WO2010135493A2 - Alzheimer's disease imaging agents - Google Patents

Abstract

This invention provides compounds and methods of imaging amyloid deposits using radiolabeled compounds. This invention also provides a method of inhibiting the aggregation of amyloid proteins to form amyloid plaques or deposits, a method of determining a therapeutic compound's ability to inhibit aggregation of amyloid protein, and a method of delivering a therapeutic agent to amyloid deposits.

Description

ALZHEIMER'S DISEASE IMAGING AGENTS

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to US provisional patent application serial number 61/179,836, filed May 20, 2009 which is hereby incorporated by reference in its entirety to the extent not inconsistent with the disclosure herewith.

BACKGROUND OF THE INVENTION

[0002] Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, irreversible memory loss, disorientation, and language impairment. Postmortem examination of AD brain sections reveals abundant amyloid plaques or deposits composed of amyloid-β (Aβ) peptides and numerous neurofibrillary tangles (NFTs) formed by filaments of highly phosphorylated tau proteins. A detailed discussion of this disease can be found in Ginsberg, S. D., et al., "Molecular Pathology of Alzheimer's Disease and Related Disorders," in Cerebral Cortex. Neurodegenerative and Age-related Changes in Structure and Function of Cerebral Cortex, Kluwer Academic/Plenum, New York (1999), pp. 603-654; Vogelsberg-Ragaglia, V., et al, "Cell Biology of Tau and Cytoskeletal Pathology in Alzheimer's Disease," Alzheimer's Disease, Lippincot, Williams & Wilkins, Philadelphia, P.A. (1999), pp.359-372.

[0003] The major component of amyloid plaques is a small 39-43 amino acid long β-amyloid peptide that is generated from the cleavage of a larger amyloid precursor protein. However, except for diffuse plaques formed almost exclusively of β-amyloid peptides, amyloid plaques are complex lesions containing numerous associated cellular products. Mutations causing increased production of the 42-43 amino acid form of this peptide have been genetically linked to autosomal dominant familial forms of Alzheimer's disease. Deposits of β-amyloid peptide occur very early in the disease process, long before clinical symptoms develop. Although the exact mechanisms underlying AD are not fully understood, β-amyloids are widely believed to play a causal role in the disease. Whether or not amyloid deposits are causal, they are certainly a key part of the diagnosis. Because amyloid plaques occur early in the disease, the ability to image amyloid plaques would provide a convenient means for early diagnosis and prevention of the disease as well as a method for monitoring effectiveness of therapeutic agents for the disease.

[0004] In addition to the role of amyloid deposits in Alzheimer's disease, the presence of amyloid deposits has also been shown in numerous diseases, which highlights the urgent need for efficient imaging agents. Amyloid deposits are shown to be present in diseases such as Mediterranean fever, Muckle-Wells syndrome, idiopathetic myeloma, amyloid polyneuropathy, amyloid cardiomyopathy, systemic senile amyloidosis, amyloid polyneuropathy, hereditary cerebral hemorrhage with amyloidosis, Down's syndrome, Scrapie, Creutzfeldt-Jacob disease, Kuru, Gerstamnn-Straussler-Scheinker syndrome, medullary carcinoma of the thyroid, Isolated atrial amyloid, β₂-microglobulin amyloid in dialysis patients, inclusion body myositis, β₂-amyloid deposits in muscle wasting disease, and Islets of Langerhans diabetes Type Il insulinoma.

[0005] The direct imaging of amyloid deposits in vivo is difficult, as the deposits have many of the same physical properties (e.g., density and water content) as normal tissues. Attempts to image amyloid deposits using magnetic resonance imaging (MRI) and computer-assisted tomography (CAT) have been disappointing and have detected amyloid deposits only under certain favorable conditions. In addition, efforts to label amyloid deposits with antibodies, serum amyloid P protein, or other probe molecules have provided some selectivity on the periphery of tissues, but have not provided clear imaging of tissue interiors.

