 ml) was added. The suspension was stirred for 20 minutes, then the solution was emptied and the resin was washed with DMA (5 x 7 ml). 4 - [[[9H-Fluoren-9-ylmethoxy) carbonyl] amino] methyl] -3-methoxybenzoic acid (398 mg, 0.98 mmol), HOBt (151 mg, 0.98 mmol), DIC (154) were added to the resin. μl; 0.98 mmol) and DMA (6 ml); the mixture was stirred for 24 hours at room temperature, the solution was emptied and the resin was washed with DMA (5 x 7 ml). The resin was subsequently stirred with 50% morpholine in DMA (6 ml) for 10 minutes, the solution was emptied, fresh 50% morpholine in DMA (6 ml) was added and the mixture was stirred for 20 minutes. The solution was emptied and the resin was washed with DMA (5 x 7 ml). Tris (1,1-dimethyl ethyl) ester adduct of 1,4,4,10-tetra-azacyclododecan-1, 4,7, 10-tetraacetic acid adduct was added to the resin with NaCl (618 mg, 0.98 mmol) , HOBt (151 mg, 0.98 mmol), DIC (154 μL, 0.98 mmol), DIEA (333 μL, 1.96 mmol) and DMA (6 mL). The mixture was stirred for 24 hours at At room temperature, the solution was emptied and the resin was washed with DMA (5 x 7 ml), CH 2 Cl 2 85 x 7 ml) and dried under vacuum. The resin was stirred in a bottle with reagent B (25 ml) for 4 hours. The resin was filtered and the solution was evaporated under reduced pressure to produce an oily crude which was triturated with Et2O (5 mL). The resulting precipitate was collected by centrifugation, washed with Et2O (5 x 5 ml), analyzed by HPLC and purified by preparative HPLC. The fractions containing the product were lyophilized to produce L125 (FIGURE 8C) in the form of a white solid (15.8 mg, 0.011 mmol). Performance 4.4%. Example IX - Figures 9A-9D Synthesis of L146, L233, L234, and L235 Summary: the products were obtained in several steps beginning from the octapeptide Gln-Trp-Ala-Val-Gly-His-Leu-Met-NH2 (BBN [7-14]) (A) in the Rínk amide resin. After dissociation and final deprotection with reagent B, the products were purified by preparative HPLC to produce L146, L233, L234 and L235. General returns: 10%, 11%, 4.5%, 5.7% respectively. A. 3-lTr Acid (9H-Fluoren-9-ylmethoxycarbonylaminolacethylaminobenzoic acid B (FIGURE 9Aj_ A solution of 3-aminobenzoic acid (0.5 g, 3.8 mmol) and N-ethyldiisopropylamine (DIEA) (0.64 ml, 3.8 mmol) in THF (20 ml) was added dropwise to a solution of Fmoc-glycine chloride ( 1.2 g, 4.0 mmol) (3) in THF (10 ml) and CH2Cl2 (10 ml). After stirring for 24 hours at room temperature, 1M HCl (50 ml) was added (final pH: 1.5). The precipitate was filtered, washed with H2O (2 x 100 ml), dried in vacuo and crystallized from CHCl3 / CH3OH (1: 1) to produce B in the form of a white solid (0.7 g, 1.6 mmol). Performance 43%. B. N- [3 - [[[[[4,7,10-Tris (carboxymethyl) -1,4,7,10-tetraazacyclododec-1-yl] acetyl] amino] acetyl] amino] benzoyl] -L- glutaminyl-L-tryptopyl-L-alanyl-L-valyl-glycyl-L-histidyl-L-leucyl-L-methioninamide, L233 (Figure 9D) Resin A (0.5 g, 0.3 mmol) was stirred in the synthesis container of solid phase peptide with 50% morpholine in DMA (7 mL) for 10 minutes, the solution was emptied and fresh 50% morpholine in DMA (7 mL) was added. The suspension was stirred for another 20 minutes, then the solution was emptied and the resin was washed with DMA (5 x 7 mL). 3 - [[9H-Fluorophen-9-ylmethoxy) carbonyl] amino] acetyl] aminobenzoic acid B (0.50 g, 1.2 mmol), HOBt (0.18 g, 1.2 mmol) DIC (0.19 mL, 1.2) was added to the resin. mmol) and DMA (7 mL), the mixture was stirred for 6 hours at room temperature, and the solution was emptied and the resin washed with DMA (5x7 mL). Subsequently the resin was stirred with 50% morpholine in DMA (7 mL) for 10 minutes, the solution was emptied, fresh 50% morpholine in DMA (7 mL) was added and the mixture was stirred for another 20 minutes. The solution was emptied and the resin was washed with DMA (5x7 mL). Adsorbent of tri-t-butyl ester DOTA with NaCl2 (0.79 g, 1.2 mmol) (5), HOBt (0.18 g, 1.2 mmol), DIC (0.19 mL: 1.2 mmol), DIEA (0.40 mL; 2.4 mmol) and DMA (7 mL) to the resin. The mixture was stirred for 24 hours at room temperature, the solution was emptied and the resin was washed with DMA (5x7 mL), CH2Cl2 (5x7 mL) and dried under vacuum. The resin was stirred in a flask with Reagent B (25 mL) for 4.5 hours. The resin was filtered and the solution was evaporated under reduced pressure to produce an oily crude which after treatment with Et2O (20 mL) produced a precipitate. The precipitate was collected by centrifugation and washed with Et2O (3x20 mL), to yield a solid (152 mg) which was analyzed by HPLC. Purified an amount of crude (50 mg) was purified by preparative HPLC. The fractions containing the product were lyophilized to yield L233 (17.0 mg, 11.3 x 10"3 mmol) in the form of a white solid, Yield 11% C. N- [4 - [[[[[4, 7, 10-Tris (carboxy methyl) -1,4, 7,10-tetraazacyclododec-1-yl] acetyl] amino] acetyl] amino] phenylacetyl] - L-glutaminyl-L-tryptopyl-L-alanyl-L-valyl-glycyl-L-histidyl-L-leucyl-L-methioninamide, L146 (FIG.9D) Resin A (0.5 g) was stirred; 0.3 mmol) in a solid phase peptide synthesis container with 50% morpholine in DMA (7 mL) for 10 minutes, the solution was filtered and 50% fresh morpholine in DMA (7 mL) was added. The suspension was stirred for another 20 minutes, then the solution was filtered and the resin was washed with DMA (5 x 7 mL). Fmoc-4-aminophenylacetic acid (0.45 g, 1.2 mmol), HOBt (0.18 g, 1.2 mmol), DIC (0.19 mL, 1.2 mmol) and DMA (7 mL) were added to the resin, the mixture was stirred for 6 hours. Room temperature was filtered and the resin was washed with DMA (5x7 mL). The resin was then stirred with 50% morpholine in DMA (7 mL) for 10 minutes, the solution was filtered, fresh 50% morpholine in DMA (7 mL) was added and the mixture was stirred for another 20 minutes. The solution was filtered and the resin was washed with DMA (5x7 mL). Fmoc-glycine (0.36 g, 1.2 mmol), HATU (0.46 g, 1.2 mmol) and DIEA (0.40 mL, 2.4 mmol) were stirred for 15 minutes in DMA (7 mL), then the solution was added to the resin. , the mixture was stirred for 2 hours at room temperature, filtered and the resin was washed with DMA (5x7 mL). Subsequently, the resin was stirred with 50% morpholine in DMA (7 mL) for 10 minutes, the solution was filtered, 50% fresh morpholine was added DMA (7 mL) and the mixture was stirred for another 20 minutes. The solution was filtered and the resin was washed with DMA (5x7 mL). DOTA tri-t-butyl adductor ester with NaCl (0.79 g, 1.2 mmol), HOBt (0.18 g, 1.2 mmol), DIC (0.19 mL, 1.2 mmoi), DIEA (0.40 mL, 2.4 mmol) were added to the resin. and DMA (7 mL). The mixture was stirred for 24 hours at room temperature, filtered and the resin was washed with DMA (5x7 mL), CH2Cl2 (5x7 mL) and dried under vacuum. The resin was stirred in a flask with Reagent B (25 mL) for 4.5 hours. The resin was filtered and the solution was evaporated under reduced pressure to produce an oily crude which after treatment with Et2O (20 mL) produced a precipitate. The precipitate was collected by centrifugation and washed with Et2O (3x20 mL), to yield a solid (203 mg) which was analyzed by HPLC. A quantity of crude (50 mg) was purified by preparative HPLC. The fractions containing the product were lyophilized to yield L146 (11.2 mg, 7.4 x 10-3) in the form of a white solid. 10% yield. D. 6 - [[[(9H-Fluoren-9-ylmethoxy) carbonyl] amino] acetyl] aminonaphthoic acid, C (Fig. 9B) 6-Aminonaphthoic acid (500 mg, 2.41 mmol) was added dropwise.; and DIEA (410 μL 2.41 mmol) in THF (20 mL) to a solution of Fmoc-glycine chloride (760 mg, 2.41 mmol) in CH2Cl2 / THF 1: 1 (10 mL) and stirred at room temperature. After 24 hours the solvent was evaporated under vacuum. The residue was stirred with 0.5 N HCl (50 mL) and stirred for 1 hour. The precipitate was filtered and dried. The white solid was suspended in methanol, and boiled for 5 minutes, then filtered to yield product C (690 mg, 1.48 mmol). Performance 62%. E. N- [6 - [[[[[4,7,10-Tris (carboxymethyl) -1,4,7,10-tetraazacyclododec-1-yl] acetyl] amino] Acetyl] amino] naphthoyl] -L- glutaminyl-L-tryptopyl-L-alanyl-L-valyl-glycyl-L-histidyl-L-leucyl-L-methioninamide, L234 Resin A (500 mg, 0.3 mmol) was stirred in a peptide synthesis package with morpholine 50% in DMA (7 mL) for 10 minutes, the solution was emptied and 50% fresh morpholine in DMA (7 mL) was added. The suspension was stirred for another 20 minutes, then the solution was emptied and the resin was washed with DMA (5x7 mL). 6 - [[(9H-Fluoren-9-ylmethoxy) carbonyl] amino] acetyl] aminonaphthoic acid C (560 mg, 1.2 mmol), HOBt (184 mg, 1.2 mmol), DIC (187 μL; 1.2 mmol) and DMA (7 mL), the mixture was stirred for 6 hours at room temperature, evacuated and the resin was washed with DMA (5x7 mL). The resin was then stirred with 50% morpholine in DMA (6 L) for 10 minutes, the solution was emptied, fresh 50% morpholine in DMA (7 mL) was added and the mixture was stirred for another 20 minutes. The solution was emptied and the resin was washed with DMA (5x7 mL). Adsorbent of tri-t-butyl ester DOTA with NaCl (757 mg, 1.2 mmol), HOBt (184 mg, 1.2 mmol), DIC (187 μL, 1.2 mmol), and DIEA (537 μL, 2.4 mmol) were added. ) and DMA (7 mL). The mixture was stirred in an empty flask and the resin was washed with DMA (2x7 mL), CH2Cl2 (5x7 mL). The resin was stirred in a flask with Reagent B (25 mL) for 4.5 hours. The resin was filtered and the solution was evaporated under reduced pressure to produce an oily crude which after treatment with Et2O (20 mL) produced a precipitate. The precipitate was collected by centrifugation and washed with Et2O (3x20 mL) to yield a solid (144 mg) which was analyzed by HPLC. A quantity of crude (54 mg) was purified by preparative HPLC. The fractions containing the product were lyophilized to produce L234 (8 mg, 5.1 x 10"3 mmol) in the form of a white solid, yield 4.5% F. 4 - [[[[(9H-Fluoren-9- ilmethoxy) carbonyl] amino] acetyl] methylamino] benzoic, D (Fig.9Ci) A solution of 4-N-methylaminonaphthoic acid (500 mg, 3.3 mmol) and DIEA (562 μL 3.3 mmol) in THF (20 mL) was added to a solution of Fmoc-glycine chloride (1.04 g; mmol) in CH2Cl2 / THF 1: 1 (10 mL) and stirred at room temperature. After 24 hours, the solvent was evaporated under vacuum. The residue was taken with 0.5 N HCl (30 mL) and stirred for 3 hours at a temperature of 0 ° C. The precipitated white solid was filtered and dried. The crude was purified by flash chromatography to yield Compound D (350 mg, 0.81 mmol). Performance 25%. F. N- [4 - [[[[[4,7,10-Tris (carboxymethyl) -1,4,7,10-tetraazacyclododec-1-yl] acetyl] amino] acetyl] methylamino] benzoyl] - L-glutaminyl-L-tryptopyl-L-alanyl-L-valyl-glycyl-L-histidyl-L-leucyl-L-methioninamide. L235 (Fig. 9D) G. Resin A (500 mg.; 0.3 mmol) in a solid phase peptide synthesis container with 50% morpholine in DMA (7 mL) for 10 minutes, the solution was emptied and 50% fresh morpholine in DMA (7 mL) was added. The suspension was stirred for another 20 minutes, then it was evacuated and the resin was washed with DMA (5x7 mL). 4 - [[[[9H-Fluoren-9-ylmethoxy) carbonyl] amino] acetyl] -N-methyl] amino-benzoic acid D was added to the resin. (510 mg, 1.2 mmol), HOBt (184 mg, 1.2 mmol), DIC (187 μL, 1.2 mmol) and DMA (7 mL), the mixture was stirred for 6 hours at room temperature, vacuum and the resin was washed with DMA (5x7 mL). The resin was subsequently stirred with 50% morpholine in DMA (7 mL) for 10 minutes, the Solution was emptied, fresh 50% morpholine in DMA (7 mL) was added and the mixture was stirred for another 20 minutes. The solution was emptied and the resin was washed with DMA (5x7 mL). DOTA tri-t-butyl ester adductor resin was added with NaCl (757 mg, 1.2 mmol), HOBt (184 mg, 1.2 mmol), DIC (187 μL, 1.2 mmol), and DIEA (537 μL, 2.4 mmol). ) and DMA (7 mL). The mixture was stirred in an empty flask and the resin was washed with DMA (2x7 Ml); CH2Cl2 (5x7 mL) and dried in vacuo. The resin was stirred in a flask with Reagent B (25 mL) for 4.5 hours. The resin was filtered and the solution was evaporated under reduced pressure to produce an oily crude which after treatment with Et2O (20 mL) produced a precipitate. The precipitate was collected by centrifugation and collected by centrifugation and washed with Et2O (3x20 mL) to yield a solid (126 mg) which was analyzed by HPLC. A quantity of crude (53 mg) was purified by preparative HPLC. The fractions containing the product were lyophilized to yield L235 (11 mg, 7.2 x 10"3 mmol) in the form of a white solid, Yield 5.7% EXAMPLES - Figures 10A-B Synthesis of L237 Summary: Protected selectively 1-Formyl-1, 4,7, 10-tetraazacyclododecane (A) with chloroformate benzyl at a pH of 3 to produce B, which was alkylated with t-butyl bromoacetate and deformed with hydroxylamine hydrochloride to produce D. Reaction with P (OtBu) 3 and paraformaldehyde produced E, which was deprotected by hydrogenation and it was alkylated with benzyl bromoacetate to produce G, which is finally hydrogen to obtain H. The Rink amide resin functionalized with the octapeptide Gln-Trp-Ala-Val-Gly-His-Leu-Met-NH2 (BBN [7-14]) (A) was reacted in sequences with Fmoc-4-aminobenzoic acid, Fmoc-glycine and H. After dissociation and deprotection with Reagent B, the crude was purified by preparative HPLC. produce L237. Overall performance 0.21%. A. 7-Formyl-1,4,7,10-tetraazacyclododecane-1-carboxylic acid phenylmethyl ester dichloride. B (Fig. 10A) 1-Formyl-1,4,7,10-tetraazacyclododecane A (14 g, 69.9 mmol) was dissolved in H 2 O (100 mL) and 12 N HCl (11 mL) was added to a pH of 3, then 1,4-dioxane (220 mL) was added. A solution of benzyl chloroformate (13.8 g, 77 mmol) in 1,4-dioxane (15 mL) in 3.5 hours was slowly added dropwise, keeping the reaction mixture constant at a pH of 3 by continuous addition of 2N NaOH (68.4 mL) with a pHstat apparatus. At the end of the addition, the reaction was stirred for 1 hour, then washed with n-hexane (4x100 mL) and 'Pr2O (4x100 mL). The aqueous phase was brought to a pH of 13 by the addition of 10N NaOH (6.1 mL) and extracted with CHCl3 (4x100 mL). The organic phase was washed with brine (100 mL), dried (Na2SO), filtered and evaporated. The oily residue was dissolved in acetone (200 mL) and 6N HCl (26 mL) was added. The precipitated solid was filtered, washed with acetone (2x50 mL) and dried under vacuum to yield compound B (23.6 g, 58 mmol) in the form of a white crystalline solid. Performance 83%. B. 4- (Phenylmethoxy) carbonyl-1,4,7,10-tetraazacyclododecane-1,7-diacetic acid bis (1,1-dimethylethyl) ester. D (Ph. 10A) A solution of B (14.4 g, 35.3 mmol) in H 2 O (450 mL) and 1N NaOH (74 L, 74 mmol) was stirred for 20 minutes, then extracted with CHCl 3 (4 × 200 mL). The organic layer was evaporated to obtain an oily residue (12.3 g) which was dissolved in CH3CN (180 mL) and N-ethyldiisopropylamine (DIEA) (15 mL, 88.25 mmol). A solution of t-butyl bromoacetate (16.8 g, 86.1 mmol) in CH3CN (15 mL) was added dropwise to the previous solution in 2.5 hours. After 20 hours at room temperature the solvent was evaporated and the oily residue was dissolved in CHCl3 (150 mL) and washed with H2O (5x100 mL). The organic layer was dried (Na2SO), filtered and evaporated until dry to produce C in the form of a yellow oil. Crude C (22 g) was dissolved in EtOH (250 mL), NH 2 OH HCl (2.93 g, 42.2 mmol) was added and the solution was heated to reflux. After 48 hours the solvent was evaporated, the residue was dissolved in CH 2 Cl 2 (250 mL), washed with H 2 O (3 x 250 mL) subsequently with brine (3 x 250 mL). The organic layer was dried (Na2SO), filtered and evaporated. The oily residue (18.85 g) was purified by flash chromatography. The fractions containing the product were collected and evaporated to obtain a white glazed solid (17.62 g) which was dissolved in H2O (600 mL) and 1N NaOH (90 mL, 90 mmol) and extracted with CHCI3 (3x250 mL). . The organic layer was dried (Na 2 SO 4) and evaporated to dry to yield D (16.6 g, 31 mmol) in the form of an oil. 88% yield. C. 4- (Phenylmethoxy) carbonyl-10 - [[bis (1,1-dimethylethoxy) phosphinillmetip-1.4.7.10-tetraazacyclododecane-1,7-diacetic acid bis (1,1-dimethylethyl) ester. E (Fig. 10A) A mixture of Compound D (13.87 g, 26 mmol), P (OfBu) 3 (7.6 g, 28.6 mmol) (10) and paraformaldehyde (0.9 g, 30) was heated to a temperature of 60 ° C. mmol). After 16 hours, more P (OtBu) 3 (1 g, 3.76 mmol) and paraformaldehyde (0.1 g, 3.33 mmol) were added. The reaction was heated to a temperature of 60 ° C for another 20 hours, subsequently at a temperature of 80 ° C for 8 hours under vacuum to eliminate volatile impurities. The crude was purified by flash chromatography to produce E (9.33 g, 8 mmol) in the form of an oil. Performance 31%. D. 1-Phenylmethyl-4,10-bis (1,1-dimethylethyl) acid ester of 7-rrBis (1,1-dimethylethoxy) phosphiniHmetip-1,4,7,10-tetraazacyclododecane-1.4.1 O-triacetic acid, G (Fig. 10A). To solution E (6.5 g, 5.53 mmol) in CH 3 OH (160 mL) was added 5% Pd / C (1 g, 0.52 mmol) and the mixture was stirred under a hydrogen atmosphere at room temperature. After 4 hours (165 mL of H2 consumed, 6.7 mmol) the mixture was filtered through a Miliipore® filter (FT 0.45 μm) and the solution was evaporated under reduced pressure. The crude (5.9 g) was purified by flash chromatography to produce F (4.2 g) in the form of an oil. The benzyl bromoacetate (1.9 g, 8.3 mmol) was dissolved in CH3CN (8 mL) was added as drops in 1 hour, to a solution of F (4.2 g) in CH3CN (40 mL) and DIEA (1.5 mL; 8.72 mmol). After 36 hours at room temperature the solvent was evaporated and the residue (5.76) was dissolved in CHCl3 (100 mL), washed with H2O (2x100 mL) subsequently with brine (2x70 mL). The organic layer was dried (Na2SO), filtered and evaporated. The crude (5.5 g) was purified twice by flash chromatography, the fractions were collected and evaporated to dryness for produce G (1.12 g, 1.48 mmol) in the form of an oil. Yield 27%. E. Ester 4,10-bis (1,1-dimethylethyl) of 7 - [[Bis (1,1-dimethyl-ethoxy-osphinin-met-1,4,7,10-tetraazacyclododecane-1, 4,10-triacetic acid H (Fig. 10A)] 5% Pd / C (0.2 g, 0.087 mmol) was added to a solution of G (1.12 g, 1.48 mmol) in CH3OH (27 mL) and the mixture was stirred under a hydrogen atmosphere at room temperature. (35 mL of H2 consumed, 1.43 mmol) the mixture was filtered through a Millipore® filter (FT 0.45 μm) and the solution was evaporated to dry to yield H (0.94 g, 1.41 mmol) in the form of a yellow oil. pale Yield 97% F. N- [4 - [[[[[4,10-Bis (carboxymethyl) -7- (dihydroxyphosphinyl) methyl-l, 4,7,10-tetraazacyclododec-1-yl] acetyl] amino] Acetyl] amino] benzoyl] -L-glutaminyl-L-tryptopyl-L-alanyl-L-valyl-glycyl-L-histidyl-L-leucyl-L-methioninamide, L237 (Fig. 10B) Resin A was stirred (330 mg, 0.20 mmol) (17) in a solid phase peptide synthesis container with 50% morpholine in DMA (5 mL) for 10 minutes, The solution was emptied and 50% fresh morpholine in DMA (5 mL) was added. The suspension was stirred for another 20 minutes, then the solution was emptied and the resin was washed with DMA (5x5 mL). Fmoc-4- acid was added to the resin aminobenzoic acid (290 mg, 0.80 mmol), HOBt (120 mg, 0.80 mmol), DIC (130 μL, 0.80 mmol) and DMA (5 mL), the mixture was stirred for 3 hours at room temperature, was emptied and the resin was washed with DMA (5x5 mL). The resin was subsequently stirred with 50% morpholine in DMA (5 mL) for 10 minutes, the solution was emptied, fresh 50% morpholine in DMA (5 mL) was added, and the mixture was stirred for another 20 minutes. The solution was emptied and the resin was washed with DMA (5x5 mL). Fmoc-glycine (240 mg, 0.8 mmol9, HATU (310 mg, 0.8 mmol) and DIEA (260 μL, 1.6 mmol) were stirred for 15 minutes in DMA (5 mL) after the solution was added to the resin, the mixture it was stirred for 2 hours at room temperature, it was drained and the resin was washed with DMA (5x5 mL), the resin was subsequently stirred with 50% morpholine in DMA (5 mL) for 10 minutes, the solution was emptied, morpholine was added. 50% fresh in DMA (5 mL) and the mixture was stirred for another 20 minutes, the solution was emptied and the resin was washed with DMA (5x5 mL), H (532 mg, 0.80 mmol) was added to the resin. HOBt (120 mg, 0.80 mmol9, DIC (130 μL, 0.80 mmol), and DIEA (260 μL, 1.6 mmol) and DMA (5 mL) The mixture was stirred in a flask for 40 hours at room temperature, evacuated and the resin was washed with DMA (5x5 mL), CH2Cl2 (5x5 mL) and dried in vacuo.The resin was stirred in a flask with Reagent B (25 mL) for 4 hours.The resin was filtered and the solution it was evaporated under reduced pressure to produce an oily crude which after treatment with Et2O (20 mL) produced a precipitate. The precipitate was collected by centrifugation and washed with Et2O (3x20 mL) to yield a solid (90 mg) which was analyzed by HPLC. A quantity of crude (50 mg) was purified by preparative HPLC. The fractions containing the product were lyophilized to produce L237 (6 mg, 3.9 x 10"3 mmol) in the form of a white solid, yield 3.5% EXAMPLE XI - Figures 11A-B Synthesis of L238 and L239 Summary: The products were obtained in several steps starting from the octapeptide Gln-Trp-Ala-Val-Gly-His-Leu-Met-NH2 (BBN [7-14]) (A) in the Rink amide resin After dissociation and deprotection with Reagent B, the crude was purified by HPLC preparation to produce L238 and L239.General yields: 14 and 9%, respectively A. N, N-Dimethylglycyl-L-seryl- [S - [(acetylamino) methyl ]] - L-cysteinyl-glycyl-4-aminobenzoyl-L-glutaminyl-L-tryptopyl-L-alanyl-L-valyl-glycyl-L-histidyl-L-leucyl-L-methioninamide L238 (Fig. 11A) The resin A (0.5 g, 0.3 mmol) was stirred in a solid phase peptide synthesis container with 50% morpholine in DMA (7 mL) for 10 minutes, the solution was emptied and the added 50% fresh morpholine in DMA (7 mL). The suspension was stirred for another 20 minutes, then the solution was emptied and the resin was washed with DMA (5x7 mL). Fmoc-4-aminobenzoic acid (0.43 g, 1.2 mmol), HOBt (0.18 g, 1.2 mmol), DIC (0.19 mL, 1.2 mmol) and DMA (7 mL) were added to the resin, the mixture was stirred for 3 hours at room temperature, it was drained and the resin was washed with DMA (5x7 mL). The resin was then stirred with 50% morpholine in DMA (7 mL) for 10 minutes, the solution was emptied, fresh morpholine at 150% in DMA (7 mL) was added and the mixture was stirred for another 20 minutes. The solution was emptied and the resin was washed with DMA (5x7 mL). They were stirred for 15 minutes in DMA (7 mL) Fmoc-glycine (0.36 g, 1.2 mmol), HATU (0.46 g, 1.2 mmol) and N-ethyldiisopropylamine (0.40 mL, 2.4 mmol), then the solution was added to the resin , the mixture was stirred for 2 hours at room temperature, it was evacuated and the resin was washed with DMA (5x7 mL). The resin was subsequently stirred with 50% morpholine in DMA (7 mL) for 10 minutes, the solution was emptied, fresh 50% morpholine in DMA (7 mL) was added and the mixture was stirred for another 20 minutes. The solution was emptied and the resin was washed with DMA (5x7 L). Na-Fmoc-S-acetamidomethyl-L-cysteine (0.50 g, 1.2 mmol), HOBt (0.18 g, 1.2 mmol), DIC (0.19 mL, 1.2 mmol) and DMA (7 mL) were added to the resin. it stirred for 3 hours at room temperature, it was evacuated and the resin was washed with DMA (5x7 mL). The resin was then stirred with 50% morpholine in DMA (7 mL) for 10 minutes, the solution was emptied and 50% fresh morpholine in DMA 17 mL was added) and the mixture was stirred for another 20 minutes. The solution was emptied and the resin was washed with DMA (5 x 7 mL). Na-Fmoc-Ot-butyl-L-serine (0.46 g, 1.2 mmol), HOBt (0.18 g, 1.2 mmol), DIC (0.19 mL, 1.2 mmol), and DMA (7 mL) were added to the resin. The mixture was stirred for 3 hours at room temperature, it was evacuated and the resin was washed with DMA (5x7 mL). The resin was stirred with 50% morpholine in DMA (7 mL) for 10 minutes, the solution was emptied, and 50% fresh morpholine in DMA (7 mL) was added and the mixture was stirred for another 20 minutes. The solution was emptied and the resin was washed with DMA (5x7 mL). N, N-Dimethylglycine (0.12 g, 1.2 mmol), HATU (0.46 g, 1.2 mmol 9 and N-ethyldiisopropylamine (0.40 mL, 2.4 mmol) in DMA (7 mL) were subsequently stirred for 15 minutes then the solution was added to the resin The mixture was stirred for 2 hours at room temperature, it was evacuated and the resin was washed with DMA (5x7 mL), CH2Cl2 (5x7 mL) and dried in vacuo The resin was stirred in a flask with Reagent B (25 mL ) for 4.5 hours The resin was filtered and the solution was evaporated under reduced pressure to produce an oily crude that after treatment with Et2O (20). mL) a precipitate was produced. The precipitate was collected by centrifugation and washed with Et2O (3x20 mL) to yield a solid (169 mg) which was analyzed by HPLC. A quantity of crude (60 mg) was purified by preparative HPLC. The fractions containing the product were lyophilized to yield L238 (22.0 mg, 0.015 mmol) in the form of a white solid. Performance 14%. B. N, ND imeti glycyl-L-seryl- [S - [(acetylamide) methyl]] - L-cysteinyl-glycyl- (3ß, 5ß, 7a, 12a) -3-amino-7, 12-Dihydroxy-24-oxocolan-24-yl-L-glutaminyl-L-tryptopyl-L-alanyl-L-valyl-glycyl-L-histidyl-L-eucyl-L-methionamide. L239 (Fig. 11B) Resin A (0.5 g, 0.3 mmol) was stirred in a solid phase peptide package with 50% morpholine in DMA (7 mL) for 10 minutes, the solution was emptied and fresh morpholine was added 50% in DMA (7 mL). The suspension was stirred for another 20 minutes, then the solution was emptied and the resin was washed with DMA (5x7 mL). To the resin were added (3β, 5β, 7a, 12a) -3 - [[(9H-Fluoren-9-ylmethoxy) amino] acetyl] amino-7,12-dihydroxycolan-24-oico B (0.82 g; 1.2 mmol) (7), HOBt (0.18 g, 1.2 mmol), DIC (0.19 mL, 1.2 mmol) and DMA (7 mL), the mixture was stirred for 24 hours at room temperature, vacuum and the resin was washed with DMA (5x7 mL). The resin was stirred with 50% morpholine in DMA (5x7 mL). Subsequently the resin was stirred with 50% morpholine in DMA (7 mL) for 10 minutes, the The solution was emptied, and 50% fresh morpholine in DMA (7 mL) was added, the mixture was stirred for another 20 minutes. The solution was emptied and the resin was washed with DMA (5x7 mL). To the resin were added Na-Fmoc-S-acetamidomethyl-L-cysteine (0.50 g, 1.2 mmol), HOBt (0.18 g, 1.2 mmol), DIC (0.19 mL, 1.2 mmol) and DMA (7 mL), the mixture it was stirred for 3 hours at room temperature, it was evacuated and the resin was washed with DMA (5x7 mL). The resin was then stirred with 50% morpholine in DMA (7 mL) for 10 minutes, the solution was emptied, fresh 50% morpholine in DMA (7 mL) was added and the mixture was stirred for another 20 minutes. The solution was emptied and the resin was washed with DMA (5x7 mL). To the resin was added NA-Fmoc-Ot-butyl-L-serine (0.46 g, 1.2 mmol), HOBt (0.18 g, 1.2 mmol), DIC (0.19 mL, 1.2 mmol), and DMA (7 mL), the The mixture was stirred for 3 hours at room temperature, it was evacuated and the resin was washed with DMA (5x7 mL). The resin was then stirred with 50% morpholine in DMA (7 mL) for 10 minutes, the solution was emptied, and 50% fresh morpholine in DMA (7 mL) was added and the mixture was stirred for another 20 minutes. The solution was emptied and the resin was washed with DMA (5x7 mL). The mixture was stirred for 15 minutes in DMA (7 mL) N, N-Dimethylglycine (0.12 g, 1.2 mmol), HATU (0.46 g, 1.2 mmol) and N-ethyldiisopropylamine (0.40 mL, 2.4 mmol), after which the solution was added. the resin.