[0006] There have been various approaches for developing ligands which can specifically and selectively bind amyloid plaques. [Ashburn, T. T., et al., (1996) Chem. Biol. 3:351 -358; Zhen, W., et al., (1999) J. Med. Chem. 42:2805-2815]. Examples include highly conjugated chrysamine-G (CG), Congo red (CR), and 3'- bromo- and 3'-iodo derivatives of CG. These compounds have been shown to bind selectively to amyloid beta peptide aggregates in vitro as well as to fibrillar amyloid beta deposits in AD brain sections [Mathis, C. A., et al., Proc. Xllth Intl. Symp. Radiopharm. Chem., Uppsala, Sweden:94-95 (1997)]. However, ligands useful for detecting amyloid plaque aggregates in the living brain must cross the intact blood- brain barrier. Thus, ligands that are relatively small in size and lipophilic have been sought as candidate imaging agents for amyloid plaques.

[0007] The development of radiolabeled ligands to image amyloid deposits using positron emission tomography (PET) and single photon emission computed tomography (SPECT) has been underway for some time. Highly conjugated thioflavins (S and T) are commonly used as dyes for staining the amyloid beta aggregates in the AD brain [Elhaddaoui, A., et al., Biospectroscopy 1 : 351 -356 (1995)]. These compounds are based on benzothiazole, which is relatively small in molecular size. However, thioflavins contain an ionic quarternary amine, which is permanently charged and unfavorable for brain uptake.

[0008] There have been further efforts in developing ligands for imaging amyloid deposits. U.S. Patent 6,696,039, US 2004/0131545, and WO 02/085903 disclose thioflavin derivatives as amyloid plaque aggregation inhibitors and diagnostic imaging agents; U.S. Patent 6,001 ,331 discloses a method of imaging amyloid deposits using radiolabeled benzothiazole derivatives; WO 2004/032975 describes various biphenyls and fluorenes as imaging agents in Alzheimer's disease; WO 2004/064869 discloses metal-chelating agents for the diagnosis, prevention, and treatment of pathophysiological conditions associated with amyloid accumulation; US 2005/0043377 describes further thioflavin derivatives for in vivo imaging and prevention of amyloid deposition. WO 2006/035316 describes derivatives for imaging amyloid deposits.

[0009] Definitive diagnosis of Alzheimer's disease is currently only possible by postmortem staining of brain tissue. Considering that Alzheimer's disease affects approximately 20 to 40% of the population over 80 years of age, the fastest growing age group in the United States and other post-industrial countries, there is a continuing need for an agent with high selectivity and specificity for binding amyloid deposits or plaques which can be used in a simple, noninvasive method for in vivo imaging and quantitating amyloid deposits in a patient. Such an agent will allow early detection and monitoring of treatment efficacy for maximum cognitive preservation. SUMMARY OF THE INVENTION

[0010] The present invention provides compounds and compositions which bind to amyloid β plaques. The compounds and compositions of the invention can be readily labeled with positron emitting radio-elements such as carbon-11 and fluohne-18 or single photon radio-elements. The compounds and compositions of the invention are useful for identifying amyloid β plaques via PET or SPECT imaging, for example. The compounds and compositions of the invention are useful for detecting and quantitating amyloid deposits. The compounds and compositions are also useful in inhibiting the aggregation of amyloid proteins to form amyloid deposits and in delivering a therapeutic agent selectively and specifically to amyloid deposits.

[0011] In an embodiment, provided is a compound of formula I:

where Z is O, S, N or NH; R2 and R3 are each independently H, Ci-4 aminoalkyl, C1-4 haloalkyl or C1-C4 alkyl; A, B and D are each independently N, NH, C-Y or C=O, provided that at least one of A, B and D is not CH; each Y is independently selected from the group consisting of: H, X, CH2(CH2)nX, CH2CH=CH(CH2)nX, O(CH2)nX, OCH2CH=CH(CH2)nX, (OCH₂CH₂)_nX, S(CH2)nX, SCH2CH=CH(CH2)nX, (SCH₂CH₂)_nX, and Tc-99m complexed compounds; each n is independently an integer from 0 to 7; each X is independently I, F, Br or Cl; R4 and Rs are each independently selected from the group consisting of: H, X, OH, C1 -C4 alkyl, O-(C1 - C4 alkyl), CH2(CH₂)nX, CH₂CH=CH(CH2)nX, OCH2(CH₂)nX, OCH₂CH=CH(CH2)nX, (OCH₂CH₂)_nX, S(CH₂)nX, SCH₂CH=CH(CH2)nX, and (SCH₂CH₂)_nX; where each n is independently an integer from 0 to 7; E and G are independently C, CH, or N; and pharmaceutically acceptable salts thereof.

[0012] In an embodiment of the compounds of formula I, both E and G are CH.

In an embodiment of the compounds of formula I, one of E and G is N and the other of E and G is CH. In an embodiment of compounds of formula I, Z is S. In an embodiment of compounds of formula I, Z is NH. In an embodiment of compounds of formula I, B and D are CH. In an embodiment of compounds of formula I, B and D are CH and A is C-Y. In an embodiment of compounds of formula I, R4 and R5 are H. In an embodiment of compounds of formula I, one of R5 or R6 is halogen, -OMe, or -OH and the other of R5 or R6 is H. In an embodiment of the compounds of formula I, there are three nitrogen atoms as ring substituents. In an embodiment of the compounds of formula I, there are four nitrogen atoms as ring substituents. In an embodiment of the compounds of formula I, there is one halogen atom present as a substituent. In an embodiment of the compounds of formula I, the compound is radiolabeled. In an embodiment, provided is a compound of formula I wherein B and D are C-Y and Y is H.

[0013] Also provided is a compound of formula II:

where R₂ and R₃ are each independently H, Ci_-4 aminoalkyl, Ci_-4 haloalkyl or CrC₄ alkyl; A is C-Y or C=O; Y is selected from the group consisting of: X, CH₂(CH₂)_nX, CH₂CH=CH(CH₂)_nX, O(CH₂)_nX, OCH₂CH=CH(CH₂)_nX, S(CH₂)_nX, SCH₂CH=CH(CH₂)_nX , where each n is independently an integer from O to 7, and Tc- 99m complexed compounds; each X is independently I, F, Br or Cl; R₄ and Rs are each independently selected from the group consisting of: H, X, OH, C1 -C4 alkyl, O- (C1 -C4 alkyl), CH₂(CH₂)_nX, CH₂CH=CH(CH₂)_nX, OCH₂(CH₂)_nX, OCH₂CH=CH(CH₂)_nX, S(CH₂)_nX, and SCH₂CH=CH(CH₂)_nX; where each n is independently an integer from O to 7, and pharmaceutically acceptable salts thereof.

[0014] In an embodiment of the compounds of formula II, one of R2 and R3 is hydrogen and the other of R2 and R3 is C1 -C4 alkyl.

[0015] Also provided is a compound of formula III:

where Z is S, N or NH; R2 and R3 are each independently H, Ci-4 aminoalkyl, C1-4 haloalkyl or C1-C4 alkyl; J, A, B and D are each independently N, NH, C-Y or C=O, provided that at least one of J, A, B and D is not CH; each Y is independently selected from the group consisting of: H, X, CH2(CH2)nX, CH2CH=CH(CH2)nX, O(CH2)nX, OCH2CH=CH(CH2)nX, (OCH₂CH₂)_nX, S(CH2)nX, SCH2CH=CH(CH2)nX, (SCH₂CH₂)_nX, and Tc-99m complexed compounds; each n is independently an integer from O to 7; each X is independently I, F, Br or Cl; R4 and Rs are each independently selected from the group consisting of: H, X, OH, C1 -C4 alkyl, O-(C1 - C4 alkyl), CH2(CH₂)nX, CH₂CH=CH(CH2)nX, OCH2(CH₂)nX, OCH₂CH=CH(CH2)nX, (OCH₂CH₂)_nX, S(CH₂)nX, SCH₂CH=CH(CH2)nX, and (SCH₂CH₂)_nX; where each n is independently an integer from O to 7; and pharmaceutically acceptable salts thereof.

[0016] In an aspect of compounds of formula III, J is N. In an aspect of compounds of formula III, J is CH. In an aspect of compounds of formula III, one or J, A, B, and D is N and the others of J, A, B and D are CH or C-Y. In an aspect of compounds of formula III, Z is NH. In an aspect of compounds of formula III, J, A or D is C-Y and Y is a halogen.