Resin A (0.5 g, 0.3 mmol) was stirred in a solid phase peptide package with 50% morpholine in DMA (7 mL) for 10 minutes, the solution was emptied and fresh morpholine 50% in DMA was added ( 7 mL). The suspension was stirred for another 20 minutes, then the solution was emptied and the resin was washed with DMA (5x7 mL). To the resin were added (3β, 5β, 7a, 12a) -3 - [[(9H-Fluoren-9-ylmethoxy) amino] acetyl] amino-7,12-dihydroxycolan-24-oico B (0.82 g; 1.2 mmol), HOBt (0.18 g, 1.2 mmol), DIC (0.19 mL, 1.2 mmol) and DMA (7 mL), the mixture was stirred for 24 hours at room temperature, evacuated and the resin was washed with DMA (5x7 mL ). The resin was stirred with 50% morpholine in DMA (5x7 mL). The resin was then stirred with 50% morpholine in DMA (7 mL) for 10 minutes, the solution was emptied, and 50% fresh morpholine in DMA (7 mL) was added, the mixture was stirred for another 20 minutes. The solution was emptied and the resin was washed with DMA (5x7 mL). Na-Fmoc-S-acetamidomethyl-L-cysteine (0.50 g, 1.2 mmol), HOBt (0.18 g, 1.2 mmol), DIC (0.19 mL, 1.2 mmol) and DMA (7 mL) were added to the resin. it was stirred for 3 hours at room temperature, it was evacuated and the resin was washed with DMA (5x7 mL). The resin was then stirred with 50% morpholine in DMA (7 mL) for 10 minutes, the solution was emptied, fresh 50% morpholine in DMA (7 mL) was added and the mixture was stirred for another 20 minutes. minutes The solution was emptied and the resin was washed with DMA (5x7 mL). To the resin was added NA-Fmoc-Ot-butyl-L-serine (0.46 g, 1.2 mmol), HOBt (0.18 g, 1.2 mmol), DIC (0.19 mL, 1.2 mmol), and DMA (7 mL), the The mixture was stirred for 3 hours at room temperature, it was evacuated and the resin was washed with DMA (5x7 mL). The resin was then stirred with 50% morpholine in DMA (7 mL) for 10 minutes, the solution was emptied, and 50% fresh morpholine in DMA (7 mL) was added and the mixture was stirred for another 20 minutes. The solution was emptied and the resin was washed with DMA (5x7 mL). The mixture was stirred for 15 minutes in DMA (7 mL) N, N-Dimethylglycine (0.12 g, 1.2 mmol), HATU (0.46 g, 1.2 mmol) and N-ethyldiisopropylamine (0.40 mL, 2.4 mmol), after which the solution was added. the resin. EXAMPLE Xll-Fiouras 12A-F Synthesis of L240, L241, L242 Summary: The products were obtained in several steps starting from the octapeptide Gln-Trp-Ala-Val-Gly-His-Leu-Met-NH2 (BBN [7- 14]) (A) in the Rink amide resin. After dissociation and deprotection with Reagent B, the crudes were purified by preparative HPLC to produce L240, L241, and L242. Overall yields: 7.4, 3.2, 1.3 respectively. A. 4 - [[[(9H-Fluoren-9-ylmethoxy) carbonyl1-arninolacetyl-amino-3-methoxybenzoic acid (Fig.12A) A solution of 4-amino-3-methoxybenzoic acid (1.0 g, 5.9 mmol) was added dropwise; and N-ethyldiisopropylamine (1.02 mL 5.9 mmol) in THF (20 mL) was added to a solution of Fmoc-glycylchloride (1.88 g, 5.9 mmol) in CH2Cl2 / THF 1: 1 (20 mL) and stirred at room temperature under N2. After 3 hours the solvent was evaporated under vacuum. The residue was taken with 0.5 N HCl (50 mL), stirred for 1 hour at a temperature of 0 ° C, then filtered and dried. The white solid was suspended in MeOH (30 mL) and stirred for 1 hour, then filtered and suspended a solution of CHCl3 / hexane 1: 4 (75 mL). The suspension was filtered to yield compound A in the form of a white solid (1.02 g, 2.28 mmol). Performance 39%. B. N- [4 - [[[[4,7,10-Tris (carboxymethyl) -1,4,7,10-tetraazacyclododec-1-yl] acetyl] glycyl] amino] -3-methoxybenzoyl] -L-glutam n-L-tr-phenyl-1-alanyl-L-valyl-glycyl-L-histidyl-L-leucyl-L-methionamide L240 Resin A (0.5 g, 0.3 mmol) was stirred in a solid-phase peptide package with 50% morpholine in DMA (7 mL) for 10 minutes, the solution was emptied and 50% fresh morpholine in DMA (7 mL) was added. The suspension was stirred for another 20 minutes, then the solution was emptied and the resin was washed with DMA (5x7 mL). HE They added to the resin 4 - [[[(9H-Fluoren-9-yl-methoxy) carbon] l] ami no] a cet i I] a m i no-3-methoxy benzoic A (0.50 g, 1.2 mmol), HOBt (0.18 g, 1.2 mmol), DIC (0.19 mL, 1.2 mmol) and DMA (7 mL), the mixture was stirred for 5 hours at room temperature, vacuum and the resin was washed with DMA (5x7 mL). The resin was stirred with 50% morpholine in DMA (7 mL) for 10 minutes, the solution was emptied and 50% fresh morpholine was added in DMA (7 mL) the mixture was stirred for another 20 minutes. The solution was emptied and the resin was washed with DMA (5x7 mL). Adsorbent of tris (1,1-dimethylethyl) ester of 1,4,7,10-Tetrazazacyclododecane-1,4,7,10-tetraacetic acid with NaCl (0.79 g, 1.2 mmol), HOBt (0.18) was added to the resin. g; 1.2 mmol), DIC (0.19 mL: 1.2 mmol), N-ethyldiisopropylamine (0.40 mL, 2.4 mmol) and DMA (7 mL). The mixture was stirred for 24 hours at room temperature, it was evacuated and the resin was washed with DMA (5x7 mL), CH2Cl2 (5x7 mL) and dried under vacuum. The resin was stirred in a flask with Reagent B (25 mL) for 4.5 hours. The resin was filtered and the solution was evaporated under reduced pressure to produce an oily crude which after the treatment with Et2O (20 mL) produced the precipitate. The precipitate was collected by centrifugation and washed with Et2O (5x20 mL) to yield a solid (152 mg) which was analyzed by HPLC. A quantity of crude (52 mg) was purified by preparative HPLC. The fractions containing the product were lyophilized to produce L240 (12.0 mg, 7.8 x 10"3 mmol) in the form of a white solid, yield 7.4% C. 4-amino-3-chlorobenzoic acid C (Fig. 12B) 1N NaOH (11 mL, 11 mmol) was added to a solution of methyl 4-amino-3-chlorobenzoate (2 g, 10.8 mmol) in MeOH (20 mL) at a temperature of 45 [deg.] C. The reaction mixture was stirred for 5 hours at a temperature of 45 ° C and overnight at room temperature, additional 1N NaOH (5 mL, 5 mmol) was added and the reaction was stirred at a temperature of 45 ° C for 2 hours. of solvents was added 1N HCl (16 ml) The solid precipitate was filtered and dried to yield 4-amino-3-chlorobenzoic acid, C, in the form of a white solid (1.75 g, 10.2 mmol) Yield 94.6% D. 4 - [[[(9H-Fluoren-9-ylmethoxy) carbonyl] amino1acetylamino-3-chlorobenzoic acid D (Fig. 1_2Bj) A solution of 4-amino-3-chlorobenzoic acid was added dropwise. (1.5 g; 8.75 mmol) and N-ethyldiisopropylamine (1.46 mL, 8.75 mmol) in THF (50 mL) were added to a solution of Fmoc-glycylchloride (2.76 g; 8.75 mmol) in CH2Cl2 / THF 1: 1 (30 mL) and stirred at room temperature under N2. After 3 hours the solvent was evaporated under vacuum. The residue was taken with 0.5N HCl (50 mL), filtered and dried.