[0017] In an embodiment, provided is a compound of formula IV:

where Z is S, N or NH; R2 and R3 are each independently H, Ci-4 aminoalkyl, C1-4 haloalkyl or C1-C4 alkyl; J, A, B and D are each independently N, NH, C-Y or C=O, provided that at least one of J, A, B and D is not CH; each Y is independently selected from the group consisting of: H, X, CH2(CH2)nX, CH2CH=CH(CH2)nX, O(CH₂)nX, OCH₂CH=CH(CH2)nX, (OCH₂CH₂)_nX, S(CH₂)nX, SCH₂CH=CH(CH2)nX, (SCH₂CH₂)_nX, and Tc-99m complexed compounds; each n is independently an integer from 0 to 7; each X is independently I, F, Br or Cl; R4 and Rs are each independently selected from the group consisting of: H, X, OH, C1 -C4 alkyl, O-(C1 - C4 alkyl), CH2(CH2)nX, CH2CH=CH(CH2)nX, OCH2(CH2)nX, OCH2CH=CH(CH2)nX, (OCH₂CH₂)_nX, S(CH2)nX, SCH2CH=CH(CH2)nX, and (SCH₂CH₂)_nX; where each n is independently an integer from 0 to 7; and pharmaceutically acceptable salts thereof.

[0018] In an aspect of compounds of formula IV, J is N. In an aspect of compounds of formula IV, J is CH. In an aspect of compounds of formula IV, one or J, A, B, and D is N and the others of J, A, B and D are CH or C-Y. In an aspect of compounds of formula IV, Z is NH. In an aspect of compounds of formula IV, J, A or D is C-Y and Y is a halogen.

[0019] Also provided is a compound of formula V:

where Z is O, S, N or NH; R2 and R3 are each independently H, Ci-4 aminoalkyl, C1-4 haloalkyl or C1-C4 alkyl; J, A, B and D are each independently N, NH, C-Y or C=O, provided that at least one of J, A, B and D is not CH; each Y is independently selected from the group consisting of: H, X, CH2(CH2)nX, CH2CH=CH(CH2)nX, O(CH2)nX, OCH2CH=CH(CH2)nX, (OCH₂CH₂)_nX, S(CH2)nX, SCH2CH=CH(CH2)nX, (SCH₂CH₂)_nX, and Tc-99m complexed compounds; each n is independently an integer from 0 to 7; each X is independently I, F, Br or Cl; R4 and Rs are each independently selected from the group consisting of: H, X, OH, C1 -C4 alkyl, O-(C1 - C4 alkyl), CH2(CH₂)nX, CH₂CH=CH(CH2)nX, OCH2(CH₂)nX, OCH₂CH=CH(CH2)nX, (OCH₂CH₂)_nX, S(CH₂)nX, SCH₂CH=CH(CH2)nX, and (SCH₂CH₂)_nX; where each n is independently an integer from 0 to 7; E and G are independently C, CH or N; and pharmaceutically acceptable salts thereof.

[0020] In an embodiment, provided is an isotopically labeled compound of formula I-V. In an embodiment, provided is a compound of formula I-V wherein one or more carbon atoms in R₂ or R₃ is isotopically labeled. In an embodiment, provided is a compound of formula I-V wherein one or more oxygen atoms in R₂ or R₃ is isotopically labeled. In an embodiment, provided is a compound of formula I -V wherein one or more carbon atoms in R₂ or R₃ is ¹¹C. In an embodiment, provided is a compound of formula I-V wherein one or more oxygen atoms in R₂ or R₃ is ¹⁵O or ¹⁸O. In an embodiment, provided is a compound of formula I-V wherein R₂ and R3 are each independently H or C1 -C4 alkyl. In an embodiment, provided is a compound of formula I-V wherein X is selected from the group consisting of: I, F, Br and Cl. In an embodiment, provided is a compound of formula I-V, wherein R4 and R5 are each independently selected from the group consisting of: H; X; OH; C1 -C4 alkyl; and O-(C1 -C4 alkyl). In an embodiment, provided is a compound of formula I- V, wherein X is ¹²⁴I, ¹²⁵I, ¹³¹I, ¹²³1, ⁷⁶Br, ⁷⁷Br, ⁸²Br, ¹⁸F, or ³²CI. In an embodiment, provided is a compound of formula I-V wherein one of R₂ and R₃ is hydrogen and the other of R₂ and R3 is C1 -C4 alkyl. In an embodiment, provided is a compound of formula I-V wherein both of R₂ and R₃ are C1-C4 alkyl. In an embodiment, provided is a compound of formula I-V wherein both of R₂ and R₃ are hydrogen.

[0021] In an embodiment, provided is a radiolabeled compound of any of the formulas described herein. As used herein, "radiolabeled" means a compound in which the naturally occurring isotope of an element is replaced with a radioisotope of the element (also referred to as "isotopically labeled"). A compound of the invention may have more than one radiolabel. In an embodiment, any of F, Cl, Br, I, O or C in the formulas shown herein may be in stable isotopic or radioisotopic form. Particularly useful radioisotopic labels are ¹⁸F, ¹²³I, ¹²⁵I, ¹³¹1, ⁷⁶Br, ⁷⁷Br, ¹⁸O and ¹¹C. In an embodiment, one or more F, Br or I in the formulas provided herein is in radioisotopic form. In an embodiment, any F, Br or I in the formulas provided herein is in radioisotopic form.

[0022] In an embodiment, provided is a compound or radiolabeled compound having one of the formulas:

[0023] In an embodiment, provided is a compound or radiolabeled compound having a formula below:

[0024] In an embodiment, provided is a compound or radiolabeled compound having a formula below:

[0025] In embodiments, provided is a compound or radiolabeled compound having a formula below:

where R₂ and R₃ are each independently H, C1 -4 aminoalkyl, C1 -4 haloalkyl or C1 - C4 alkyl; X is I, F, Br or Cl; R₄ and R₅ are each independently selected from the group consisting of: H, X, OH, C1 -C4 alkyl, O-(C1 -C4 alkyl), CH₂(CH₂)nX, CH₂CH=CH(CH₂)nX, OCH₂(CH₂)nX, OCH₂CH=CH(CH₂)nX, (OCH₂CH₂)nX, S(CH₂)nX, SCH₂CH=CH(CH₂)nX, and (SCH₂CH₂)nX; where each n is independently an integer from 0 to 7.

[0026] When a line without a specific substituent indicated is attached to an atom, such as a nitrogen atom in the formulas shown here, it is understood that a

,H methyl group is attached. For example, \ indicates there is one hydrogen atom and one methyl group attached to the nitrogen atom. It is also recognized that in the compounds and compositions described here, the valences of the atoms are satisfied. For example, when functioning as a ring atom, a nitrogen may appear as - N- or -NH, depending on the bonding around the nitrogen atom. The proper valences and hydrogen attachments for any ring atoms is provided here, even if not specifically drawn or written out. Also, the attachments of various substituents is not necessarily shown here, but will be clear to one of ordinary skill in the art. [0027] In an embodiment, provided is a pharmaceutical composition comprising a compound of Formula I-V and a pharmaceutically acceptable carrier. In an embodiment, provided is diagnostic composition for imaging amyloid deposits, comprising a radiolabeled compound of formula I-V. In an embodiment, provided is a method of inhibiting amyloid plaque aggregation in a mammal, comprising administering the composition of Formula I-V in an amount effective to inhibit amyloid plaque aggregation. In an embodiment, provided is a method of imaging amyloid deposits, comprising: a) introducing into a mammal a detectable quantity of a diagnostic composition of Formula I -V; b) allowing sufficient time for the labeled compound to become associated with amyloid deposits; and c) detecting the labeled compound associated with one or more amyloid deposits. In an embodiment, the detection is performed using PET or SPECT imaging.