The white solid was suspended in MeOH (30 mL) and stirred for 1 hour, then filtered and dried to yield 4 - [[[9H-fluoren-9-ylmethoxy) carbonyl] amino] acetyl] amino acid. 3-chlorobenzoic acid (2.95 g, 6.5 mmol). Performance 75%. E. N- [4 - [[[[4,7,10-Tris (carboxymethyl) ~ 1,4,7,10-tetraazacuckididec-1-yl] acetyl] glycyl] amino] 3-chlorobenzoyl-L-glutaminyl-L-triphenylphyl 1-alanyl-L-valyl-glycyl-L-histidyl-L-leucyl-L-methioninanmide, L241 (Fig. 12E) Resin A (0.5 g, 0.3 mmol) was stirred in a solid-phase peptide package with morpholine 50% in DMA (7 mL) for 10 minutes, the solution was emptied and 50% fresh morpholine in DMA (7 mL) was added. The suspension was stirred for another 20 minutes, then the solution was emptied and the resin was washed with DMA 7 mL). 4 - [[[(9H-Fluoren-9-ylmethoxy) carbonyl] amino] acetyl] amino-3-chlorobenzoic acid was added to the resin. (0.54 g, 1.2 mmol), HOBt (0.18 g, 1.2 mmol), DIC (0.19 mL, 1.2 mmol) and DMA (7 mL), the mixture was stirred for 5 hours at room temperature, vacuum and the resin was washed with DMA (5x7 mL). The resin was stirred with 50% morpholine in DMA (7 mL) for 10 minutes, the solution was emptied and 50% fresh morpholine was added in DMA (7 mL) the mixture was stirred for another 20 minutes. The solution was emptied and the resin washed with DMA (5x7 mL). Adsorbent of tri s (1,1-dimethylethyl) ester of 1,4,7,10-Tetrazazacyclododecane-1,4,7,10-tetraacetic acid with NaCl (0.79 g) was added to the resin.; 1.2 mmol), HOBt (0.18 g, 1.2 mmol), DIC (0.19 mL: 1.2 mmol), N-ethyldiisopropylamine (0.40 mL, 2.4 mmol) and DMA (7 mL). The mixture was stirred for 40 hours at room temperature, evacuated and the resin was washed with DMA (5x7 mL), CH2Cl2 (5x7 mL) and dried under vacuum. The resin was stirred in a flask with Reagent B (25 mL) for 4.5 hours. The resin was filtered and the solution was evaporated under reduced pressure to produce an oily crude which after the treatment with Et2O (20 mL) produced the precipitate. The precipitate was collected by centrifugation and washed with Et2O (5x20 mL) to yield a solid (151 mg) which was analyzed by HPLC. A quantity of crude (56 mg) was purified by preparative HPLC. The fractions containing the product were lyophilized to produce L241 (5.6 mg, 3.6 x 10"3 mmol) in the form of a white solid, Yield 3.2% F. 4 - [[[(9H-Fluoren-9-ylmethoxy ) carbonillamino1 Acetypamino-3-methylbenzoic, E_ (Fig.2C) A solution of 4-amino-3-methylbenzoic acid (0.81 g, 5.35 mmol) and N-ethyldiisopropylamine (0.9 mL, 5.35 mmol) in THF (30 mL) was added dropwise as drops. a solution of Fmoc-glycylchloride (1.69 g, 5.35 mmol9 in CH2Cl2 / THF 1: 1 (20 mL) and stirred at room temperature under N2.After 3 hours the solvent was evaporated under vacuum, the residue was taken with 0.5 HCl N (50 mL) and stirred for 3 hours at 0 ° C, then filtered and dried The white solid was suspended in MeOH (1.69 g, 3.9 mmol) Yield 73% G. N- [4 - [[[[4,7,10-Tris (carboxymethyl) -1,4,7,10-tetraazacyclododec-1-yl] acetyl] glycyl] amino] 3-methylbenzoyl] L-glutaminyl-L-triptophyl- L-alanyl-L-valyl-glycyl-L-histidyl-L-leucyl-L-methioninamide L242 (Fig. 12F) Resin A (0.5 g, 0.3 mmol) was stirred in a solid-phase peptide package with morpholine 50% in DMA (7 mL) for 10 minutes, the solution was emptied and fresh 50% morpholine in DMA (7 mL) was added The suspension was stirred for another 20 minutes, then the solution was emptied and the resin was washed with DMA (5x7 mL). 4 - [[(9H-Fluoren-9-ylme) was added to the resin. toxy) amino] acetyl] amino-3-methylbenzoic E (0.52 g; 1.2 mmol), HOBt (0.18 g, 1.2 mmol), DIC (0.19 mL, 1.2 mmol) and DMA (7 mL), the mixture was stirred for 5 hours at room temperature, evacuated and the resin was washed with DMA (5x7 mL). The resin was stirred with 50% morpholine in DMA (7 mL) for 10 minutes, the solution was emptied and 50% fresh morpholine in DMA (7 mL) was added to the mixture was stirred for another 20 minutes. The solution was emptied and the resin was washed with DMA (5x7 mL). 1,4-, 1- Tetrazazacyclododecane-1,4,7,10-tetraacetic acid adsorbent of tri-S (1,1-dimethylethyl) ester with NaCl (0.76 g, 1.2 mmol), N- was added to the resin. ethyldiisopropylamine (0.40 mL, 2.4 mmol) and DMA (7 mL). The mixture was stirred for 40 hours at room temperature, evacuated and the resin was washed with DMA (5x7 mL), CH2Cl2 (5x7 mL) and dried under vacuum. The resin was stirred in a flask with Reagent B (25 mL) for 4.5 hours. The resin was filtered and the solution was evaporated under reduced pressure to produce an oily crude which after the treatment with Et2O (20 mL) produced the precipitate. The precipitate was collected by centrifugation and washed with Et2O (5x20 mL) to yield a solid (134 mg) which was analyzed by HPLC. A quantity of crude (103 mg) was purified by preparative HPLC. The fractions containing the product were lyophilized to produce L242 (4.5 mg, 2.9 x 1 O, 3 mmol) in the form of a white solid, Yield 1.3% EXAMPLE Xlll - Figures 13A-C Synthesis of L244 Summary: The product is obtained in several steps starting from the octapeptide Gln-Trp-Ala-Vai-Gly-His-Leu-Met-NH2 (BBN [7-14]) in the Rink amide resin (TO). The final coupling step was carried out with tri-t-butyl ester DOTA in the solution phase after dissociation and deprotection with Reagent B of Linker-BBN [7-14]. The crude was purified by HPLC preparation to produce L244. Overall performance: 0.4%. A. N.N '- (lm-nodi-2.1-ethanediyl) b1s.2.2.2- trifluoroacetamidal. A (Fig. 13A) Trifluoroacetic acid ethyl ester (50 g; 0. 35 mmol) in a solution of diethylenetriamine (18 g, 0.175 mol) in THF (180 mL) at a temperature of 0 ° C in 1 hour. After 20 hours at room temperature, the mixture was evaporated to an oily residue (54 g). The oil was crystallized from Et2O (50 mL), filtered, washed and cooled with Et2O (2x3 mL) and dried to obtain A in the form of a white solid (46 g, 0.156 mol).

Performance 89%. B. 4- [N, N'-Bis [2- (trifluoroacetyl) aminoethyl] amino] -4-oxobutanoic acid, B.

(FÍQ.13A) Succinic anhydride (0.34 g, 3.4 mmol) was added in a solution of A (1 g, 3.4 mmol) in THF (5 mL) at room temperature. After 28 hours the crude was concentrated to obtain the residue (1.59 g), washed with EtOAc (2x10 mL) and 1N HCl (2x15 mL). The organic layer was dried with Na 2 SO 4, filtered and evaporated to produce a oily residue (1.3 g) which was purified by flash chromatography (5) to yield B in the form of an oil (0.85 g, 2.15 mmol). Performance 63%. C. 4- [N, N'-Bis [2- [89-H-fluoren-9-ylmethoxy) carbomipaminoethamino-4-oxobutanoic acid, D (Fig. 13A) Succinic anhydride (2 g, 20 mmol) was added. ) in a solution of A (5 g, 16.94 mmol) in THF (25 mL) at room temperature. After 28 hours the crude was concentrated to the residue (7 g), washed with ethyl acetate (100 mL) and in 1N HCl (2x50 mL). The organic layer was dried with Na 2 SO 4, filtered and evaporated to yield crude B in the form of an oily residue (6.53 g). It was added to the crude suspension B (5 g) in EtOH (35 mL) obtaining a complete solution after 1 hour at room temperature. After 20 hours the solvent was evaporated to obtain C in the form of an oil (8.48 g). A solution of 9-fluorenylmethyl chloroformate (6.54 g, 25.3 mmol) in 1,4-dioxane (30 mL), was dropped into a solution of C in 10% aqueous Na 2 CO 3 (30 mL) in 1 hour at a temperature of 0 ° C. After 20 hours at r.t. a gelatinous suspension was obtained and filtered to yield a white solid (3.5 g) and a yellow solution. The solution was evaporated and the remaining aqueous solution was diluted in H2O (150 mL) and extracted with EtOAc. (70 mL). Fresh EtOAc (200 mL) was added to the aqueous phase, obtaining a suspension which was cooled to a temperature of 0 ° C and acidified to a pH of 2 with concentrated HCl. The organic layer was washed with H2O (5x200 mL) until a neutral pH was obtained, then dried to produce a glazed solid (6.16 g). The compound was suspended in boiling p-Hexane (60 mL) for 1 hour, filtered to yield D in the form of a white solid (5.53 g, 8.54 mmol). Overall performance 50%. D. N- [4 - [[4- [Bis [2 - [[[4,7,10-tris (carboxymethyl) -1,4, 7,1 O-tetraazacyclodode c-1-yl] acetyl] amino] ethyl] amino-1,4-dioxobutyl] amino] benzoyl] -L-glutaminyl-L-tryptopyl-L-alanyl-L-valyl-glycyl-L-histidyl-L-leucyl-L-methioninamide. L244 (Fig. 13B) Resin A (0.5 g, 0.3 mmol) was stirred in a solid phase peptide synthesis container with 50% morpholine in DMA (7 mL) for 10 minutes, the solution was emptied and added 50% fresh morpholine in DMA (7 mL). The suspension was stirred for another 20 minutes, then the solution was emptied and the resin was washed with DMA (5x7 mL). 4-N'-Bis [2 - [(9H-fluoren-9-ylmethoxy) carbonyl] aminoethyl] amino-4-oxobutanoic acid (777.3 mg, 1.2 mmol), HOBt (184 mg) was added to the resin. , 1.2 mmol), DIC (187 μL, 1.2 mmol) and DMA (7 mL), the mixture was stirred for 40 hours at room temperature, it was the resin was washed with DMA (5x7 mL). The solution was emptied, fresh 50% morpholine in DMA (7 mL) was added and the mixture was stirred for 20 minutes. The solution was emptied and the resin was washed with DMA (2x7 mL) and with CH2Cl2 (5x7 mL) subsequently stirred in a flask with Reagent B (25 mL) for 4.5 hours. The resin was filtered and the solution was evaporated under reduced pressure to produce an oily crude which after treatment with Et2O (20 mL) produced a precipitate. The precipitate was collected by centrifugation and washed with Et2O (5x20 mL) to produce F in the form of a white solid (140 mg). Tri-t-butyl ester DOTA (112 mg, 0.178 mmol) HATU (70 mg, 0.178 mmol) and DIEA (60 μL, 0.356 mmol) were added to a solution of F (50 mg, 0.0445 mmol) in DMA (3 mL ) and CH2Cl2 (2 mL) and stirred for 24 hours at room temperature. The crude was evaporated to a reduced volume (1 mL) and stirred with Reagent B (25 mL) for 4.5 hours. After evaporation of the solvent, the residue was treated with Et2O (20 mL) to produce a precipitate. The precipitate was collected by centrifugation and washed with Et2O (5x20 mL) to yield a beige solid (132 mg) which was analyzed by HPLC. A quantity of crude (100 mg) was purified by preparative HPLC. The fractions containing the product were lyophilized to produce L244 (Fig. 13C) (3.5 mg, 1.84 x 10"3 mmol) in the shape of a white solid. Performance 0.8%. General Experiments for Examples XIV to XLI1 L201-L228 A. Manual Couplings 6.0 equivalents of the protected amino acid were treated in an appropriate manner with 6.0 equivalents each of HOBt and DIC and were activated outside the reaction vessel. This activated carboxylic acid in NMP was subsequently transferred to the resin containing the amine and the reaction was carried out for 4 to 6 hours and subsequently the resin was drained and washed. B. Special coupling of Fmoc-GIv-OH to amides of 4-aminobenzoic acid and aminobiphenylcarboxylic acid: Fmoc-Gly-OH (10.0 equiv.) Was treated with HATU (10.0 equiv.) And DIEA (20.0 equiv.) In NMP ( and 10 mL of NMP for one gram of amino acid by weight) and the solution was stirred for 10 to 15 minutes at RT before being transferred to the container containing the amine-loaded resin. The volume of the solution was carried out until obtaining 15.0 mL for each gram of the resin. The coupling was continued for 20 hours at RT and the resin was drained of all reagents. This procedure was repeated one more time and subsequently washed with NMP before proceeding to the next step.

C. Preparation of monoamide D03A: 0.8 equivalent of DOTA monoacid was dissolved in NMP and treated with 8.0 equivalents of BUT and 16.0 equivalents of DIEA. This solution was stirred for 15 minutes at RT and subsequently transferred to the resin amine and the coupling was continued for 24 hours at RT. The resin was subsequently drained, washed and subsequently the peptide dissociated and purified. D. Dissociation of the crude peptides from the resin and purification: The resin was suspended in Reagent B (15.0 ml / g) and stirred for 4 hours at RT. The resin was subsequently extracted and washed with 2 x 5 mL and Reagent B was again combined with the previous filtrate. The filtrate was subsequently concentrated under reduced pressure to a paste / liquid at RT and titrated with 25.0 mL of anhydrous ether (for each gram of resin used). The suspension was subsequently centrifuged and the ether cap was decanted. This procedure was repeated twice more and the colorless precipitate after the ether wash was purified by preparative HPLC. Example XIV - Figure 21 Synthesis of L201 0.5 g of Fmoc-Q (Trt) -W (Boc) -A-V-G-H (Trt) -M-Resin (0.4 mmol / g, 0.5 g, 0.2 mmol) (Resin A) was used.

The rest of the amino acid units were added as described in the general procedure for preparing [bis] (carboxymethyl) amino] ethyl acid} amino) propane-3-carboxylic acid (1R) -1- (Bis. {2-1-carboxyl-glycyl-4-aminobenzoyl-L-glutaminyl-L-tryptopyl-L-alanyl-L-valyl-glycyl-L- histidyl-L-leucyl-L-methioninamide (L201), Yield: 17.0 mg (5.4%) Example XI - Figures 22A and 22B Synthesis of L202 A. 4-Fmoc-hydrazinobenzoido acid (Fig. 22A): A suspension was treated of 4-hydrazinobenzoic acid (5.0 g, 32.9 mmol) in water (100 ml) with cesium carbonate (21.5 g, 66.0 mmol). Fmoc-CI (9.1 g, 35.0 mmol) in THF (25 mL) was added to the above solution with stirring over a period of 1 hour. The solution was stirred for a further 4 hours after the addition and the reaction mixture was concentrated to about 75 mL and extracted with ether (2x100 mL). The ether layer was discarded and the aqueous layer was acidified with 2N HCl. The separated solid was filtered, washed with water (5 x 100 mL) and subsequently recrystallized from acetonitrile to yield the product (compound B) in the form of a colorless solid. Yield: 11.0 g (89%). 1 H NMR (DMSO-d 6): d 4.5 (m, 1H, Ar, DH ^ -CH), 4.45 (m, 2H, Ar-CHgj, 6.6. (Bs, 1H, Ar-H.), 7.4-7.9 ( m, 9, Ar-H and Ar-CH ^), 8.3 (s, 2H, Ar-JH), 9.6 (s, 2H, Ar-H.) MS-m / z 373.2 [MH]. 0.5 g of Fmoc-Q (Trt) -W (Boc) -A-V-G-H (Trt) -M-Resin (0.4 mmol7g, 0.5 g, 0.2 mmol) (Resin A) was used. Amino acid units such as those described in the general procedure were added, including Compound B to prepare N - [(3β, 5β, 12a) -3 - [[[[[4,7,10-Tris (carboxymethyl)] -1, 4, 7,1 O-tetraazacyclodode c-1 -yl] acetyl] amino] acetyl] amino] -4-hydrazinobenzoyl-L-glutaminyl-L-tryptopyl-L-alanyl-L-valyl-glycyl-L- histidyl-L-leucyl-L-methioninamide (L202) (Fig. 22B), Yield: 25.0 mg (8.3%). Example XVI - Figures 23A and 23B Synthesis of L203 A. Preparation of Benzoate Compound 4-Boc-aminobenzyl B (Fig. 23A): A suspension of 4-boc-aminobenzoic acid was treated (0.95 g, 4.0 mmol) in dry acetonitrile (10.0 mL) with powdered cesium carbonate (1.3 g, 4.0 mmol) and stirred vigorously under nitrogen. Benzyl bromide (0.75 mg, 4.4 mmol) was added and the reaction mixture was refluxed for 20 hours under nitrogen. The reaction mixture was subsequently poured into ice water (200 mL) and the separated solid was filtered and washed with water (5x50 mL). Subsequently, the crude material was recrystallized from aqueous methanol to produce the product in the form of a colorless solid (Compound B).

Yield: 0.8 g (61% 9. 1 H NMR (CDCl 3): d 1.5 (s, 9 H, tertiary methyl), 5.4 (s, 2 H, Ar-CF, 7.4 (m, 7 H, Ar-H.) And 8.0 ( m, 2H, Ar-H_) MS-m / z 326.1 [M + H] B. Compound of 4-aminobenzyl benzoate C (Fig. 23A): 4-Boc-aminobenzyl benzoate (0.8 g, 2.5 mmol) in DCM (20 mL) containing TFA (25% volume) and stirred for 2 hours at RT The reaction mixture was poured into 100.0 crushed ice and neutralized with a saturated sodium bicarbonate solution until the pH reached to about 8.5.The organic layer was separated and the aqueous layer was extracted with DCM (3x20 mL) and all the organic layers were combined.The DCM layer was subsequently washed with 1 x 50 mL of saturated sodium bicarbonate, water (2x50 mL) and dried (sodium sulfate) The removal of the solvent yielded a colorless solid (Compound C) which was taken for the next step without further purification Yield: 0.51 g (91%) 1 H NMR (CDCl 3 ): d 5.3 (s, 2H, Ar-CI ± gJ, 6.6 (d, 2H, Ar-H.,; = 1.0 Hz), 7.4 (m, 5H, Ar, J ±, J = 1.0 Hz) and 7.9 (d, 2H, Ar-H., J = 1.0 Hz). C. 4- (2-ChloroacetyDaminobenzyl D Benzoate Compound (Fig. 23A): The amine (0.51 g, 2.2 mmol) was dissolved in dry dimethylacetamide (5.0 mL) and cooled in ice Chloroacetyl chloride (0.28 g) was added. , 2.5 mmol) in the form of drops through a syringe and the solution was allowed to reach RT and stirred for 2 hours. An additional 2.5 mmol of chloroacetyl chloride was added and stirring was continued for a further 2 hours. The reaction mixture was subsequently poured into ice-cold water (100 mL). The precipitated solid was filtered and washed with water and subsequently crystallized from hexane / ether to yield a colorless solid (Compound D). Yield: 0.38 g (56%). 1 H NMR (CDCl 3): d 4.25 (s, 2H, CJH¿-CI), 5.4 (s, 2H, Ar-H.), 7.4 (m, 5H, Ar-Jl), 7.6 (d, 2H, Ar- j ±), 8.2 (d, 2H, Ar-H.) and 8.4 (s, 1H, -CONI ±). Ter-Butil-2-. { 1,4,7,10-tetraaza-7-10-bis. { [tert-butyl) oxycarbonyl] methyl} -4 - [(N-. {4- [benzyloxycarbonyl] phenyl} carbamoyl] cyclododecyl} acetate, Compound E (Fig. 23A): Tri-t-butyl ester DO3A (5.24 g, 0.5 mmol ) in 30.0 mL of dry acetonitrile and anhydrous potassium carbonate (2.76 g, 20 mmol) was added and stirred for 30 minutes, then chloroacetamide D (2.8 g, 9.2 mmol) in dry acetonitrile was added dropwise. (20.0 mL) in the form of droplets to the above mixture for 10 minutes.The mixture was then stirred overnight.The solution was filtered and then concentrated under reduced pressure to a paste.The paste was dissolved in approximately 200.0 mL of Water and extracted with 5x50 mL of ethyl acetate. The combined organic layer was washed with water (2x100 mL) and dried (sodium sulfate). The solution was filtered and evaporated under reduced pressure to a paste and the paste was chromatographed on flash silica gel (600.0 g). Elution with 5% methanol in DCM eluted the product. All fractions that were homogeneous on TLC were pooled and evaporated to yield a colorless gum. The gum was recrystallized from isopropyl ether and DCM to prepare Compound E. Yield: 4.1 g (55%). 1 H NMR (CDCl 3): d 1.5 (s, 27H, methyl), 2.0-3.75 (m, 24H, NCj_b.s), 5.25 (d, 2H, Ar-Cj_), 7.3 (m, 5H, Ar, l ±), 7.8 (d, 2H, Ar-h) and 7.95 (D, 2h, Ar-H.). M. S-m / z 804.3 [M + H]. D. Reduction of acid E to prepare compound F,. (Fig. 23A): Benzyl ester E above (1.0 g, 1.24 mmol) was dissolved in a methanol-water mixture (10.0 mL, 95: 5) and palladium on carbon (10%, 0.2 g) was added. The solution was subsequently hydrogenated using a Parr apparatus at 50.0 psi for 8 hours. The solution filtered the catalyst and was then concentrated under reduced pressure to produce a colorless fluffy solid F. It was not further purified and taken for the next step immediately. MS: m / z 714.3 [M + Na]. E. Preparation of L203 (FIGURE 23B) The above F acid was coupled to the amine in the resin [H-Q (Trt) -W (Boc) -A-V-G-H (Trt) -L-MR-Resin] Resin A and F from the above using standard coupling procedures described above. 0.5 g (0.2 mmol) of the resin yielded 31.5 mg of the final purified peptide (10.9%) N - [(3ß, 5β, 12a) -3 - [[[4,7,10-tris (carboxymethyl) -1], 4,7,1 O-tetra-azacyclodode c-1 -yl] acetyl] amino] -4-aminobenzoyl-L-glutaminyl-L-tryptopyl-L-alanyl-L-valyl-glycyl-L-histidyl-L-leucyl -L-methioninamide (L203) (FIGURE 23B). Example XVII - Figure 24 Synthesis of L204 Fmoc-Q (Trt) -W (Boc) -A-V-G-H (Trt) -L-M-resin (0.5 g, 0.2 mmol) (Resin A) was used. Fmoc-Gly-OH was first charged followed by F from the previous procedure (FIGURE 23A), using standard coupling conditions. Yield: 24.5 mg (8.16%) of N - [(3β, 5β, 12) -3 - [[[4,7,10-tris (carboxymethyl) -1,4,1,7,1-tetra-azacyclodode c- 1 -yl] -1-yl] acetyl] amino] -4-aminobenzoyl-glycyl-L-glutaminyl-L-tryptopyl-L-alanyl-L-valyl-glycyl-L-histidyl-L-leucyl-L-methionimamide ( L204) (FIGURE 24). Example XVIII - Figure 25 Synthesis of L205 Fmoc-6-aminonicotinic acid 1 was prepared as described in the literature ("Synthesis of diacylhydrazine compounds for therapeutic use." Hoelzemann, G., Goodman, S. (Merck Patent G. m.B., Germany). Ger. Offen 2000, page 16, CODEN: GWXXBX DE 19831710 A1 20000120) and was coupled with Fmoc-Q (Trt) -W (Boc) -AVGH (Trt) -LM-resin (0.5 g, 0.2 mmol) Resin A, followed by the other amino groups as indicated above to prepare N - [(3β, 5β, 12a) -3 - [[[4,7,10-tris (carboxymethyl) -1,4,7,10-tetra-azacyclododec-1] -yl] acetyl] amino] -4-aminobenzoiI-glycyl-L-glutaminyl-L-tryptopyl-L-alanyl-L-valyl-glycyl-L-histidyl-L-leucyl-L-methioninamide (L205) Yield: 1.28 mg (0.4%). Example XIX - Figures 26A and 26B Synthesis of L206 A. 4'-Fmoc-amino-3'-methylbiphenyl-4-carboxylic acid B: The amino acid (0.41 g, 1.8 mmol) was dissolved in a solution of cesium carbonate (0.98) g, 3.0 mmol) in 10.0 ml of water. See publication "Rational Design of Diflunisai Analogues with Reduced Affinity for Human Albumin Serum". Mao, H. and Associates, J. Am. Chem. Soc. 2001, 123 (43), 10429-10435. This solution was cooled in a bath with ice and added dropwise to a solution of Fmoc-CI (0.52 g, 2.0 mmol) in THF (10.0 ml) with vigorous stirring. After the addition, the reaction mixture was stirred at RT for 20 hours. The solution was subsequently acidified with 2N HCl. The precipitated solid was filtered and washed with water (3 x 20 ml) and dried with air. The crude solid was subsequently recrystallized from acetonitrile to produce a colorless fluffy solid B (FIGURE 26A). Yield: 0.66 g (75%). H NMR (DMSO-d6): d 2.2 (s, Ar-Me), 4.25 (t, 1H, Ar-Cl ±, j = 5 Hz), 4.5 (d, 2H, O-Cj ± 2, j = 5.0 Hz), 7.1 (bs, 1H, CONj ±), 7.4 - 8.0 (m, 8H, Ar-H) and 9.75 (bs, 1H, -COOH). M. S .: m / z 472.0 [M-H]. The above B acid was coupled to Fmoc-Q (Trt) -W (Boc) -A-V-G-H (Trt) -L-M-resin (0.2 g, 0.08 mmol) resin A, under the standard coupling conditions. Additional groups were added as indicated above, to prepare N - [(3β, 5β, 12a) -3 - [[[[[4-7, 1 O-tris (carboxymethyl) -1,4,7,10- tetra-azacyclododec-1-yl] acetyl] amino] acetyl] amino] - [4'-amino-2'-metii-biphenyl-4-carboxyl] -L-glutaminyl-L-triptophoyl-L-alanyl-L-valil -glycyl-L-histidyl-L-leucyl-L-methioninamide (L206). Yield: 30.5 g (24%). Example XX - Figures 27A-B Synthesis of L207 3'-Fmoc-amino-biphenyl-3-carboxylic acid was prepared from the corresponding amine using the procedure described above. See the publication "Synthesis of 3'-methyl-4'-nitrobiphenylcarboxylic acids by the reaction of 3-methyl-4-nitrobenzenenediazonium acétate with methyl benzoate", Boyland, E. and Gorrod, J., J. Chem. Soc, Abstrais (1962), 2209-11. 0.7 g of the amine produced 0.81 g of the Fmoc derivative (58%) (compound B, FIGURE 27A). 1 H NMR (DMSO-d6): d 4.3 (t, 1H, Ar-Cj ±), 4.5 (d, 2H, O-CH__), 7.25-8.25 (m, 16H, Ar-J ±) and 9.9 (s), 1H, -COOj ±). M. S. - m / z 434 [M-H]. Fmoc-Q (Trt) -W (Boc) -A-V-G-H (Trt) -L-M-resin (0.2 g, 0.08 mmol) resin A was coupled to the above acid B and to additional groups as indicated above (FIGURE 27B). 29.0 mg of N - [(3ß, 5β, 12a) -3 - [[[[[4,7,10-tris (carboxymethyl) -1,4,7,10-tetra-azacyclododecide] was prepared (23%). 1-yl] acetyl] amino] acetyl] amino- [3'-amino-biphenyl-3-carboxyl] L-glutaminyl-L-triptophoyl-L-alanyl-L-valyl-glycyl-L-histidyl-L-leucyl- L-methioninamide (L207). Example XXI - Figure 28 Synthesis of L208 Fmoc-Q (Trt) -W (Boc) -AVGH (Trt) -LM-resin (0.2 g, 0.08 mmol) A was unblocked and coupled to terephthalic acid using HATU as the agent of coupling The resulting acid in the resin was activated with DIC and NHS and subsequently acolóed to ethylenediamine. Finally, monoacid-DOTA was coupled to the amine in the resin. It was prepared for a production of 17.5 mg (14%) N - [(3β, 5β, 12a) -3 - [[[[[4,7,10-tris (carboxymethyl) -1,4, 7,1 O- tetra-azacyclodode c-1-yl] acetyl] amino] acetyl] amino] - [1,2-diaminoethyl-terephthalyl] -L-glutaminyl-L-tryptopyl-L-alanyl-L-valyl-glycyl-L-histidyl- L-leucyl-L-methionimamide (L208). Example XXII - Figures 29A-B Synthesis of L209 A. Boc-Glu (G-OBn) -G-OBn: Boc-glutamic acid (5.0 g, 20.2 mmol) was dissolved in THF (50.0 mL) and cooled to a temperature of 0 ° C in an ice bath. HATU (15.61 g, 41.0 mmol) was added followed by DIEA (6.5 g, 50.0 mmol). The reaction mixture was stirred at a temperature of 0 ° C for 30 minutes. It was added in THF (25.0 ml) glycine benzyl ester [8.45 g, 50 mmol, generated from the neutralization of benzyl glycine hydrochloride with sodium carbonate and through extraction with DCM and solvent removal]. The reaction mixture was allowed to reach rt and stirred for 20 minutes at rt. All volatiles were removed under reduced pressure. The residue was treated with a saturated sodium carbonate solution (100 ml) and extracted with ethyl acetate (3 x 100 ml). The organic layers were combined and washed with 1N HCl (2 x 100 ml) and water (2 x 100 ml) and dried (sodium sulfate). The solution was filtered and the solvent was removed under reduced pressure to produce a paste which was chromatographed on flash silica gel (500.0 g). Elution with 2% methanol in DCM produced the product in the form of a colorless paste (compound B, FIGURE 29A). Yield: 8.5 g (74.5%). 1 H NMR (CDCl 3): d 1.4 (s, 9H, -CJ ± 3s), 2.0-2.5 (m, 4H, -CH-CH_2 and CO-Cj ±), 4.2 (m, 5H, N-Cj ± s- CO), 5.15 (s, 4H, Ar-Cj ±), 5.45 (bs, 1H, Boc-NJ ±), 7.3 (m, 10H, AR-H) and 7.6 (2bs, 2H, CONj ±). M. S. - m / z 564.1 [M + H]. Analytical HPLC retention time - 8.29 minutes (> 97% pure, 20.65% B for 15 minutes). B. H-Glu (G-OBn) -G-OBn: The fully protected glutamic acid derivative (1.7 g, 3.2 mmol) B above was dissolved in DCM / TFA (4: 1, 20 ml) and stirred until that the starting material disappeared in TLC (2 h). The reaction mixture was poured into a saturated ice-cold sodium bicarbonate solution (200 ml) and the organic layer was separated and the aqueous layer was extracted with 2 x 50 ml of DCM and combined with the organic layer. The DCM layer was washed with saturated sodium bicarbonate (2 x 100 ml), water (2 x 100 ml) and dried (sodium sulfate). The solution was filtered and evaporated under reduced pressure and the residue was dried under vacuum to produce a glass (compound C, FIGURE 29A) which was taken for the next step without further purification. Production: 0.72 g (95%). M.S.-m / z 442.2 [M + H]. C. (DOTA-tri-t-butyl) -Glu- (G-OBn) -G-OBn: The above amine C (1.33 g, 3 mmol) in anhydrous DCM (10.0 ml) was added to an activated ester solution. tri-t-butyl-DOTA [2.27 g, 3.6 mmol was treated with HBTU, 1.36 g, 3.6 mmol and DIEA 1.04 g, 8 mmol and stirred for 30 minutes at rt in 25 ml of dry DCM], and stirred at rt during hours]. The reaction mixture was diluted with 200 ml of DCM and washed with saturated sodium carbonate (2 x 150 ml) and dried (sodium sulfate). The solution was filtered and the solvent was removed under reduced pressure to produce a brown paste. The crude product was chromatographed on flash silica gel (500.0 g). Elution with 2% methanol in DCM afforded the product in the form of a colorless gum (compound D, FIGURE 29A). Production 1.7 g (56.8%). 1 H NMR (CDCl 3): d 1.3 and 1.4 (2 s, 9 H, three methyls each of free base and sodium adduct of DOTA), 2.0 -3.5 (m, 20H, N-CH__s and -CH-CJ ±. -CI ± z), 3.75-4.5 (m, 13H, N-CI_b-CO), 5.2 (m, 4H, Ar-CH__) and 7.25 (m, 10H, Ar-H.). M.S. m / z - 1018.3 [M + Na] and 996.5 [M + H] and 646.3 [M + Na + H] / 2. HPLC - Retention time: 11.24 minutes (> 90%, 20-80% B for 30 minutes). D. (DOTA-tri-t-butii) -Glu- (G-OH) -G-OH: The bis-benzyl ester (0.2 g, 0.2 mmol) D above in methanol-water (20 ml, 9: 1) and hydrogenated at 50 psi in the presence of 10% Pd / C catalyst (0.4 g, 50 wt.% water). After the starting material disappeared on HPLC and TLC (4h), the solution filtered the catalyst and the solvent was removed under reduced pressure and the residue was dried under high vacuum for about 20 hours (<0.1 mm) to produce the product in the form of a colorless foam (compound E, FIGURE 29A).

Yield: 0.12 g (73.5%). 1 H NMR (DMSO-d 6): d 1.3 and 1.4 (2s, 9H corresponding to free base methyls and the DOTA sodium adduct), 1.8 - 4.7 (m, 33H, NCI ± sS, COCj ± s and CH-CH2 and NH-CI ± -CO), 8.1, 8.2, and 8.4 (3 bs, NHCO). M. S .: m / z - 816.3 [M + H] and 838.3 [M + Na]. HPLC retention time: 3.52 min (20-80% B for 30 minutes,> 95% pure). E. H-8-amino-3,6-dioxaoctanoyl-8-amino-3,6-dioxaoctanoyl-Gln-Trp-Ala-Val-Glv-His-Leu-Met-NHg Fmoc-Q (Trt) -W ( Boc) -AVGH (Trt) -LM-resin (0.5 g, 0.2 mmol) A and was coupled twice in sequences to 8-amino-3,6-dioxaoctanoic acid to produce the above deprotected peptide (compound F, FIGURE 29B) after purification by HPLC preparation. Yield: 91.0 mg (37%). HPLC retention time: 8.98 minutes (> 95% purity, 10-40% B for 10 minutes). M. S .: m / z-1230.6 [M + H], 615.9 [M + 2H] / 2. F. Solution phase coupling of bis-acid E and amine F above: (FIGURE 29B). The bis-acid (13.5 mg, 0.0166 mmol) E was dissolved in 100 μi of dry acetonitrile and treated with NHS (4.0 mg, 0. 035 mmol) and DIC (5.05 mg, 0.04 ml) and stirred for 24 hours at RT. The above activated acid, the free amine F (51.0 mg, 0.41 mmol) [generated from the TFA salt by treatment with saturated sodium bicarbonate and freeze drying the solution to produce the amine in the form of a fluffy solid] and was added followed by 100 μi of NMP and stirring was continued for an additional 40 hours at RT. The solution was diluted with anhydrous ether (10 ml) and the precipitate was collected by centrifugation and washed with 2 x 10 ml of anhydrous ether again. The crude solid was subsequently purified by HPLC preparation to produce the product in the form of a colorless fluffy solid L209 as in FIGURE 29B with a production of 7.5 mg (14.7%). Example XXIII - Figures 30A-B Synthesis of L210 A. H-8-amino-octanoyl-8-amino-octanoyl-Gln-Trp-Ala-Val-GIv-His-Leu-Met-NH ?: This also prepared in exactly the same manner as in the case of compound F (FIGURE 29B), but using amino-octanoic acid and the amine (compound B, FIGURE 30A) was purified by preparative HPLC. Yield: 95.0 mg (38.9%). HPLC retention time: 7.49 min (> 95% purity, 10-40% B for 10.0 minutes). M. S .: m / z - 1222.7 [M + H], 611.8 [M + 2H] / 2. It was converted (DOTA-tr-t-butyl) -Glu- (G-OH) -G-OH (0.0163 g, 0.02 mmol) in its NHS bis-ester as in the case of L209 in 100 μl of acetonitrile and treated with the base free, compound B (60.0 mg, 0.05 mmol) in 100 μl of NMP and the reaction was continued for 40 hours and subsequently worked up and purified as indicated above to prepare L210 (FIGURE 30B) for a yield of 11.0 mg (18% ). Example XXIV - Figure 31 Synthesis of L211 It was prepared from 0.2 g of Fmoc-Q (Trt) -W (Boc) -A-V-G-H (Trt) -L-M-resin (0.08 mmol) using standard protocols. N - [(3β, 5β, 12a) -3 - [[[4,7,10-tris (carboxymethyl) -1,4,7,10-tetra-azacyclododec-1-yl] acetyl] amino] glycyl was prepared -glycyl-4-aminobenzoyl-L-glutaminyl-L-tryptopyl-L-alanyl-L-valyl-glycyl-L-histidyl-L-leucyl-L-methioninamide L211 in a yield of 4.7 mg (FIGURE 31). Example XXV - Figure 32 Synthesis of L212 Prepared from the resin of Amide of Rink Novagel (0.47 mmol / g, 0.2 g, 0.094 mmol) building the sequence in the resin through standard protocols. N - [(3β, 5β, 12a) -3 - [[[4,7,10-tris (carboxymethyl) -1,4,7,1-tetra-azacyclodode c-1 -yl] acetyl was prepared ] amino] -glycyl-4-aminobenzoyl-L-glutamyl-L-tryptopyl-L-alanyl-L-valyl-glycyl-L-histidyl-L-leucyl-L-methioninamide L212 for a yield of 25.0 mg (17.7%) (FIGURE 32).