[0028] Compounds of the invention bind to amyloid deposits with high affinity and selectivity. The inventive compounds labeled with an appropriate radioisotope are useful as imaging agents for visualizing the location and density of amyloid deposits by PET and SPECT imaging, for example. Accordingly, the labeled compounds of the invention are useful for diagnostic imaging and evaluating efficacy of any therapeutic compounds for Alzheimer's disease. A method of imaging amyloid deposits provided comprises (a) introducing into a subject a detectable quantity of a labeled compound of Formula I-V; and/or a pharmaceutically acceptable salt, ester or amide thereof; (b) allowing sufficient time for the labeled compound to become associated with amyloid deposits; and (c) detecting the labeled compound associated with one or more amyloid deposits.

[0029] The present invention also provides diagnostic compositions comprising a radiolabeled compound of Formula I-V and/or a pharmaceutically acceptable carrier or diluent. Also within the scope of the invention are pharmaceutical compositions which comprise a compound of Formula I-V and/or a pharmaceutically acceptable carrier or diluent. The pharmaceutical compositions are useful for inhibiting the aggregation of amyloid proteins or for delivering a therapeutic agent to a subject. Also provided are pharmaceutically acceptable salts of the compounds of Formula I -V. Also provided herein are methods of making the compounds of Formula I-V. Methods of quantitating amyloid deposits are also provided herein. BRIEF DESCRIPTION OF THE FIGURES

[0030] Figure 1 shows the time-activity curves of brain regions for [¹⁸F]-FZ 2-

110 in a rhesus monkey (Ki = 0.53 nM vs. [³H]-PIB; logP=2.96). In the figure, the diamond represents data from the frontal cortex; the square represents data from the pons; and the triangle represents data from the cerebellum.

[0031] Figure 2 shows the portions of the brain used for Figure 1.

DETAILED DESCRIPTION OF THE INVENTION

[0032] In general, the terms and phrases used herein have their art-recognized meaning, which can be found by reference to standard texts, journal references and contexts known to those skilled in the art. The definitions provided are intended to clarify their specific use in the context of the invention.

[0033] The term "pharmaceutically acceptable salt" as used herein refers to those carboxylate salts or acid addition salts of the compounds of the present invention which are suitable for use in contact with the tissues of patients without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of the compounds of the invention. The term "salts" refers to the relatively nontoxic, inorganic and organic acid addition salts of compounds of the present invention. Also included are those salts derived from nontoxic organic acids such as aliphatic mono and dicarboxylic acids, for example acetic acid, phenyl-substituted alkanoic acids, hydroxy alkanoic and alkanedioic acids, aromatic acids, and aliphatic and aromatic sulfonic acids. These salts can be prepared in situ during the final isolation and purification of the compounds or by separately reacting the purified compound in its free base form with a suitable organic or inorganic acid and isolating the salt thus formed. Further representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate mesylate, glucoheptonate, lactiobionate and laurylsulphonate salts, propionate, pivalate, cyclamate, isethionate, and the like. These may include cations based on the alkali and alkaline earth metals, such as sodium, lithium, potassium, calcium, magnesium, and the like, as well as nontoxic ammonium, quaternary ammonium and amine cations including, but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like. See, for example, Berge S. M, et al., Pharmaceutical Salts, J. Pharm. Sci. 66:1 -19 (1977) which is incorporated herein by reference.

[0034] Similarly, the term, "pharmaceutically acceptable carrier," as used herein, is an organic or inorganic composition which serves as a carrier/stabilizer/diluent of the active ingredient of the present invention in a pharmaceutical or diagnostic composition. In certain cases, the pharmaceutically acceptable carriers are salts. Further examples of pharmaceutically acceptable carriers include but are not limited to water, phosphate-buffered saline, saline, pH controlling agents (e.g. acids, bases, buffers), stabilizers such as ascorbic acid, isotonizing agents (e.g. sodium chloride), aqueous solvents, a detergent (ionic and non-ionic) such as polysorbate or TWEEN 80.

[0035] The term "alkyl" as used herein by itself or as part of another group refers to both straight and branched chain radicals of up to 8 carbons, preferably 6 carbons, more preferably 4 carbons, such as methyl, ethyl, propyl, isopropyl, butyl, t- butyl, and isobutyl.