Example XXVI - Figure 33 Synthesis of L213 It was prepared from the resin of Fmoc-Met-2-chlorotrityl chloride (NovaBioChem, 0.78 mmol / g, 0.26 g, 0.2 mmol) and the rest of the sequence was constructed using standard methodology . N - [(3β, 5β, 12a) -3 - [[[4,7,10-tris (carboxymethyl) -1] was prepared, 4, 7,1 O-tetra-azacyclodode c-1-yl] acetyl] amino] -glycyl-4-aminobenzoyl-L-glutaminyl-L-tryptopyl-L-alanyl-L-valyl-glycyl-L-histidyl- L-leucyl-L-methionine L213 for a yield of 49.05 mg (16.4%). Example XXVII - Figure 34 Synthesis of L214 Fmoc-Q (Trt) -W (Boc) -AVGH (Trt) -LM-resin (0.2 g, 0.08 mmol) A was used to prepare N - [(3ß, 5ß, 12a) -3 - [[[4, 7,10 -tris (carboxymethyl) -1,4,7,10-tet ra-azacyl ododec- 1 -yl] acetyl] amino] -glycyl-4-aminobenzoyl-D-phenylalanyl- L-glutaminyl-L-tryptopyl-L-alanyl-L-valyl-glycyl-L-histidyl-L-leucyl-L-methioninamide L214 using standard conditions. 8.5 mg of the product (6.4%) was obtained (FIGURE 34). Example XXXVIII - Figure 35 Synthesis of L215 Fmoc-Q (Trt) -W (Boc-AVGH (Trt) -LM-resin (0.2 g, 0.08 mmol) A was used to prepare N - [(3ß, 5β, 12a) - 3 - [[[4,7,10-tris (carboxymethyl) -1,4,7,10-tetra-azacyclododec-1-yl] acetyl] amino] -glycyl-4-aminobenzoyl-L-glutaminyl-L-arginyl - L-leucyl-glycyl-L-asparaginyl-L-glutaminyl-L-tryptopyl-L-alanyl-L-valyl-glycyl-L-histidyl-L-leucyl-L-methioninamide L215. 9.2 mg (5.5%) were obtained (FIGURE 35). Example XXIX - Figure 36 Synthesis of L216 Fmoc-Q (Trt) -W (Boc) -AVGH (Trt) -LM-resin (0.2 g, 0.08 mmol) A was used to prepare N - [(3ß, 5ß, 12a) -3 - [[[4,7,10-tris (carboxymethyl) -1,4,7,10-tetra-aza-cid ododec-1-yl] acetyl] amino] -glycyl-4-aminobenzoyl-L-glutaminyl- arginyl-L-tyrosinyl-glycyl-L-asparaginyl-L-glutaminyl-L-tryptopyl-L-alanyl-L-valyl-glycyl-L-histidyl-L-leucyl-L-methioninamide L216. 25.0 mg (14.7%) were obtained (FIGURE 36). Example XXX - Figure 37 Synthesis of L217 We used Fmoc-Q (Trt) -W (Boc) -A-V-G-H (Trt) -L-M-resin A (0.2 g, 0.08 mmol) to prepare N - [(3β, 5β, 12a) -3 - [[[4,7,10-tris (carboxymethyl) -1,4,7,10-tet ra-azacicl ododec - 1 -yl] acetyl] amino] -glycyl-4-aminobenzoyl-L-glutaminyl-L-lysyl-L-tyrosinyl-glycyl-L-glutaminyl-L-tryptopyl-L-alanyl-L-valyl-glycyl-L- histidyl-L-leucyl-L-methioninamide L217. 58.0 mg (34.7%) were obtained (FIGURE 37). Example XXXI - Figure 38 Synthesis of L218 Fmoc-Q (Trt) -W (Boc) -A-V-G-H (Trt) -L-M-resin A (0.2 g, 0.08 mmol) was used. Fmoc-Lys (ivDde) was used for the introduction of lysine. Once the linear sequence was completed, the lysine protection group was removed using 10% hydrazine in DMF (2 x 10 ml, 10 minutes each and subsequently washed). The rest of the amino acids were subsequently introduced using the procedures described in the "general" section to complete the required peptide sequence. L218 in FIGURE 38 as obtained in a yield of 40.0 mg (23.2%). Example XXXII - Figure 39 Synthesis of L219 4-sulfamyl butyryl AM Novagel resin (1.1 mmol / g, 0.5 g, 0.55 mmol) was used. The first amino acid was loaded on this resin at a temperature of -20 ° C for 20 hours. The rest of the sequence was completed using normal coupling procedures. After washing, the resin was rented with 20.0 eq. of iodoacetonitrile and 10.0 equivalents of DIEA for 20 hours. After the resin the liquids were drained and washed, and later dissociated with 2.0 eq. of pentylamine in 5.0 ml of THF for 20 hours. Subsequently, the resin was washed with 2 x 5.0 ml of THF and all the filtrates were combined. THF was then evaporated under reduced pressure and the residue was subsequently deblocked with 10.0 ml of reagent B and the N-peptide was purified. [(3β, 5β, 12a) -3 - [[[4,7,10-tris (carboxymethyl) -1,4,7,1-tetraazacyclodode c-1 -yl] acetyl] amino] -glycyl-4- aminobenzoyl-D-phenylalanyl-L-glutaminyl-L-tryptopyl-L-alanyl-L-valyl-glycyl-L-histidyl-L-leucyl-aminopentyl, L219 as previously described. 28.0 mg (2.8%) were obtained (FIGURE 39). Example 33 - Figure 40 Synthesis of L220 Resin A NovaSyn TGR (0.25 mmol / g, 0.15 g, 0.05 mmol) was used to prepare N - [(3ß, 5β, 12a) -3 - [[[4,7,10 -tris (carboxymethyl) -1,4,7,10-tetra-azacyclododec-1-yl] acetyl] amino] -glycyl-4-aminobenzoyl-L-glutaminyl-L-triptophoyl-L-alanyl-L-valil-D -alanyl-L-histidyl-L-leucyl-L-methioninamide, L220. 31.5 mg (41.4%) were obtained (FIGURE 40). Example XXXIV - Figure 41 Synthesis of L221 Resin A NovaSyn TGR (0.25 mmol / g, 0.15 g, 0.05 mmol) was used to prepare N - [(3ß, 5β, 12a) -3 - [[[4.7, 10 -tris (carboxymethyl) -1,4,17 O-tetra-azacyclodode c-1-yl] acetyl] amino] -glycyl-4-aminobenzoyl-L-phenylalanyl-glutaminyl-L-triptophoyl-L-alanyl- L-valii-glycyl-L-histidyl-L-leucyl-L-leucine ida, L221. 28.0 mg (34.3%) were obtained (FIGURE 41). Example 35 - Figure 42 Synthesis of L222 Resin A NovaSyn TGR (0.25 mmol / g; 0.15 was used. g, 0.05 mmol) to prepare N - [(3β, 5β, 12a) -3 - [[[4,7, 10-tris (carboxymethyl) -1,4,7,1-tetra-azacyclododec-1-yl] ] acetyl] amino] -glycyl-4-aminobenzoyl-D-tyrosinyl-L-glutaminyl-L-tryptopyl-L-alanyl-L-valyl-beta-alanyl-L-histidyl-L-phenylalanyl-L-norleucinamide, L222. 34.0 mg (40.0%) were obtained (FIGURE 42). Example XXXVI - Figure 43 Synthesis of L223 Resin A NovaSyn TGR (0.25 mmol / g) was used; 0.15 g, 0.05 mmol) to prepare N - [(3ß, 5β, 12a) -3 - [[[4,7,10-tris (carboxymethyl) -1,4,7,10-tetra-azacyclododec-1-yl] ] acetyl] amino] -glycyl-4-aminobenzoyl-L-phenylalanyl-L-glutaminyl-L-tryptopyl-L-alanyl-L-valyl-beta-alanyl-L-histidyl-L-phenylalanyl-L-norleucinamide, L223. 31.2 mg (37.1%) were obtained (FIGURE 43). Example XXXVI - Figure 44 Synthesis of L224 Resin A NovaSyn TGR (0.25 mmol / g, 0.15 g, 0.05 mmol) was used to prepare N - [(3ß, 5β, 12a) -3 - [[[4.7, 10 -tris (carboxymethyl) -1,4,7,10-tetra-azacyclododec-1-yl] acetyl] amino] -glycyl-4-aminobenzoyl-L-glutaminyl-L-tryptopyl-L-alanyl-glycyl-L-histidyl -L-phenylalanyl-L-leucinamide, L224. 30.0 mg (42.2%) were obtained (FIGURE 44). Example XXXVIII - Figure 45 Synthesis of L225 Resin A NovaSyn TGR (0.25 mmol / g, 0.15 g, 0.05 mmol) was used to prepare N - [(3ß, 5β, 12a) -3 - [[[4,7,10-tris (carboxymethyl) -1, 4,7,10-tetra-azacyclododec-1-yl] acetyl] amino] -glycyl-4-aminobenzoyl-L-leucyl-L-tryptopyl-L-alanyl-L-valinyl-glycyl-L-serinyl-L-phenylalanyl -L-methioninamide, L225. 15.0 mg (20.4%) were obtained (FIGURE 45). Example XXXIX - Figure 46 Synthesis of L226 Resin A NovaSyn TGR (0.25 mmol / g, 0.15 g, 0.05 mmol) was used to prepare N - [(3β, 5β, 12a) -3 - [[[4,7,10 -tris (carboxymethyl) -1,4,7,10-tetra-azacyclododec-1-yl] acetyl] amino] -glycyl-4-aminobenzoyl-L-histidyl-L-triptophoyl-L-alanyl-L-valyl-glycyl -L-histidyl-L-leucyl-L-methioninamide, L226. 40.0 mg (52.9%) were obtained (FIGURE 46). Example XL - Figure 47 Synthesis of L227 Resin A NovaSyn TGR (0.25 mmol / g, 0.15 g, 0.05 mmol) was used to prepare N - [(3ß, 5β, 12a) -3 - [[[4,7,10 -tris (carboxymethyl) -1,4,7,10-tetra-azacyclododec-1-yl] acetyl] amino] -glycyl-4-aminobenzoyl-L-leucyl-L-triptophoyl-L-alanyl-L-threonyl] - glycyl-L-histidyl-L-phenylalanyl-L-methioninamide, L227. 28.0 mg (36.7%) were obtained (FIGURE 47). Example XLI - Figure 48 Synthesis of L228 Resin A NovaSyn TGR (0.25 mmol / g, 0.15 g, 0.05 mmol) was used to prepare N - [(3ß, 5β, 12a) -3 - [[[4,7,10-tris (carboxymethyl) -1, 4,7,10-tetra-azacyclododec-1-yl] acetyl] amino] -glycyl-4-aminobenzoyl-L-glutaminyl-L-triptophoyl-L-alanyl-glycyl-L-valyl-glycyl-L-histidyl-L -phenylalanyl-L-methioninamide, L228. 26.0 mg (33.8%) were obtained (FIGURE 48). Example XLII - Synthesis of additional GRP compounds A. General procedure for the preparation of 4,4'-aminomethylbiphenylcarboxylic acid (B2) and 3,3'-aminomethylbiphenylcarboxylic acid (B3): 1. Methyl-hydroxymethylbiphenylcarboxylates: 4-hydroxymethylphenylboronic acid was stirred or acid 3-hydroxymethylphenylboronic acid (1.0 g, 6.58 mmol) commercially available (Aldrich Chemical Co.) with isopropanol (10 ml) and 2M sodium carbonate (16 ml) until the solution became homogeneous. Gases were removed to the solution by passing nitrogen through the solution and subsequently treated with methyl-3-bromobenzoate, or solid methyl-4-bromobenzoate 81.35 g, 6.3 mmol) followed by catalyst Pd (0). { [(C6H5) 3P] Pd; 0.023 g, 0.003 mmol} . The reaction mixture was refluxed under nitrogen until the starting bromobenzoate was consumed as determined by TLC analysis (2-3 hours). The reaction mixture was subsequently diluted with 250 ml of water and extracted with ethyl acetate (3 x 50 ml). The organic layers were combined and washed with saturated sodium bicarbonate solution (2 x 50 ml) and dried (Na2SO). The solvent was removed under reduced pressure and the residue was chromatographed on flash silica gel (100 g). Elution with 40% ethyl acetate in hexanes afforded the product either in solid form or in the form of oil. Yield: B2-0.45 g (31%); p.f. = 170-171 ° C. B3 - 0.69 g (62%); oil. 1 H NMR (CDCl 3) d B2 - 3.94 (s, 3 H, -COOCH 3), 4.73 (s, 2 H, -CH 2-Ph), 7,475 (d, 2 H, J = 5 Hz), 7.6 (d, 2 H, J = 10 Hz), 7.65 (d, 2H, J = 5 Hz) and 8.09 (d, 2H, J = 10 Hz). M. S.-m / e-243.0 [M + H]. B3-3.94 (s, 3H, -COOCH3), 4.76 (s, 2H, -CH2-Ph), 7.50 (m, 4H), 7.62 (s, 1H), 7.77 (s, 1H), 8.00 (s, 1H) ) and 8.27 (s, 1H). M.S.-m / e 243.2 [M + H]. 2. Azidomethyl biphenyl carboxylate: The above biphenyl alcohols (2.0 mmol) in dry dichloromethane (10 ml) were cooled on ice and treated with diphenylphosphoryl azide (2.2 mol) and DBU (2.0 mmol) and stirred under nitrogen for 24 hours. hours. The reaction mixture was diluted with water and extracted with ethyl acetate (2 x 25 ml). The organic layers are they combined and washed successfully with a solution of 0.5 M citric acid (2 x 25 ml), water (2 x 25 ml) and dried (Na2SO4). The solution was filtered and evaporated under reduced pressure to produce the crude product. The 4,4'-isomer was crystallized from hexane / ether and the 3,3'-isomer was titrated with isopropyl ether to remove all impurities; the product became homogeneous as determined in the TLC analysis and no further purification was required. Yield: Metii-4-azidomethyl-4-biphenylcarboxylate - 0.245 g (46%); p. F. = 106-108 ° C. Methyl-azidomethyl-4-biphenyl-carboxylate - 0.36 g (59%, oil). 1 H NMR (CDCl 3) d - 4,4'-isomer-3.95 (s, 3 H, -COOCH 3), 4.41 (s, 2 H, -CH 2 N 3), 7.42 (d, 2 H, J = 5 Hz), 7.66 (m , 4H), and 8.11 (d, 2H, J = 5 Hz). 3,3'-isomer - 3.94 (s, 3H, -COOCH3), 4.41 (s, 2H, -CH2N3), 7.26-7.6 (m, 5H), 7.76 (d, 1H, J = 10 Hz), 8.02 ( d, 1H, J = 5 Hz) and 8.27 (s, 1H). 3. Hydrolysis of the methyl esters of biphenylcarboxylates: Approximately 4 mmol of methyl esters were treated with 20 ml of 2M lithium hydroxide solution and stirred until the solution became homogeneous (20-24 hours). The aqueous layer was extracted with 2 x 50 ml of ether and the organic layer was discarded. Subsequently, the aqueous layer was acidified with 0.5 M citric acid and the precipitated solid was filtered and dried. No further purification was necessary and the acids were taken for the next step. Yield: 4,4'-isomer - 0.87 g of methyl ester produced 0.754 g of the acid (86.6%); p. F. = 205-210 ° C. 3,3'-isomer - 0.48 g of methyl ester produced 0.34 g of the acid (63.6%); p. F. 102-105 ° C. 1 H NMR (DMSO-de) d: 4,4'-isomer-4.52 (s, 2 H, -CH 2 N 3), 7.50 (d, 2 H, J = 5 Hz), 7.9 (m, 4 H), and 8.03 (d, 2H, J = 10 Hz). 3,3'-isomer - 4.54 (s, 2H, -CH2N3), 7.4 (d, 1H, J = 10 Hz), 7.5-7.7 (m, 4H), 7.92 (ABq, 2H), and 8.19 (s, 1 HOUR). 4. Reduction of the azides to the amine: This was carried out in the solid phase and the amine never isolated. The azidocarboxylic acid was loaded into the resin using standard peptide coupling protocols. After washing, the azide-containing resin was stirred with 20 equivalents of triphenylphosphine in THF / water (95: 5) for 24 hours. The solution was drained under a positive nitrogen pressure and subsequently washed with a standard washing procedure. The resulting amine was used in the next coupling. 5. Acid (3ß.5ß.7a.12a) -3-r ((9H-fluoren-9- ilmethoxy) amino] acetyl) amino-7,12-dihydroxycolan-24-oico: Tributylamine (3.2 ml, 13.5 mmol) was added dropwise to a solution of Fmoc-glycine (4.0 g, 13.5 mmol) in THF (80 g). ml) stirred at a temperature of 0 ° C. Subsequently isobutylchloroformate (1.7 ml, 13.5 mmol) was added, and after 10 minutes, a suspension of tributylamine (2.6 ml, 11.2 mmol) and acid (3ß, 5ß, 7a) was added as drops for 1 hour to the cooled solution. , 12a) -3-amino-7,12-dihydroxycolan-24-oico (4.5 g, 11.2 mmol) in DMF (80 ml). The mixture was allowed to warm to room temperature and after 6 hours, the solution was concentrated to 120 ml, then (final pH 1.5), water (180 ml) and 1N HCl (30 ml) were added. The precipitated solid was filtered, washed with water (2 x 100 ml), dried in vacuo and purified by flash chromatography. Elution with chloroform / methanol (8: 2) afforded the product in the form of a colorless solid. Yield: 1.9 g (25%). TLC: Rf 0.30 (CHCl 3 / MeOH / NH 4 OH - 6: 3: 1). ELABORATION OF IN VITRO AND IN VIVO TESTS OF THE COMPOUNDS Example XLIII: In vitro binding assay for GRP receptors in PC3 cell lines - Figures 14A-B To identify potential conductive compounds, an in vitro assay was used to identify compounds with high affinity for GRP-R. From PC3 cell line, derived from human prostate cancer, it is known to exhibit high expression of GRP-R on the cell surface, a radioligand binding assay was developed in a 96-well plate format and validated to measure the binding of 125 I-BBN to PC3 positive GRP-R cells and the ability of the compounds of the present invention to inhibit this binding. This assay was used to measure IC50 for ligand RP527, DO3A-monoamide-Aoc-QWAVGHLM-NH2 (controls) and compounds of the present invention that inhibit the binding of 125I-BBN to GRP-R. (RP527 = N, N-dimethylglycine-Ser-Cys (Acm) -Gly-5-aminopentanoic acid-BBN (7-14) acid [SEQ ID NO: 1], which has MS = 1442.6 e 1C50 -0.84). Van de Wiele C, Dumont F. and Associates, Technetium-99m RP527, to GRP analogue for visualization of GRP receptor-expressing malignancies: a feasibility study. Eur. J. Nucí. Med. 27; 1694-1699 (2000). It also refers to DO3A-monoamide-Aoc-QWAVGHLM-NH2 as the acid DO3A-monoamide-8-amino-octanoic-BBN (7-14) [SEQ ID NO: 1], and has MS = 1467.0. DO3A monoamide-amino-octanyl-BBN [7.14]. The Radioligand Link Plate Assay for BBN and BBN analogs (including commercially available BBN and L1) was validated and also using 99mTc RP527 as the radioligand.

A. Materials and methods: 1. Cell culture: PC3 (human prostate cancer cell line) was obtained from the American Type Culture Collection and cultured in RPMl 1640 (ATCC) in tissue culture flasks (Corning). This growth medium was supplemented with FBS deactivated with 10% heat(Hyclone, SH30070.03), 10 mM HEPES (Gibco BRL, 15630-080), and antibiotic / antifungal (GibcoBRL, 15240-062) for a final concentration of penicillin-streptomycin (100 units / ml), and fungizone (0.25) μg / ml). All the cultures were kept in a humidified atmosphere containing % CO2 / 95% air at a temperature of 37 ° C and passed routinely using 0.05% trypsin / EDTA (GibcoBRL 25300-054) when indicated. Cells for experiments were plated at a concentration of 2.0x104 / deposit in either 96-well clear / white microtiter plates.

(Falcon Optilux-I) or in 96-deposit black / clear collagen cell plates (Beckton Dickinson Biocoat). The plates were used for link studies on day 1 62 after plating. 2. Link regulator: RPMl 1640 (ATCC) supplemented with 20 mM HEPES, 0.1% BSA (w / v), 0.5 mM PMSF (AEBSF), bacitracin (50 mg / 500 ml), pH 7.4. 125 I-BBN (vehicle-free, 2200 Ci / mmol) in Perkin-Elmer. B. 125I-BBN competition assay for GRP-R in PC3 cells: A 96-well plate assay was used to determine the EC50 of various compounds of the present invention to inhibit the binding of 125 I-BBN of human GRP-R . The following general procedure was followed: All the tested compounds were dissolved in the binding buffer and also suitable dilutions were carried out in the binding buffer. PC3 cells (human prostate cancer cell line) were plated for assay at a concentration of 2.0x104 / deposit either in 96-well white / clear microtiter plates (Falcon Optilux-I) or in collagen cellware plates I black / clear 96 deposits (Beckton Dickinson Biocoat). The plates were used for link studies on day 1 or 2 after plating. Plates were checked for confluence (more than 90% confluent) before assay. For the assay, RP527 or ligand DO3A-monoamide-Aoc-QWAVGHLM-NH2 (controls) or compounds of the present invention were incubated in concentrations ranging from 1.25 x 10"9M to 5x10" 9M, with 125I-BBN (25,000 cpm / Deposit). These studies were carried out with a test volume of 75 μl per Deposit. Deposits were used in triplicate for each data point. After the addition of the appropriate solutions, the plates were incubated for 1 hour at a temperature of 4 ° C to avoid internalization of the ligand-receptor complex. The incubation was terminated by the addition of 200 μl of ice-cooled incubation buffer. The plates were washed five times and dried with blotting paper. Radioactivity was detected using either the LKB CompuGamma counter or a microplate scintillation counter. The competition binding curves for RP527 (control) and L70, a compound of the present invention, can be found in Figures 14A-B. These data show that the IC50 of the RP527 control is 2.5 nM and that L70, a compound of the present invention is 5 nM. The IC50 of the DO3A-monoamide-Aoc-QWAVGHLM-NH2 control was 5 nM. The IC50 controls for these tested compounds of the present invention can be found in Tables 1 to 3, supra. and show that they are comparable to those of the controls and therefore can be expected to have sufficient affinity for the receptor to allow uptake by the receptor containing the cells in vivo. C. Internalization and effluvium assay: These studies were carried out on a 96-well plate deposits. After washing to remove serum proteins, PC3 cells were incubated with 125I-BBN, 177Lu-DO3A-monoamide-Aoc-QWAVGHLM-NH2 or radiolabelled compounds of the present invention for 40 minutes at a temperature of 37 ° C. Incubations were stopped by the addition of 200 μl of ice-cold binding buffer. The plates were washed twice with linker. To eliminate bound radioligand on the surface, cells were incubated with 0.2M acetic acid (in saline) pH 2.8 for 2 minutes. The plates were centrifuged and the acid washing media was collected to determine the amount of radioactivity that was not internalized. The cells were harvested to determine the amount of internalized 125I-BBN, and the samples were analyzed in the gamma counter. The internalization test data were normalized by comparing the counts obtained at various points in time with the counts obtained at the final time point (T40 minutes). For the effluvium studies, after loading the PC3 cells with 125 I-BBN or radiolabelled compounds of the present invention for 40 minutes at a temperature of 37 ° C, the unbound material was filtered and the percent internalization was determined as described above. Subsequently, the cells they were suspended again in the binding regulator at a temperature of 37 ° C for up to 3 hours. At 0.5, 1, 2, or 3 hours, the remaining amount interned was determined in relation to the initial loading level as described above, and was used to calculate the percentage of effluvium recorded in Table 5. TABLE 5 Internalization and effluvium of complexes 125I-BBN and Lu-177 of DO3A-monoamide-Aoc-QWAVGHLM-NH2 (control) and compounds of the present invention These data show that the compounds of the present invention are interned and retained by the PC3 cells to a degree similar to that of the controls. Example XLIV - Preparation of Te-labeled GRP compounds Solutions of peptide compounds of the present invention identified in Table 6 were prepared in a concentration of 1 mg / ml in aqueous TFA a. 0.1%. A solution of stannous chloride was prepared by dissolving SnCl2 »2H2O (20 mg / ml) in 1N HCl. They prepared stannous gluconate solutions containing 20 μg of SnCl * 2H2O / 100 μl, adding an aliquot of the SnCl2 solution (10 μl) to a solution of sodium gluconate prepared by dissolving 13 mg of sodium gluconate in water. A solution of hydroxypropyl gamma-cyclodextrin [HP-α-CD] was prepared by dissolving 50 mg of HP-α-CD in 1 ml of water. Compounds labeled with 99mTc, identified below, were prepared by mixing 20 μl of solution of the unlabeled compounds (20 μg), 50 μl of HP-α-CD solution, 100 μl of Sn-gluconate solution and from 20 to 50 μl of 99mTc pertechnetate (5 to 8 mCi, Syncor). The final volume was around 200 μl and the final pH was 4.5 to 5. The reaction mixture was heated to a temperature of 100 ° C for 15 to 20 minutes, and subsequently analyzed by reverse phase HPLC to determine the radiochemical purity (RCP). The peaks of the desired product were isolated by HPLC, collected in a stabilization buffer containing 5 mg / ml of ascorbic acid, 16 mg / ml of HP-α-CD and 50 mM of phosphate buffer, pH 4.5, and concentrated using a speed vacuum to remove acetonitrile. The HPLC system used for analysis and purification was as follows: Vydac C18 column, 4.6 x 250 mm, aqueous phase: 0.1% TFA in water, organic phase: 0.085% TFA in acetonitrile. Flow range: 1 ml / min. Socratic elution in 20 to 25% acetonitrile / 0.085% TFA was used, depending on the nature of the individual peptide. The labeling results are summarized in table 6. TABLE 6 n.d. = not detected. 1: All the compounds were conjugated with a metal chelator N, N'-dimethylglycyl-Ser-Cys-Gly. The protected form of ligand mAb was used. Therefore, the ligand used to prepare the 99mTc complex of L2, was N, N'-dimethylglycyl-Ser-Cys (Acm) -Gly-RJQWAVGHLM-NH2. The mAb group was eliminated during chelation to Te. 2: In the sequence, "J" refers to 8-amino-3,6- dioxaoctanoic and "a" refers to D-alanine. 3: The initial CPR measurement was taken immediately after heating and before HPL purification. 4: CPR was determined after HPLC isolation and removal of acetonitrile through speed vacuum. Example XLV - Preparation of 177Lu-L64 for cell-binding studies and biodistribution: This compound was synthesized by incubating 10 μg of LC64 ligand (10 μl of a 1 mg / ml solution in water), 100 μl of ammonium acetate buffer ( 0.2M, pH 5.2) and -1-2 mCi of 177LuCI3 in 0.05N HCl (MURR) at a temperature of 90 ° C for 15 minutes. Free 177Lu was purified by adding 20 μl of a 1% Na2EDTA * 2H2O (Aldrich) solution in water. The resulting radiochemical purity (RCP) was ~ 95%. The radiolabelled product was separated from unlabeled ligand and other impurities by HPLC, using a YMC Basic C8 column [4.6 x 150 mm], a column temperature of 30 ° C and a flow range of 1 ml / min, with a gradient from 68% A / 32% B to 66% A / 34% B for 30 minutes, where A is citrate regulator (0.02M, pH 3.0) and B is 80% CH3CN / 20% CH3OH. The isolated compound had a PCR of ~ 100% and an HPLC retention time of 23.4 minutes. Samples were prepared for the biodistribution and cell link studies collecting the HPLC peak desired in 1000 μl of citrate regulator (0.05 M, pH 5.3, containing 1% ascorbic acid, and 0.1% HSA). The organic eluent in the collected eluate was removed by centrifugal concentration for 30 minutes. For cell binding studies, the purified mixture was diluted with a cell binding medium at a concentration of 1.5 μCi / ml in 30 minutes of the in vitro study. For biodistribution studies, the mixture was diluted with citrate buffer (0.05 M, pH 5.3, containing 1% sodium ascorbic acid and 0.1% HSA) to a final concentration of 50 μCi / ml at 30 minutes of the study in vivo Example 46 - Preparation of 177Lu-L64 for radiotherapy studies: This compound was synthesized by incubating 70 μg of L64 ligand (70 μl of a 1 mg / ml solution in water), 200 μl of ammonium acetate buffer (0.2M, pH 5.2) and -30-40 mCi of 177LuCI3 in 0.05N HCl (MURR) at a temperature of 85 ° C for 10 minutes. After cooling to room temperature, free 177Lu was purified by adding 20 μl of a 2% Na2EDTA «2H2O (Aldrich) solution in water. The resulting radiochemical purity (RCP) was -95%. The radiolabelled product was separated from the unlabeled ligand and other impurities by HPLC, using a 300VHP Anion Exchange column (7.5 x 50 mm) (Vydac) which was eluted in sequences in a range of flow of 1 ml / min with water, 50% acetonitrile / water and subsequently 1 g / l of aqueous ammonium acetate solution. The desired compound was eluted from the column with 50% CH3CN and mixed with -1 ml of citrate buffer (0.05 M, pH 5.3) containing 5% ascorbic acid, 0.2% HSA and 0.9% benzyl alcohol (v. : v). The organic part of the isolated fraction was removed by vacuum with turns for 40 minutes, and the concentrated solution (-20-25 mCi) was adjusted to 30 minutes of the in vivo study to a concentration of 7.5 mCi / ml using citrate buffer (0.05 M, pH 5.3) containing 5% ascorbic acid, 0.2% HSA and 0.9% benzyl alcohol (v: v). The resulting compound had an RCP of > 95% Example XLVII - Preparation of 111ln-L64: This compound was synthesized by incubating 10 μg of L64 ligand (5 μl of a 2 mg / ml solution in 0.01 N HCl), 60 μl of ethanol, 1.12 mCi of 111 lnCl 3 in 0.05 N HCl ( 80 μl) and 155 μl of sodium acetate buffer (0.5 M, pH 4.5) at a temperature of 85 ° C for 30 minutes. Free 111 ln was purified by adding 20 μl of a 1% solution Na2EDTA »2H2O (Aldrich) in water. The resulting radiochemical purity (RCP) was 87%. The radiolabelled product was separated from unlabeled ligand and other impurities by HPLC, using a Vydac C18 column [4.6 x 250 mm], at a column temperature of 50 ° C and a range flow rate of 1.5 ml / min. with a gradient of 75% A / 25% B at 65% A / 35% B for 20 minutes, where A is 0.1% TFA in water, B is 0.085% TFA in acetonitrile. With this system, the retention time for 111ln-L64 is 15.7 minutes. The isolated compound had a PCR of 96.7%. Example XLVIII - Preparation of 177Lu-DO3A-monoamide-Aoc-QWAVGHLM-NH2 (Control) An existing peptide solution was prepared by dissolving the ligand DO3A-monoamide-Aoc-QWAVGHLM-NH2 (prepared as described in the Application Publication No. 2002/0054855 and Publication No. WO 02/87637, both incorporated herein by reference) in 0.01 N HCl at a concentration of 1 mg / ml. 177Lu-DO3A-monoamide-Aoc-QWAVGHLM-NH2 was prepared by mixing the following reagents in the order shown. 0.2 M NH4OAc, pH 6.8 100 μl Peptide stock, 1 mg / ml, in 0.01N 5 μl HCl 11LuCI3 (MURR) in 0.05M HCl 1.2 μl (1.4 mCi) The reaction mixture was incubated at a temperature of 85 ° C for 10 minutes. After cooling to room temperature in a water bath, 20 μl of a 1% EDTA solution and 20 μl of EtOH were added. The compound was analyzed by HPLC using column C18 (VYDAC Cat. # 218TP54) which was eluted in a range of flow of 1 ml / min with a gradient of 21 to 25% B during minutes, where A is 0.1% TFA / H2O and B is 0.1% TFA / CH3CN). 177Lu-DO3A-monoamide-Aoc-QWAVGHLM-NH2 was formed in 97.1% yield (RCP) and had a retention time of -16.1 min in this system. Example XLIX - Preparation of 177Lu-L63 This compound was prepared as described for 177Lu-DO3A-monoamide-Aoc-QWAVGHLM-NH2. The compound was analyzed by HPLC using column C18 (VYDAC CAT # 218TP54) which was eluted in a flow range of 1 ml / min with a gradient of 30 to 34% B for 20 minutes (where solvent A is 0.1% TFA / H2O and B is 0. 1% TFA / CH3CN). The 177Lu-L63 that was formed had a CPR of 97.8% and a retention time of -14.2 min in this system. Example L - Preparation of "l77Lu-L70 for cell-binding studies and biodistribution: This compound was prepared following the procedures described above, but replacing L70 (the ligand of Example II). Purification was carried out using a YMC column. Basic C8 (4.6 x 150 mm), at a column temperature of 30 ° C and a flow range of 1 ml / min with a gradient of 80% A / 20% B to 75% A / 25% B for 40 minutes, in where the citrate regulator (0.02M, pH 4.5), and B is 80% CH3CN / 20% CH3OH. He The composite had a CPR of -100% and an HPLC retention time of 25.4 min. Example Ll - Preparation of 177Lu-L70 for radiotherapy studies: This compound was prepared as described for L64. Example Lll - Preparation of 111ln-L70 for cell binding studies and biodistribution: This compound was synthesized by incubating 10 μg L70 of ligand (10 μL of a 1 mg / ml solution in 0.01N HCl), 180 μL of ammonium acetate buffer (0.2M, pH 5.3), 1.1 mCi of 111lnCI3 in 0.05N HCL (61 μl, Mallinckrodt) and 50 μl of saline at a temperature of 85 ° C for 30 minutes. Free 111 ln was purified by adding 20 μl of a 1% solution Na2EDTA »2H2O (Aldrich) in water. The resulting radiochemical purity (PCR) was 86%. The radiolabelled product was separated from unlabeled ligand and other impurities by HPLC, using a Waters cartridge XTerra C18 bound to a Vydac strong anion exchange column [7.5 x 50 mm], at a column temperature of 30 ° C and a flow range of 1 ml / min with the gradient described in the table below , where A is 0.1 mM NaOH in water, pH . 0, B is 1 g / l of ammonium acetate in water, pH 6.7 and C is acetonitrile. With this system, the retention time for 111ln-L70 it is 15 minutes while the retention time for ligand L70 is 27 to 28 minutes. The isolated compound had a PCR of 96%. Samples from the biodistribution and cell binding studies were prepared by collecting the desired HPLC peak in 500 μl citrate buffer (0.05 M, pH 5.3, containing 5% ascorbic acid, 1 mg / ml L-methionine and 0.2% HSA) ). The organic part of collection was eliminated by rotary vacuum for 30 minutes. For cell-binding studies, the purified, concentrated sample was used at 30 minutes of the in vitro study. For biodistribution studies, the sample was diluted with citrate buffer (0.05M, pH 5.3, containing ascorbic acid of only 5% and 0.2% HSA) to a final concentration of 10 μCi / ml at 30 minutes of study in vitro.

Example Lili - In vivo pharmacokinetic studies a. Trace dose distribution: Low-dose pharmacokinetic studies (for example, biodistribution studies) were carried out using the compounds identified below of the present invention in deprived mice containing tumor PC3, xenografted ([Ncr] -Foxn1 <nu>). In all the studies, the mice were administered 100 μl of test compound labeled with 177 Lu at 200 μCi / kg, i.v., with a residence time of 1 to 24 hours per group (n = 3-4). The tissues were analyzed in a LKB 1282 CompuGamma counter with appropriate standards. TABLE 7 Pharmacokinetic comparison at 1 and 24 hours in unprotected mice containing PC3 tumor. (200 μCi / kg, values as% ID / g) of compounds labeled with 177Lu-177 of the present invention compared to the control.

Although the distribution of radioactivity in the blood, liver and kidneys after injection of L64 and L70 is similar to that of the control compound, DO3A-monoamide-Aoc-QWAVGHLM-NH2, the uptake in the tumor is much greater at 1 and 24 hours for both L64 and L70. L63 also shows higher tumor uptake although with blood and liver values increased in earlier times. Uptake in the mouse pancreas, a normal organ known to have GRP receptors, is much higher for L64, L70 and L63 than for the control compound DO3A-monoamide-Aoc-QWAVGHLM-NH2. Example LIV - Receptor Subtype Specificity. Normally, four mammalian members of the GRP receptor family are known: the receptor that prefers GRP (GRP-R), the receptor that prefers neuromedin-B (NMB-R), the bombesin 3 receptor subtype (BB3-R). ) and the bombesin 4 receptor subtype (BB4-R). The specificity of the 177Lu-L70 subtype was investigated. The results are indicated at 177Lu-L70 specifically for GRP-R and NMB-R and have little affinity for BB3-R. The specificity of the Lutetium complex subtype of L70 (here, 177Lu-L70) prepared as described supra) was determined through in vitro receptor autoradiography using the procedure described in the Reubi et al. Publication. " Bombesin Subtypes Receptor in Human Cancers: Detection with Universal Radioligand 125l- [D-Tyr6, Beta-Ala, Phe13, Nle14] ", Clin. Cancer Res. 8: 1139-1146 (2002) and in tissue samples in which they have previously been found to express only one subtype of GRP receptor, as well as non-neoplastic tissues including normal pancreas and colon, as well as chronic pancreatitis (which they are shown later in Table 8a). Human lobe carcinoid tissue was used as a source of NMB-R, human prostate carcinoma for GRP-R and human bronchial carcinoid for subtype receptors. For comparison, a receptor autoradiography was also carried out with other bombesin radioligands such as 125l-Tyr4-bombesin or a compound known in the Universal Ligand, 125 | - [DTyr6, ßAla11, Phe13, Nle1] -BBN (6- 14), which links the three subgroups of GRP-R, in sections of adjacent tissue. For an additional description, see the publication of Fleischmann et al., "Bombesin Receptors in Distinct Tissue Compartments of Human Pancreatic Diseases," Lab. Invest. 80: 1807-1817 (2000); Markwalder et al., "Gastin-Releasing Peptide Receptors in the Human Prostate: Relation to Neoplastic Transformation", Cancer Res. 59: 1152-1159 (1999); Gugger et al., "GRP Receptors in Non-Neoplastic and Neoplastic Human Breast," Am. J. Pathol. 155-2067-2076 (1999).

TABLE 8A Detection of bombesin receptor subtypes in various human tissues using different radioligands. l- [DTyrb, ßAla11, Phe ", Nle"] - BBN (6-14) and 1¿0l-Tyr -BBN As seen from Table 8a, all tumors expressing GRP-R, such as prostatic, mammary, and renal cell carcinomas, identified with established radioligands, were also visualized in vitro with 177Lu-L70. Due to better sensitivity, selected tumors with low levels of GRP-R can be identified with 177Lu-L70, but not with 25l-Tyr-BBN, as shown in Table 8a. All tumors expressing NMB-R, identified with established radioligands, were also visualized with 177Lu-L70. Fit Inverse, none of the BB3 tumors were detected with 177 Lu-L70. No conclusion should be drawn on the natural incidence of receptor expression in several types of tumors described in Table 8a, since the cases tested were chosen as positive-receptor in most cases, only with some selected negative controls . The normal human pancreas is not labeled with 177Lu-L70, whereas the mouse pancreas is strongly labeled under identical conditions. Although the normal pancreas is a tissue that degrades very quickly and protein degradation can never be completely excluded, including receptors, the factors that suggest that human pancreas data are really negative, include the positive control of the mouse pancreas under a similar condition and strongly labeled BB3 found in the respective human pancreas islets, which represent a control positive for the quality of the human pancreas investigated. In addition, the detection of GRP-R in pancreatic tissues that are pathologically altered (chronic pancreatitis) indicates that GRP-R, when found, can be identified under experimental conditions chosen in this tissue. In fact 177Lu-L70 identifies these GRP-R in chronic pancreatitis with greater sensitivity to 125l-Tyr4-BBN. Although none of the Pancreatic cancers had measurable amounts of GRP-R, some colon carcinomas showed a low density of GRP receptors distributed heterogeneously with 177Lu-L70 (Table 8a). It should also be noted that the smooth muscles of colon express GRP-R and were detected in vitro with 177Lu-L70 as well as with the established bombesin ligands. TABLE 8B Linkage affinity of 175Lu-L70 to the 3 bombesin receptor subtypes expressed in human cancers. The data are expressed as IC50 in nM (mean ± SEM, n = number of experiments in parentheses) As shown in Table 8b, 175Lu-L70 had a very high affinity with human GRP and NMB receptors expressed in human tissues while having only little affinity for BB3 receptors. These experiments used 125l- [DTyr6, ßAla11, Phe13, Nle14] -BNP (6-14) as the radiotracer. Using L70 labeled with 177Lu as radiotracer, the aforementioned data is confirmed and extended in this way. All the Human cancers expressing GRP-R were labeled very strongly with 177Lu-L70. The same was true for all NMB-R positive tumors. Conversely, tumors with BB3 will not be visualized. The sensitivity of 177Lu-L70 resembles that of 125l-Tyr4-BBN or that of the universal bombesin analog labeled with 125? Therefore, a few tumors expressing a low density of GRP-R can be easily identified with 177Lu-L70, while they are not positive with 125l-Tyr4-BBN. The linkage characteristics of 177Lu-L70 could also be confirmed in non-neoplastic tissues. Although the mouse pancreas, as a control, was shown to express a very high GRP-R density, the normal human pancreatic acini were devoid of GRP-R. However, under GRP-R conditions of chronic pancreatitis can be identified in acini, as previously reported in the Fleischmann and associates publication, "Bombesin Receptors in Distinct Tissue Compartments of Human Pancreatic Diseases," Lab. Invest. 80: 1807-1817 (2000) and tissue again with better sensitivity, using 177Lu-L70 instead of using 125l-Tyr4-BBN. Conversely, islets that express BB3 were not detected with 177Lu-L70, while they were highly labeled with the universal ligand, as previously reported in Fleischmann and associates.

"Bombesin Receptors in Distinct Tissue Compartments of Human Pancractic Diseases," Lab. Invest. 80: 1870-1817 (2000). Although a minority of colon carcinomas had GRP-R, usually in very low density and heterogeneously distributed, normal colonic smooth muscles expressed a high density of GRP-R. The results in Tables 8a and 8b indicate that L70 derivatives labeled with Lu are expected to bind well to human prostate carcinoma, which primarily expresses GRP-R. They also indicate that Lu-labeled L70 derivatives are not expected to bind either to the normal human pancreas (which mainly expresses the BB3 receptor) or to cancers that mainly express the subtype of the BB3-R receptor. Example LV - Radiotherapy Studies A. Efficacy Studies: Radiotherapy studies were carried out using an unprotected mouse model containing PC3 tumor. In Short Term Efficacy Studies, the compounds labeled with 177Lu of the present invention L64, L70, L63 and the treatment control compound DO3A-monoamide-Aoc-QWAVGHLM-NH2 were compared to an untreated control group. (n = 12 for each treatment group for up to 30 days, and n = 36 for the group of untreated control gathered for up to 31 days). For all efficacy studies, the mice were administered 100 μL of labeled 177Lu compounds of the present invention at 30 mCi / Kg, i.v. or s.c. under sterile conditions. The subjects were housed in an environment with barriers during the course of the study. Body weight and tumor size (through gauge measurement) were collected in each subject 3 times per week during the course of the study. Criteria for early termination included: deathI saw. ; total body weight loss (TBW) equal to greater than 20%; tumor size equal to or greater than 2 cm3. The results of the Short-term Efficacy Study are shown in Figure 15. These results show that animals treated with L70, L64 or L63 have increased survival with respect to control animals that did not obtain treatment or with respect to the animals that were treated. administered the same dose of the control DO3A-monoamide-Aoc-QWAVGHLM-NH2. Long-term efficacy studies L64 and L70 were conducted using the same dose as above, but using more animals per compound (n = 46) and following up for up to 120 days. The results of the Long Term Efficacy Study are shown in Figure 15B. Regarding the same controls that were previously indicated (n = 36), the treatment with both L64 and with L70 it produced a significantly increased survival (p <0.0001) with L70 being better than L64, although statistically without difference between them (p <0.067). Example LVI Alternative Preparation of L64 and L70 Using Segment Coupling Compounds L64 and L70 can be prepared by employing the intermediates generally represented by AD (Fig. 19), which by themselves are prepared by standard methods known in the art. the technique of solid phase peptide synthesis and in solution (Synthetic Peptides - A User's Guide 1992, Grant, G. Ed., WH Freeman Co., NY, Chap 3 and Cap 4 pages 77-258; WC and White, PD Basic Procedures in Fmoc Solid Phase Peptide Synthesis - A Practical Approach 2002, Chan, WC and White, PD Eds Oxford University Press, New York, Chapter 3 pages 41 - 76; Barios, K and Cats, G Convergent Peptide Synthesis in Fmoc Solid Phase Peptide Synthesis - A Practical Approach 2002, Chan WC and White, PD Eds Oxford University Press, New York, Chapter 9 page 216-228) which are incorporated herein by reference. These methods include peptide synthesis strategies based on Aloe, Boc, Fmoc or benzyloxycarbonyl or the combinations of the methods in the solid phase or solution chosen in a judicious way. The intermediaries that will be employed for a given step are chosen based on the selection of appropriate protection groups for each position in the molecule, which can be selected from the list shown in the group shown in the F ig. 1. Those skilled in the art will also understand that intermediaries, compatible with the peptide synthesis methodology, which contain alternative protection groups, can also be employed and that the described options of protection groups shown above serve as illustrative and not as inclusive, and that said alternatives are well known in the art. This is amply illustrated in Figure 20, in which he points to the method. The substitution of intermediate C2 n instead of C1 shown in synthesis L62, provides L70 when the same synthetic strategies are applied. EXAMPLE LVII - Figures 49A and 49B Synthesis of L69 Summary: The reaction of (3β, 5β, 7a, 12a) -3-amino-7,12-dihydroxycolan-24-oico A with Fmoc-C1 produced intermediate B. Rink amide resin functionalized with the octapeptide Gln-Trp-Ala-Val-Gly-His-Leu-Met-NH2 (BBN [7-14] (A), was reacted in sequences with B, Fmoc-8-amino acid -3,6-dioxaoctanoic and ester tri-t- butyl DOTA. After dissociation and deprotection with Reagent B, the crude was purified by HPLC to produce L230. Total Performance: 4.2%. A. (3β, 5β, 7a, 12a) -3- (9H-Fluoren-9-ylmethoxy) amino-7.12-dihydroxycolan-24-oic acid, B (Fig. 49A) A chloride solution was added as drops of 9-fluorophenylmethoxycarbonyl (1.4 g, 5.4 mmol) in 1,4-dioxane (18 mL) to a suspension of (3ß, 5β, 7a, 12a) -3-amino-7,12-dihydroxycolan-24-oic acid (2.0 g, 4.9 mmol) (3) in 10% aqueous Na2CO2 (30 mL) and 1,4-dioxane (18 mL) stirred at a temperature of 0 ° C. After 6 hours stirring at room temperature H2O (100 mL) the aqueous phase was washed with Et2O (2x90 mL) and then 2M HCl (15 mL) was added (final pH: 1.5). The precipitated solid was filtered, and washed with H2O (3x100 mL), dried under vacuum and then purified by flash chromatography to yield B in the form of a white solid (2.2 g, 3.5 mmol). Performance71%. B. N- [3β, 5β, 7a, 12a) -3 - [[[2 - [- 2 - [[[4,7,10-Tris (carboxymethyl) -1,4,17,1-tetraazacyclodode c] -1 -yl] -acetyl] -amino] -ethoxy] -ethoxy] -acetyl] -amino] -7,12-dihydroxy-24-oxocolan-24-ill-L-glutaminyl-L-triptophoyl-L-alanyl-L -valil-glycyl-L-histidyl-L-leucyl-L-methioninamide. L69 (FIG 49B) Resin A (0.5 g, 0.3 mmol) was stirred in the solid phase peptide synthesis package with 50% morpholine in DMA (7 mL) for 10 minutes, the solution was filtered and 50% fresh morpholine in DMA (7 mL) was added. The suspension was stirred for another 20 minutes, then the solution was filtered and the resin was washed with DMA (5 x 7 mL). Acid (3β, 5β, 7a, 12a) -3- (9H-Fluoren-9-ylmethoxy) amino-7,12-dihydroxycolan-24-oic, B (0.75 g) was added to the resin.; 1.2 mmol), N-hydroxybenzotriazole (HOBt) (0.18 g, 1.2 mmol) N, N'-diisopropylcarbodiimide (DIC) (0.19 mL, 1.2 mmol) and DMA (7 mL), the mixture was stirred for 24 hours at room temperature , the solution was emptied and the resin was washed with DMA (5x7 mL). The resin was then stirred with 50% morpholine in DMA (7 mL) for 10 minutes, the solution was emptied, fresh 50% morpholine in DMA (7 mL) was added and the mixture was stirred for another 20 minutes. The solution was filtered and the resin was washed with DMA (5x7 mL). Fmoc-8-amino-3,6-dioxaoctanoic acid (0.79 g, 1.2 mmol), HOBt (0.18 g, 1.2 mmol), DIC (0.19 mL: 1.2 mmol), and DMA (7 mL) were added to the resin. The mixture was stirred for 3 hours at room temperature, the solution was emptied and the resin was washed with DMA (5x7 mL). The resin was stirred with 50% morpholine in DMA (7 mL) for 10 minutes, the solution was filtered and 50% fresh morpholine in DMA (7 mL) was added and the mixture was stirred for another 20 minutes. The solution was filtered and the resin was washed with DMA (5 x 7 mL) were added adduct of tris (1,1-dimethylethyl) ester of 1,4,7,10-Tetrazazacyclododecane-1, 4,7,10-tetraacetic acid with NaCl (0.79 g, 1.2 mmol), HOBt (0.18 g, 1.2 mmol) , DIC (0.19 mL: 1.2 mmol), N-ethyldiisopropylamine (0.40 mL, 2.4 mmol) and DMA (7 mL) to the resin. The mixture was stirred for 24 hours at room temperature, filtered and the resin was washed with DMA (5x7 mL), CH2Cl2 (5 x 7 mL) and dried under vacuum. The resin was stirred in a flask with Reagent B (25 mL) (2) for 4.5 hours. The resin was filtered and the solution was evaporated under reduced pressure to produce an oily crude which after treatment with Et2O (20 mL) produced a precipitate . The precipitate was collected by centrifugation and washed with Et2O (3x20 mL), to yield a solid (248 mg) which was analyzed by HPLC. A quantity of crude (50 mg) was purified by preparative HPLC. The fractions containing the product were lyophilized to produce L69 (6.5 mg, 3.5 x 10"3 mmol) (Fig. 49B), in the form of a white solid Yield 5.8% EXAMPLE LVIII - Figure 50 Synthesis of L144 Summary: The functionalized Rink amide resin was reacted with the octapeptide Gln-Trp-Ala-Val-Gly-His-Leu-Met-NH2 (BBN [7-14]) (A) with 4- [2-hydroxy] 3- [4,7,10-tris [2- (1,1-dimethylethoxy) -2-oxoethyl] -1,4,7,10-tetrazacyclododec-1-yl] propoxy] benzoic acid.