[0036] The term "alkoxy" is used herein to mean a straight or branched chain alkyl radical, as defined above, unless the chain length is limited thereto, bonded to an oxygen atom, including, but not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, and the like. Preferably the alkoxy chain is 1 to 6 carbon atoms in length, more preferably 1 -4 carbon atoms in length.

[0037] The term "alkylamine" or "aminoalkyl" as used herein by itself or as part of another group refers to an amino group which is substituted with one or more alkyl groups as defined above. The term "haloalkyl" means an alkyl group substituted with one or more halo groups.

[0038] The term "dialkylamine" or other forms of the phrase as employed herein by itself or as part of another group refers to an amino group which is substituted with two alkyl groups as defined above. [0039] The term "halo" employed herein by itself or as part of another group refers to a halogen atom, including chlorine, bromine, fluorine or iodine.

[0040] The term "aryl" as employed herein by itself or as part of another group refers to monocyclic or bicyclic aromatic groups containing from 6 to 12 carbons in the ring portion, preferably 6-10 carbons in the ring portion, such as phenyl, naphthyl or tetrahydronaphthyl.

[0041] The term "heterocycle" or "heterocyclic ring", as used herein except where noted, represents a stable 5- to 7- membered mono-heterocyclic ring system which may be saturated or unsaturated, and which consists of carbon atoms and from one to three heteroatoms selected from the group consisting of N, O, and S, and wherein the nitrogen and sulfur heteroatom may optionally be oxidized. Especially useful are rings contain one nitrogen combined with one oxygen or sulfur, or two nitrogen heteroatoms. Examples of such heterocyclic groups include piperidinyl, pyrrolyl, pyrrolidinyl, imidazolyl, imidazlinyl, imidazolidinyl, pyridyl, pyrazinyl, pyrimidinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidinyl, thiazolyl, thiazolidinyl, isothiazolyl, homopiperidinyl, homopiperazinyl, pyridazinyl, pyrazolyl, and pyrazolidinyl, most preferably thiamorpholinyl, piperazinyl, and morpholinyl.

[0042] The term "heteroatom" is used herein to mean an oxygen atom ("O"), a sulfur atom ("S") or a nitrogen atom ("N"). It will be recognized that when the heteroatom is nitrogen, it may form an NR^aR^b moiety, wherein R^a and R^b are, independently from one another, hydrogen or Ci_-4 alkyl, C_2-4 aminoalkyl, Ci_-4 halo alkyl, halo benzyl, or R¹ and R² are taken together to form a 5- to 7-member heterocyclic ring optionally having O, S or NR^C in said ring, where R^c is hydrogen or Ci_-4 alkyl.

[0043] The term "heteroaromatic" is used herein to mean an aromatic ring substituted with one or more heteroatoms and may contain substituents including halogens, alkyl, alkoxy, alkythio, alkenyl, allynyl, haloalkyl, haloalkoxy, haloalkythio, haloalkenyl, haloalkynyl, haloaromatic and haloheteroaromatic.

[0044] The present invention also includes isomers, including stereoisomers as well as optical isomers, e.g. mixtures of enantiomers as well as individual enantiomers and diastereomers which arise as a consequence of structural asymmetry. Each individual stereoisomer and optical isomer is intended to be included separately and is intended to be able to be included and excluded in the claims if necessary or desirable. It is understood that there are methods known in the art to synthesize separate isomers or separate isomers from a mixture.

[0045] The compounds of the invention may also be solvated, especially hydrated. Hydration may occur during manufacturing of the compounds or compositions comprising the compounds, or the hydration may occur over time due to the hygroscopic nature of the compounds. In addition, the compounds of the present invention can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the present invention.

[0046] In order to develop new imaging agents for amyloid plaques or deposits, the inventors herein identified a new class of compounds which have high affinity for amyloid-β (Aβ) plaques and which can be readily labeled with positron emitting radioelements or single photon emitting radio-elements attached directly to or via a linker molecule.

[0047] Compounds of the invention are represented by the formulas and structures as shown herein. It is noted that all compounds described herein are intended to be disclosed to the same extent as if they were specifically shown in this disclosure. It is intended that all individual compounds separately and all possible groupings of compounds described herein can be included and/or excluded in the claims. In addition, all possibilities for each variable are intended to be disclosed to the same extent as if they were specifically shown in this disclosure. It is intended that all individual members of all groups and all possible groups provided herein can be included and/or excluded in the claims.