Dissociation and deprotection with Reagent B (2) The crude was purified by HPLC preparation to produce L144. Overall performance: 12%. A. N - [4- [2-H idroxy-3- [4,7,10-tris (carboxymethyl) -1,4,7,10-tetraazacyclododec-1-yl] propoxy] benzoyl] -L -glutaminyl-L-tryptopyl-L-alanyl-L-valyl-glycyl-L-histidyl-L-leucyl-L-methioninamide, L144 (Fig. 50) Resin A (0.5 g, 0.3 mmol) was stirred in the container of solid phase peptide synthesis with 50% morpholine in DMA (7 mL) for 10 minutes, the solution was filtered and 50% fresh morpholine in DMA (7 mL) was added. The suspension was stirred for another 20 minutes, then the solution was filtered and the resin was washed with DMA (5 x 7 mL). 4- [2-Hydroxy-3- [4,7,10-tris [2- (1,1-dimethylethoxy) -2-oxoethyl] -1,4,7,10-tetrazacyclododec-1 was added to the resin -il] propoxy] benzoic B (0.5 g, 0.7 mmol), HOBt (0.11 g, 0.7 mmol), DIC (0.11 mL, 0.7 mmol)), N-ethyldiisopropylamine (0.24 mL, 1.4 mmol) and DMA (7 mL) . The mixture was stirred for 24 hours at room temperature, evacuated and the resin was washed with DMA (5 x 7 mL), CH 2 Cl 2 (5 x 7 mL), and dried under vacuum. The resin was stirred in a flask with Reagent B (25 mL) (2) for 4.5 hours. The resin was filtered and the solution was evaporated under reduced pressure to produce an oily crude which after treatment with Et2O (20 mL) produced a precipitate. He The precipitate was collected by centrifugation and washed with Et2O (3 x 20 mL) to yield a solid (240 mg) which was analyzed by HPLC. A quantity of crude (60 mg) was purified by preparative HPLC. The fractions containing the product were lyophilized to yield L144 (10.5 mg, 7.2 x 10"3 mmol) in the form of a white solid, Yield 12% EXAMPLE LIX Preparation of L300 and 177Lu-L300 From 0.2 g of Rink Novagel amide resin (0.63 mmol / g, 0.126 mmol) L300 (0.033 g, 17%) was obtained after the preparation column chromatography. The retention time was 6.66 minutes. The molecular formula is C72H99N 9? 18. The calculated molecular weight is 1518.71; 1519.6 observed. The sequence is DO3A-Gly-Abz4-Gln-Trp-Ala-Vval-Gly-His-Phe-Lleu-NH2. The structure of L300 is shown in Figure 51. L300 (13.9 μg in 13.9 μL of 0.2M pH 4.8 of sodium acetate buffer) was mixed with 150 μL of 0.2M pH 4.8 of sodium acetate buffer and 4 μL of 177LuCI3 (1136 mCi, Missouri Research Reactor). After 10 minutes at a temperature of 100 ° C, the radiochemical purity (PCR) was 95%. The product that was purified on a Vydac C18 peptide column (4.6 x 250 mm, 5 um pore size) was eluted in a flow range of 1 mL / min using a aqueous / organic gradient of 0.1% TFA in water (A) and 0.085% TFA in acetonitrile (B). The following gradient was used: isocratic 22% B for 30 minutes, for 60% B in 5 minutes, maintained at 60% B for 5 minutes. The compound, which was eluted in a retention time of 18.8 minutes, was collected in 1 mL of a 0.8% human serum albumin solution which was prepared by adding HSA to a 9: 1 mixture of normal saline and Acid injection. Ascorbic The acetonitrile was removed using a Velocity Vacuum (Savant). After purification, the compound had a CPR of 100%. EXAMPLE LX - Characterization of Linker Specificity in Relation to GRP Receptor Subtypes Two C6 cell lines, a rodent glioblastoma cell line expressing NMB-R and PC3, a human prostate cancer cell line that was used in this assay, were used in this assay. express GRP-R. The affinity of several unlabeled compounds for each receptor subtype (NMB-R and GRP-R) was determined indirectly by measuring their ability to compete with the binding of 125 I-NMB or 125 I-BBN to their corresponding receptors in C6 cells and pc3. A. Materials and Methods: 1. Cell Culture: The C6 cells of ATCC (CCL-107) were obtained and cultured in an F12K medium (ATCC) supplemented with 2. mM L-glutamine, 1.5 g / L sodium bicarbonate, .15% horse serum and 2.5% FBS. Cells for the assays were plated at a 9.6 x 10 / tank concentration in plates covered with 48-well poly-lysine (Beckton Dickinson Biocoat). PC3 was obtained from the ATCC (CRL-1435) and cultured in an RPMl 1640 medium (ATCC) supplemented with 2 mM L-glutamine, 1.5 g / L sodium bicarbonate, 10 mM HEPES and 10% FBS. Both cultures were kept in a humidified atmosphere containing 5% CO2 / 95% air at a temperature of 37 ° C. The PC3 cells for the assays were plated at a concentration of 2.0 x 104 cells / reservoir in 96-well white / clear bottom plates (Falcon Optilux-I). The plates were used for the tests on day 2 after plating. 2.- Radio-ligand v linkage regulator: RPMl 1640 (ATCC) containing 25 mM HEPES, 0.2% BSA fraction V, 1.0 mMAEBSF (CAS # 3087-99-7) and 0.1% Bacitracin (CAS # 1405) -87-4), pH 7.4 125l- [Tyr °] NMB, > 2.0 Ci / μmol (Amersham Life Science) [125I-NMB] commercially available 125l- [Tyr4] BBN, > 2.0 Ci / μmol (Perkin Elmer Life Science) [25I-BBN] were used as radioligands. B. In vitro assays: Using a plate assay system of 48 deposits (for study C6), competition experiments were carried out using 125I-NMB. All PC3 studies were carried out as described in example XLIII using 125I-BBN. The selection of compounds for the assay was based on the linker subtype. The results are shown in Table 9. TABLE 9 Number of compounds selected for the assay and their linkers The binding parameters obtained were analyzed using a non-linear regression analysis of competition at a site with GraphPad Prism. The relative affinity of several compounds for NMB-R in C6 cells was compared with those obtained using commercially available [Tyr4] -BBN and [Tyr °] -NMB. To distinguish the compounds that prefer GRP-R from the compounds that preferred NMB-R plus GRP-R were compared IC50 values obtained from each compound with those obtained from [Tyr0] -BBN with 125I-NMB in C6 cells. The cut-off points between the two classes of compounds were taken as 10X the IC50 of [Tyr4] -BBN. Among the compounds tested, 8 of the compounds bind preferentially to GRP-R (as shown in Table 10) while 32 compounds bind to GRP-R and NMB-R with similar affinity, and two show preference with NMB-R TABLE 10 IC50 values obtained from competition experiments using 1251-NMB and 1251-BBN In the above table, "na" indicates "not applicable" (for example, the compound does not contain a compound of the present invention and therefore was not assigned an L #). Based on the above, several results were observed. The receptor binding region alone (BBN .14 or BBN8-? 4) showed no preference for GRP-R or NMB-R. The addition of a chelator alone to the binding region of the receptor does not contribute to affinity of the peptide with GRP-R or NMB-R (DO3A-monoamide-QWAVGHLM-NH2)). The coupling of the chelator to the peptide through a linker contributed to the affinity of the peptide towards the receptor. However, depending on the type of the linker this affinity varied from being dual (preference for both NMB-R and GRP-R) for GRP-R (preference to GRP-R). The co-Aminoalkanoic acids tested (acid 8- Aminooctanoic in 175Lu-DO3A-monoamide-Aoc- QWAVGHLM-NH2 and acid DO3A-monoamide-Aoc-QWAVGHL-Nle-NH2, 3-aminopropionic in DO3A-monoamide-Apa3-QWAVGHLM-NH2 and 4-aminobutanoic acid in DO3A-monoamide- Abu4-QWAVGHLM-NH2) as linkers, conferred the peptide with a dual affinity for both GRP-R and NMB-R. The replacement of "Met" in 175Lu-DOTA-Aoc-QWAVGHLM-NH2 by 'Nle' did not change this dual affinity of the peptide. Linkers containing cholic acid (3-aminocolic acid in L64, 3-amino-12-hydroxycalanic in L63 and 3-amino-12-ketocolanic in L67 gave the peptides a dual affinity for both GRP-R and NMB-R) . The linkers containing cycloalkyl and aromatic substituted alanine (3-cylcohexylanine in DO3A-monoamide-Cha-Cha-QWAVGHLM-NH2, 1-Naphthylalanine in DO3A-monoamide-Cha-Nal 1 -QWAVGHLM-NH2, 4-Benzoylphenylalanine in DO3A-monoamide -NaM-Bpa4-QWAVGHLM-NH2 and Biphenylalanine in DO3A-monoamide-NaM-Bip-QWAVGHLM-NH2) gave the peptides a selective affinity towards GRP-R. A linker containing only 4- (2-Aminoethylpiperazine) -1- also contributed to the peptides with selectivity GRP-R (L89). The introduction of the G-4-amino-benzoic acid linker to the NMB sequence conferred the compound with a affinity with GRP-R in addition to its inherent NMB-R affinity (L227 vs. GNLWATGHFM-NH2). The change in the position of Gly around the linker altered the affinity of L70 for its dual affinity to a selective affinity with NMB-R (L204). The 3-methoxy substitution in 4-aminobenzoic acid in L70 (such as in L240) changed the dual affinity to a selective affinity with GRP-R. It can be seen from previous data that the linker has a significant effect on the specificity of the receptor subtype. Three groups of compounds can be identified: * > The gue are active in the GRP-R These compounds provide specific information for this receptor in vitro and in vivo, which are radiolabelled with a therapeutic radionuclide, can be carried out therapy in tissues that have only this receptor, reserving those that they contain the NMB-R. * > The compounds are active in the NMB.R These compounds provide specific information of this receptor in vitro and in vivo, which can be used for diagnostic purposes. When radiolabeling with a therapeutic radionuclide, therapy can be carried out on tissues that contain only this receptor, reserving the that contain the GRP-R. * > Those which are active in both GRP-R and NMB-R These compounds provide information regarding the combined presence of these two receptor subtypes in vitro and in vivo, which can be used for diagnostic purposes. The direction of both receptors can increase the sensitivity of the revision at the expense of specificity. When these compounds are radiolabelled with a therapeutic radionuclide, the therapy can be carried out in tissues containing both receptors, which can increase the dose delivered to the desired tissues. Example LXI - Competition Studies of Modified Bombesin (BBN) with 125I-BBN for GRP-R in prostate cancer cells (PC3). To determine the effect of replacing certain amino acids in the BBN7 analogues "14, modified peptides were elaborated in the part of the direction and tested for competitive binding with GRP-R in human prostate cancer cells (PC3) All of these peptides have a common linker conjugated to a metal chelation portion (DOTA-Gly-Abz4) -) The link data (IC50 nM) is determined later in Table 13.

A. Materials and Methods: 1. Cell Culture PCCC cell lines were obtained from ATCC (CRL-1435) and cultured in RPMl 1640 (ATCC) supplemented with 2 mM L-glutamine, 1.5 g / L sodium bicarbonate, 10 mM of HEPES and 10% of FBS. The cultures were kept in a humidified atmosphere containing 5% CO2 / 95% air at a temperature of 37 ° C. The PC3 cells for the assays were plated at a concentration of 2.0 x 1 O4 cells / reservoir in 96-well white / clear bottom plates (Falcon Optilux-I). The plates were used for the tests on day 2 after plating. 2. Linkage Regulator: RPMl 1640 (ATCC) containing 25 mM HEPES, 0.2% BSA fraction V, 1.0 mM AEBSF (CAS # 3087-99-7) and 0.1% Bacitracin (CAS # 1405-87-4) , pH 7.4. 3. 125l-Tyr4-Bombesin f125l-BBNl 125I-BBN (Cat # NEX258) was obtained from PerkinElmer Life Sciences. B. In vitro assay: Competition competition with 125 I-BBN for GRP-R in PC3 cells: All the tested compounds were dissolved in the binding buffer and appropriate dilutions were also made in the binding buffer. Cells were seeded PC3 for testing at a concentration of 2.0 x 104 / deposit either in 96-deposit black / clear collagen 1 cell slabs (Beckton Dickinson Biocoat). The plates were used for link studies on day 2 after plating. Plates were checked for confluence (> 90% confluent) before assay. For competition testing, N, N-dimethylglycyl-Ser-Cys (Acm) -Gly-Ava5-QWAVGHLM-NH2 (control) or other competitors were incubated at concentrations ranging from 1.25x10"9 M to 500 x 10" 9 M , in conjunction with 125i-bbn (25,000 cpm / tank). The studies were carried out with a test volume of 75 μl per deposit. Deposits were used in triplicate for each data point. After the addition of the appropriate solutions, the plates were incubated for 1 hour at a temperature of 4CC. Incubation was terminated through the addition of 200 μL of ice-cooled incubation buffer. The plates were washed 5 times and dried with blotting paper. Radioactivity was detected using either a CompuGamma LKB counter or a microplate scintillation counter. The bound radioactivity of 125 I-BBN was plotted against the concentrations of inhibition of the competitors, at the concentration at which the 125 I-BBN bond was inhibited by 50% (IC 50) obtained from the binding curck. TABLE 13: Competition studies with 125I-BBN for GRP-R in PC3 cells Results / Conclusions: The analysis of the binding results of several modified peptides in the steering part indicated the following: Neuromedin analogues (GNLWATGHFM-NH2, and GNLWATGHFM-NH2) are not available to compete with GRP-R except when conjugated to DO3A-monoamide-G-Abz4 (L227). However, they are effective NMB competitors. This is similar to the requirement for derivatization of the amino terminus of the bombesin sequences as reflected in QWAVGHLM-NH2, DO3A-monoamide-QWAVGHLM-NH2 & L70. The replacement of histidine (L225) reduces competition in the GRP-R. The inversion of the two binding components in L70 to produce L204 changes the specificity of the subtype in favor of the NMB subtype. The L13F substitution in the bombesin sequence maintains the GRP-R activity. (L228). TABLE 14 As seen in the present invention, the substitution of F13M14 to F13L14 in L228 produces a compound (L300) with high level activity in the GRP-R. The elimination of methionine has advantages, since it is prone to oxidation. This benefit does not occur if the Replacement L13F is not carried out either (L221). The elimination of V10 resulted in the total loss of linkage as seen in: TABLE 15 TABLE 16 As shown in Table 16, several substitutions were allowed in the BBN2"6 region (L214, L217, L226) TABLE 17 As expected, the results of Table 17 show that universal agonists (L222 &L223) compete reasonably well at the -50 nM level.

EXAMPLE LXI - Structural Comparison MRN of 175Lu-L70 and 175Lu-DO3A-monoamide-Aoc-QWAVGHLM-NH2 The purpose of this NMR study was to provide a complete structural characterization of Lu-L70 and compare it with the structure of 175Lu-DOTA-Aoc-QWAVGHLM. L70 and 175Lu-DOTA-Aoc-QWAVGHLM are both bombesin analogs (see Figures 60 and 61), which differ only in the linker between the chelation group and the targeting peptide. In L70, there is a glycyl-4-aminobenzoyl group, while 175Lu-DOTA-Aoc-QWAVGHLM exists an 8-aminooctanoyl group. However, the biological data of these two compounds is strictly different. The detailed NRM studies were carried out to explain this difference. A. EXPERIMENTAL 1. Materials 5 mg of 75Lu-DO3A-monoamide-Aoc-QWAVGHLM-NH2 was dissolved in 225 μL of DMSO-d6 (Aldrich 100% atom% D). 5 mg of 175Lu-L70 was dissolved in 225 μL of DMSO-d6 (Aldrich 100% atom% D). 2. - Adquisition of NMR Data All the NRM experiments were carried out in a Varian lnova-500 Fourier Transform NMR spectrometer. Equipped with a 3 mm broadband inverse probe (z-axis gradient). The chemical changes for the residual CH peaks for the DMSO-d6 peaks at 2.50 ppm for the proton and 40.19 ppm for 13C were referenced. The sample temperatures were controlled through a Varian controller. The data was processed using the software RMNPipe, VNMR, PROSA, and VNMRJ in the Sun Blade 2000 Unix computer and analyzed using RMNView and SPARKY in the Linux computer. Peptide modeling was carried out using the CYANA software on the Linux computer and analyzed further using the MOLMOL software on a Compaq Deskpro Workstation workstation. B. RESULTS v DISCUSSION The proton chemical changes of 175Lu-L70 were assigned as indicated below. A rapid study of the methyl region (0.5 to 2.5 ppm) in the ID spectrum allowed the identification of a singlet at 2.02 ppm as the methionine methyl peak. In the same region of the TOCSY spectrum, the chemical change at 1.16 ppm, which correlates only with a peak of 4.32 ppm, indicates that they belong to alanine. The methyl peaks at 0.84 and 0. 85 ppm that correlate with the two peaks in 1.98 and 4.12 must belong to Valina. The remaining methyl peaks at 0.84 and 0.88 ppm which correlate with peaks 1.60, 1.48 and 4.23 belong to leucine. These chemical changes and the chemical changes of other amino acids are also found in the "fingerprint" region (see the publication by Wuthrich, K. "RMN of Proteins and Nucleic Acids", John Wiley &Sons, 1986) - the NH region -aH skeleton of the TOCSY spectrum (see figure 52). The chemical changes that belong to a spinning system of an amino acid will align themselves vertically. After a careful review of the spectrum, all chemical changes were assigned. The chemical changes were checked additionally by reviewing other spectra such as COZY (see figure 53) and NOESY (see figure 54). After the proton chemical changes were assigned, their chemical carbon changes were identified through the gHSQC spectrum (see Figure 55) and further verified by looking at the gHMBC spectra (see Figure 56) and gHSQCTOCSY (see Figure 57). ). The chemical changes of Lu-L70 are described in Table 19 (the numbers of atoms were referenced in Figure 60). Interestingly, in the TOCSY space of 175Lu-L70, the chemical changes of the NH proton at 14.15 ppm show strong correlations with the other two peaks of the histidine ring, and also with a water molecule. This water molecule is not freely exchanged and can be clearly observed in the NMR time structure. To observe that the histidine proton interacts more strongly with a water molecule, a selective homo-decoupling experiment was carried out in 175Lu-L70 at a temperature of 50 ° C. When the water peak was selectively saturated with a low power, the intensities of the histidine NH peaks were reduced dramatically at 14.16 and 14.23 ppm while the intensities of the remaining two peaks of histidine at 7.32 and 8.90 ppm were partially reduced (see figure 58). The observation of water protons in the NMR time scale suggests a rigid confirmation. In figure 62 we can see a chemical structure of 175Lu-L70 with a water molecule. A water molecule occupies a ninth coordination site, covering the square plane that is described through the coordinated oxygens. This has other antecedents. Water coordination at the ninth site of Lu in Na [Lu (DOTA) H2l)] »4H2O was observed, in an x-ray structure as shown by the publication of Aime and associates, Inorg. Chim. Acta 1996, 246, 423-429, which is incorporated herein by reference. In contrast, in the TOCSY spectrum of 175Lu-DO3A- monoamide-Aoc-QWAVGHLM-NH2, the chemical change of the NH proton shows only strong correlations with two other peaks of the histidine ring, but not with the water molecule (see figure 59). This indicates that there is no water molecule coordinated simultaneously with both 175Lu and His-NH in 75-DO3A-monoamide-Aoc-QWAVGHLM-NH2. Therefore, the difference between the two molecules is significant. In 175Lu-L70, a secondary structure of the peptide is established through the bound water molecule, and this may be responsible for increased in vivo stability. TABLE 19 - Chemical Change (ppm) of 75Lu-L70 in DMSO-d? at a temperature of 25 ° C 15 20

Claims (27)

1. A compound selected from the group consisting of: DO3A-monoamide-Gly- (3ß, 5ß, 7a, 12a) -3-amino-7,12-dihydroxycolan-24-oico-QWAVaHLM-NH2 acid, DO3A- acid monoamide-Gly- (3ß, 5ß, 7a, 12a) -3-amino-7,12-dihydroxycolan-24-oico-QWAVGHLM-NH2, acid DO3A-monoamide-Gly- (3ß, 5ß, 7a, 12a) -3 -amino-7,12-dihydroxycolan-24-oico-f-WAVGHLL-NH2, DO3A-monoamide-Gly- (3ß, 5ß, 7a, 12) -3-amino-7,12-dihydroxycolan-24-oic acid f-QWAVGHL-NH-pentyl, acid DO3A-monoamide-Gly- (3ß, 5ß, 7, 12a) -3-amino-7,12-dihydroxycolan-24-oico-y-QWAV-Bala-HF-Nle-NH2 , DO3A-monoamide-Gly- (3ß, 5ß, 7a, 12a) -3-amino-7,12-dihydroxycolan-24-oico-f-QWAV acid-Bullet-HF-Nle-NH2 acid DO3A-monoamide-Gly- (3ß, 5ß, 7a, 12a) -3-amino-7,12-dihydroxycolan-24-oico-QWAVGHFL-NH2, DO3A-monoamide-Gly- (3ß, 5ß, 7a, 12a) -3-amino-7 acid , 12-dihydroxycolan-24-oico-QWAVGNMeH-LM-NH2, acid DO3A-monoamide-Gly- (3ß, 5ß, 7a, 12a) -3-amino-7,12-dihydroxycolan-24-oico-LWAVGSFM-NH2, DO3A-monoamide-Gly- acid (3ß, 5ß, 7a, 1 2a) -3-amino-7,12-dihydroxycolan-24-oico-HWAVGHLM-NH2, DO3A-monoamide-Gly- (3ß, 5β, 7a, 12) -3-amino-7,12-dihydroxycolan-24- acid oico-LWAGHFM-NH2, acid DO3A-monoamide-Gly- (3ß, 5ß, 7a, 12a) -3-a ino-7,12-dihydroxycolan-24-oico-QWAVGHFM-NH2, acid DO3A-monoamide-Gly- (3ß, 5ß, 7a, 12a) -3-amino-7,12-dihydroxycolan-24-oico-QRLGNQWAVGHLM-NH2, acid DO3A-monoamide-Gly- (3β, 5β, 7a, 12a) -3-amino-7,12-dihydroxycolan-24- oico-QRYGNQWAVGHLM-NH2, acid DO3A-monoamide-Gly- (3ß, 5ß, 5ß, 7a, 12a) -3-amino-7,12-dihydroxycolan-24-oico-QKYGNQWAVGHLM-NH2, Pglu-Q-Lys-acid (DO3A -monoamide) -Gly- (3ß, 5ß, 7a, 12a) -3-amino-7,12-dihydroxycolan-24-oico-LGNQWAVGHLM-NH2, acid DO3A-monoamide-Gly-3-amino-3-deoxycholic- QRLGNQWAVGHLM -NH2, DO3A-monoamide-Gly-3-amino-3-deoxycholic acid-QRYGNQWAVGHLM-NH2, DO3A-monoamide-Gly-3-amino-3-deoxycholic acid-QKYGNQWAVGHLM-NH2, and Pglu-Q-Lys- (acid DO3A-monoamide-G-3-amino-3-deoxycholic) -LGNQWAVGHLM-NH2.
2. 2. A compound selected from the group consisting of: acid DO3A-monoamide-G-4-aminobenzoic acid-QWAVGHFL-NH2, acid DO3A-monoamide-4-aminomethylbenzoic acid-L-1-naphthylalanine-QWAVGHLM-NH2, and acid DO3A-monoamide -G-4-aminobenzoic- QWAVGN MeH isLM-NH2.
3. 3. A compound of the general formula: M-N-O-P-G-wherein: M is DO3A, optionally in compound with a radionuclide; N is 0, an alpha or non-alpha amino acid or another linking group; O is an alpha or non-alpha amino acid; P is 0, an alpha or non-alpha amino acid or another linking group; G is a GRP receptor targeting peptide; wherein at least one of N, O, or P is 8-amino-3,6-dioxaoctanoic acid; wherein the GRP receptor targeting peptide is selected from the group consisting of QWAVGHLM-NH2) QWAVGNMeHLM-NH2, QWAVGHFL-NH2, LWATGSFM-NH2 and QWAVaHLM-NH2.
4. 4. A compound of the general formula: M-N-O-P-G wherein: M is DO3A, optionally in compound with a radionuclide; N is 0, an alpha or non-alpha amino acid or another linking group; O is an alpha or non-alpha amino acid; P is 0, an alpha or non-alpha amino acid or another linking group; G is a GRP receptor targeting peptide; where at least one of N, O, or P is acid (3β, 5β, 12a) -3-amino-12-hydroxycolan-24-oic; and wherein the GRP receptor targeting peptide is selected from the group consisting of QWAVGHLM-NH2, QWAVGNMeHLM-NH2, QWAVGHFL-NH2, LWATGSFM-NH2 and QWAVaHLM-NH2.
5. 5. A compound of the general formula: M-N-O-P-G wherein: M is DO3A, optionally in compound with a radionuclide; N is 0, an alpha or non-alpha amino acid or another linking group; O is an alpha or non-alpha amino acid; P is 0, an alpha or non-alpha amino acid or another linking group; G is a GRP receptor targeting peptide; wherein at least one of N, O, or P is 4-aminobenzoic acid; and wherein the GRP receptor targeting peptide is selected from the group consisting of QWAVGHLM-NH2, QWAVGNMeHLM-NH2, QWAVGHFL-NH2, LWATGSFM-NH2 and QWAVaHLM-NH2, NmeQWAVGHLM-NH2, Q -? [CSNH] WAVGHLM-NH2, Q -? [CH2NH] -WAVGHLM-NH2, Q -? [CH = CH] WAVGHLM -NH2, a-MeQWAVGHLM-NH2, QNme-WAVGHLM-NH2, QW -? [CSNH] -AVGHLM-NH2, QW -? [CH2NH] -AVGHLM-NH2, QW -? [CH = CH] -AVGHLM-NH2, Qa-Me- WAVGHLM-NH2, QW-Nme-AVGHLM-NH2, QWA =? [CSNH] -VGHLM-NH2, QWA -? [CH2NH] -VGHLM-NH2, QW-Aib-VGHLM-NH2, QWAV-Sar- HLM-NH2, QWAVG -? [CSNH] -HLM-NH2, QWAVG -? [CH = CH] -HLM-NH2, QWAV-Dala-HLM-NH2, QWAVG-Nme-His-LM-NH2, QWAVG-H -? [CSNH] -L-M-NH2, QWAVG-H - [CH2NH] LM-NH2, QWAVGH -? [CH = CH] -LM-NH2, QWAVG-a-Me-HLM-NH2, QWAVGH-Nme-LM-NH2, QWAVGH-a-MeLM-NH2 , QWAVGHF-L-NH2, and QWAVGHLM-NH2.
6. 6. A compound selected from the group consisting of: D03A-monoamide-G-4-aminobenzoic acid-QWAVaHLM-NH2, acid D03 A- ono ami a- G-4-amino benzo i co-f QWAVGHL M-NH2, acid D03A-monoamide-G-4-aminobenzoic acid-fQWAVGHLL-NH2, D03A-monoamide-G-4-aminobenzoic acid-fQWAVGHL-NH-pentyl, D03A-monoamide-G-4-aminobenzoic acid-and QWAV-Bala- HFNIe-NH2, acid D03A-monoamide-G-4-aminobenzoic acid-fQWAV-Bala-HFNIe-NH2, acid D03A-monoamide-G-4-aminobenzic-QWAVGHFL-NH2, acid D03A-monoamide-G-4-aminobenzoic- QWAVGNMeHisLM -NH2, D03A-monoamide-G-4-aminobenzoic acid-LWAVGSFM-NH2, D03A-monoamide-G-4-aminobenzoic acid-HWAVGHLM-NH2, D03A-monoamide-G-4-aminobenzoic acid-LWATGHFM-NH2, acid D03A -monoamide-G-4-aminobenzoic acid-QWAVGHFM-NH2, D03A-monoamide-G-4-aminobenzoic acid- QRLGNQWAVGHLM-NH2, D03A-monoamide-G-4-aminobenzoic acid- QRYGNQWAVGHLM-NH2, D03A-monoamide-G- acid 4-aminobenzoic- QKYGNQWAVGHLM-NH2, Pglu-Q-Lys (DO3A-monoamide-G-4-aminobenzoic acid) - LGNQWAVGHLM-NH2, acid DO3A-monoamide-G-3-amino-3-deoxycholic-QWAVaHLM-NH2, acid DO3A-monoamide-G-3-amino-3-deoxycholic-fQWAVGHLM-NH2, acid DO3A-monoamide-G-3-amino-3-deoxycholic-fQWAVGHLL-NH2, acid DO3A-monoamide-G-3-amino-3 -deoxycholic-fQWAVGHL-NH-pentyl, acid DO3A-monoamide-G-3-amino-3-deoxycholic-yQWAV-Bale-HFNIe-NH2, acid DO3A-monoamide-G-3-amino-3-deoxycholic-fQWAV-Bullet -HFNIe-NH2, acid DO3A-monoamide-G-3-amino-3-deoxycholic- QWAVGHFL-NH2, acid DO3A-monoamide-G-3-amino-3-deoxycholic- QWAVGNMeHLM-NH2, acid DO3A-monoamide-G- 3-amino-3-deoxycholic- LWAVGSFM-NHs, acid DO3A-monoamide-G-3-amino-3-deoxycholic- HWAVGHLM-NH2, acid DO3A-monoamide-G-3-amino-3-deoxycholic-LWATGHFM-NH2, acid DO3A-monoamide-G-3-amino-3-deoxycholic- QWAVGHFM-NH2, acid DO3A-monoamide-G-3-amino-3-deoxycholic- QRLGNQWAVGIyHLM-NH2, acid DO3A-monoamide-G-3-amino-3 -deoxycholic- QRYGNQWAVGHLM-NH2, acid DO3A-monoamide-G-3-amino-3-deoxycholic- QKYGNQWAVGHLM-NH2, and Pglu-Q-Lys (acid DO3A-monoamide-G-3-amino-3-deoxycholic) -LGNQWAVGHLM-NH2.
7. 7. A compound of the general formula: M-N-O-P-G wherein: M is DO3A, optionally in compound with a radionuclide; N is 0, an alpha or non-alpha amino acid or another linking group; O is an alpha or non-alpha amino acid; P is 0, an alpha or non-alpha amino acid or another linking group; G is a GRP receptor targeting peptide; wherein at least one of N, O, or P is 8-amino-3,6-dioxaoctanoic acid or (3β, 5β, 12a) -3-amino-12-hydroxycolan-24-oic acid; and where G is selected from the group consisting of Nme-QWAVGHLM-NH2, Q -? [CSNH] WAVGHLM-NH2, Q -? [CH2NH] -WAVGHLM-NH2, Q -? [CH = CH] WAVGHLM-NH2, a- MeQWAVGHLM-NH2, QNme-WAVGHLM-NH2 , QW -? [CSNH] - AVGHLM-NH2, QW -? [CH2NH] -AVGHLM-NH2, QW -? [CH = CH] -AVGHLM-NH2, Qa-Me-WAVGHLM-NH2, QW-Nme-AVGHLM- NH2, QWA =? [CSNH] -VGHLM-NH2, QWA -? [CH2NH] -VGHLM-NH2, QW-Aib-VGHLM-NH2, QWAV-Sar-HLM-NH2, QWAVG -? [CSNH] -HLM-NH2 , QWAVG -? [CH = CH] -HLM-NH2, QWAV-Dala-HLM-NH2, QWAVG-Nme-His-LM-NH2, QWAVG-H -? [CSNH] -LM-NH2, QWAVG-H-? [CH2NH] LM-NH2, QWAVGH -? [CH = CH] -LM-NH2, QWAVG-a-Me-HLM-NH2, QWAVGH-Nme-LM-NH2, QWAVGH-a-MeLM-NH2, QWAVGHF-L- NH2, and QWAVGHLM-NH2.
8. 8. A method for directing the gastrin-releasing peptide receptor (GRP-R) and the neuromedin-B receptor (NMB-R), wherein the method comprises administering a compound of the general formula: MNOPG wherein: M is an optical label or a metal chelator, optionally in a compound with a radionuclide; N is 0, an alpha or non-alpha amino acid or another linking group; O is an alpha or non-alpha amino acid; P is 0, an alpha or non-alpha amino acid or another linking group; G is a GRP receptor targeting peptide; wherein at least one of N, O, or P is a non-alpha amino acid.
9. 9. The method according to claim 8, characterized in that at least one of N, O, or P is a non-alpha amino acid with a cyclic group.
10. The method according to claim 9, characterized in that N is Gly, O is 4-aminobenzoic acid and P is 0.
11. 11. A method for directing GRP-R and NMB-R, wherein the method comprises administering a compound of the general formula: -NOPG wherein: M is an optical label or a metal chelator, optionally in compound with a radionuclide; N is 0, an alpha amino acid, a substituted biary acid or another linking group; O is an alpha amino acid or a substituted bile acid; P is 0, an alpha amino acid, a substituted biary acid or another linking group; G is a GRP receptor targeting peptide; wherein at least one of N, O, or P is substituted biary acid.
12. 12. The method according to claim 11, characterized in that N is Gly, O is (3ß, 5ß, 7a, 12a) -3-amino-7,12-dihydroxycolan-24-oic acid, and P is 0.
13. 13 The method of compliance with any of the claims 8, 9, or 12, characterized in that the GRP receptor targeting peptide is selected from the group consisting of: Nme-QWAVGHLM-NH2, Q -? [CSNH] WAVGHLM-NH2, Q -? [CH2NH] -WAVGHLM- NH2, Q -? [CH = CH] WAVGHLM-NH2, a-MeQWAVGHLM-NH2, QNme-WAVGHLM-NH2, QW -? [CSNH] -AVGHLM-NH2, QW -? [CH2NH] -AVGHLM-NH2, QW- ? [CH = CH] -AVGHLM-NH2, Qa-Me-WAVGHLM-NH2, QW-Nme-AVGHLM-NH2, QWA =? [CSNH] -VGHLM-NH2, QWA -? [CH2NH] -VGHLM-NH2, QW -Aib-VGHLM-NH2, QWAV-Sar-HLM-NH2, QWAVG -? [CSNH] -HLM-NH2, QWAVG -? [CH = CH] -HLM-NH2, QWAV-Dala-HLM-NH2, QWAVG-Nme -His-LM-NH2, QWAVG-H -? [CSNH] -LM-NH2, QWAVG-H -? [CH2NH] -LM-NH2, QWAVGH -? [CH = CH] -LM-NH2, QWAVG-a-Me-HLM-NH2, QWAVGH-Nme-LM-NH2, and QWAVGH-a-MeLM-NH2.
14. 14. A method for improving the live activity of a compound according to any of claims 1 to 7, characterized in that it comprises the step of modifying the GRP receptor targeting peptide to reduce the proteolytic dissociation of the peptide.
15. 15. The method of compliance with the claim 14, characterized in that the modified GRP-R targeting peptide is an agonist.
16. 16. A method for reducing the proteolytic cleavage of a gastrin-releasing peptide (GRP) analogue according to any of claims 1 to 7, characterized in that the method comprises the step of modifying the peptide bond in the targeting portion GRP-R.
17. 17. The method according to claim 16, characterized in that the modified GRP-R address peptide is an agonist.
18. 18. A method for reducing the proteolytic dissociation of a gastrin-releasing peptide analogue (GRP-R) having a targeting portion of the gastrin-releasing peptide receptor (GRP-R) that is an agonist, wherein the method comprises the step of modifying the peptide bond in the GRP-R address portion.
19. 19. The method according to any of claims 14, 16, or 18, characterized in that the address portion GRP-R is selected from the group consisting of: Nme-QWAVGHLM-NH2, Q -? [CSNH] WAVGHLM-NH2 , Q -? [CH2NH] -WAVGHLM-NH2, Q -? [CH = CH] WAVGHLM-NH2, a-MeQWAVGHLM-NH2, QNme-WAVGHLM-NH2, QW -? [CSNH] -AVGHLM-NH2, QW-? [CH2NH] -AVGHLM-NH2, QW -? [CH = CH] -AVGHLM-NH2, Qa-Me-WAVGHLM-NH2, QW-Nme-AVGHLM-NH2, QWA =? [CSNH] -VGHLM-NH2, QWA- ? [CH2NH] -VGHLM-NH2, QW-Aib-VGHLM-NH2, QWAV-Sar-HLM-NH2) QWAVG -? [CSNH] -HLM-NH2, QWAVG -? [CH = CH] -HLM-NH2, QWAV -Dala-HLM-NH2, QWAVG-Nme-His-LM-NH2, QWAVG-H -? [CSNH] -LM-NH2, QWAVG-H -? [CH2NH] -LM-NH2, QWAVGH -? [CH = CH] -LM-NH2, QWAVG -a-Me-HLM-NH2, QWAVGH-Nme-LM-NH2, and QWAVGH-a-MeLM-NH2.
20. 20. A compound according to any of claims 1 to 7, characterized in that G is a GRP receptor targeting peptide that has been modified to reduce proteolytic cleavage.
21. 21. A method for conferring specificity for GRP-R and / or NMB-R in a compound comprising an optical tag or a metal chelator optionally in compound with a radionuclide and a GRP-R targeting peptide, wherein the The method comprises including in the compound a linker of the general formula: NOP wherein: N is 0, an alpha or non-alpha amino acid or another linking group; O is an alpha or non-alpha amino acid; P is 0, an alpha or non-alpha amino acid or another linking group; and where at least one of N, O, or P is an amino acid no alpha
22. 22. A method for conferring specificity for GRP-R and / or NMB-R in a compound comprising an optical tag or a metal chelator optionally in compound with a radionuclide and a GRP-R targeting peptide, wherein the method comprises to include in the compound a linker of the general formula: NOP wherein: N is 0, an alpha amino acid, a substituted biary acid or another linking group; O is an alpha amino acid or a substituted bile acid; P is 0, an alpha amino acid, a substituted biary acid or another linking group; and wherein at least one of N, O, or P is a substituted bile acid.
23. 23. A method for conferring specificity of GRP-R and / or NMB-R in a compound comprising an optical tag or a metal chelator optionally in compound with a radionuclide and a GRP-R targeting peptide, wherein the method comprises include in the compound a linker of the general formula: NOP where: N is 0, an alpha amino acid, a non-alpha amino acid with a cyclic group or another linking group; O is an alpha amino acid or a non-alpha amino acid with a cyclic group; P is 0, an alpha amino acid, a non-alpha amino acid with a cyclic group or another linking group; and wherein at least one of N, O, or P is a non-alpha amino acid with a cyclic group.
24. 24. A method for improving the in vivo activity of a compound comprising an optical tag or metal chelator optionally in compound with a radionuclide and a GRP-R targeting peptide, wherein the method comprises including in the compound a linker of the general formula: NOP wherein: N is 0, an alpha or non-alpha amino acid or another linking group; O is an alpha or non-alpha amino acid; P is 0, an alpha or non-alpha amino acid or another linking group; and wherein at least one of N, O, or P is a non-alpha amino acid.
25. 25. A method for improving the in vivo activity of a compound comprising an optical tag or metal chelator optionally in compound with a radionuclide and a GRP-R targeting peptide, wherein the method comprises including in the compound a linker of the general formula: N-O-P wherein: N is 0, an alpha amino acid, a substituted biary acid or another linking group; O is an alpha amino acid or a substituted bile acid; P is 0, an alpha amino acid, a substituted biary acid or another linking group; and wherein at least one of N, O, or P is a substituted bile acid.
26. 26. A method for improving the in vivo activity of a compound comprising an optical label or metal chelator optionally in compound with a radionuclide and a GRP-R targeting peptide, wherein the method comprises including in the compound a linker of the general formula: NOP wherein: N is 0, an alpha amino acid, a non-alpha amino acid with a cyclic group or another linking group; O is an alpha amino acid or a non-alpha amino acid with a cyclic group; P is 0, an alpha amino acid, a non-alpha amino acid with a cyclic group or another linking group; and wherein at least one of N, O, or P is a non-alpha amino acid with a cyclic group.
27. 27. A compound that has the following structure: L218 RESUEN New and improved compounds for use in generating diagnostic therapy images, which have the formula MNOPG, where M is an optical label or a metal chelator (in the form of a compound with a metal radionuclide or not), NOP is the linker, and G is the GRP receptor targeting peptide. Methods for generating images of a patient and / or for providing radiotherapy or phototherapy to a patient using the compounds of the present invention are also provided. In addition, methods and equipment for preparing a diagnostic image generation agent of the compound are provided. And methods and equipment for preparing a radiotherapeutic agent are also provided.