[0048] The examples presented below are intended to illustrate particular embodiments of the present invention and are not intended to limit the scope of the specification, including the claims in any manner. EXAMPLES

Example 1 : Competitive binding assays

[0049] Exemplary compounds of the invention have been evaluated for their binding affinities via the binding competition with known compound PIB using human AD cortical tissues. The inhibition constants Ki (nM), for the competitive inhibition of the unlabeled compounds for amyloid-β plaques and neurofibrillary tangles vs.[³H]PIB using postmortem AD homogenate tissues is shown in Table 1 and 2. These results demonstrate that certain compounds of the invention have higher affinity for amyloid plaques than PIB or IMPY. The rank in affinity of the compounds tested was FZ 2-107 > FZ 2-111 > FZ 2-110 > FZ 2-100 > PIB >IMPY >FZ 2-114 > FZ 2-112. Also shown are IC50 values for certain compounds. The different data obtained for the same compounds represent differences in experimental conditions and other factors.

[0050] Compounds with nitrogen heteroatoms and polar halogens on the aromatic rings have less non-specific binding of the compounds on non Aβ-amyloid brain tissue. This provides greater Aβ-amyloid to normal ratios and more sensitive detection.

Table 1: Ki constants for selected compounds

Table 2. Additional results of Ki constants for compounds

Table 3. Inhibition Constants (Ki, nM) of Various Ligands In Synthetic AD Homogenate tissue vs [H-3]PIB

Tables 1 and 2 are derived from human amyloid from post mortem AD subjects whereas Table 3 is from synthetic AD homogenate tissue. Procedure:

[0051] Standard procedures were used to determining Ki and IC50 values. As an example, the following assay was used to measure the values listed in Table 3.

[0052] In Vitro Binding Assay. Human Aβ(1-40) was purchased from Bachem,

Inc. (USA). Aggregation was carried out by dissolving 1 mg of peptide in a solution of 2.3 mL of PBS (pH 7.0) containing 1.30 mM of sodium hydroxide. The solution was incubated at room temperature for 56h with constant magnetic stirring (1200 rpm). The aggregate were aliquoted into 170 ml. portions and stored at -78 ⁰C for 3-6 months without noticeable change in the binding results. [³H]BTA-I (82 Ci/mmol and 99% purity) was obtained from American Radiolabeled Chemicals, Inc., St. Louis, MO.

[0053] Binding assays were carried out in 12 x 75 mm borosilicate glass tubes. All compounds were prepared as 1 mM dimethyl sulfoxide (DMSO) stocks solution before dilution into PBS. The maximum final concentration of DMSO in the assays was 0.25%. The reaction mixture contained 50 ml. of Aβ (1-40) aggregates (0.86 mg in the final assay mixture), 100 mL of [³H]BTA-I (0.8-1 nM diluted in PBS) and 500 mL of inhibitors (3.10^"6 to 10^"11 M diluted serially in PBS containing 0.5% DMSO) in a final volume of 1 mL. Non specific binding was defined in the presence of 3 mM of PIB in the same assay tubes. The mixture was incubated at room temperature for 120 min, and the bound and free fractions were separated by vacuum filtration through Whatman GF/B glass filters using a Brandel M- 24 cell harvester followed by 2 x 2 mL washes with PBS. Filters containing the bound ligand were counted in a gamma counter. Values for the half-maximum inhibitory concentration (IC₅₀) were determined from displacement curves of three independent experiments in triplicate subject to non linear regression analysis using GraphPad Prism. The inhibition constant (K₁) were calculated using the Cheng-Prusoff equation: K₁ = IC₅₀/(1 +[L]/K_d), where [L] is the concentration of [3H]BTA-I used in the assay, and K_d is the dissociation constant of BTA-1.

Example 2: Micro-PET imaging studies

[0054] In order to assess the brain uptake and clearance, compounds were radiolabeled with fluorine-18. The kinetics of fluorine-18 labeled compounds in brain were determined by micro-PET in rhesus monkeys. The rhesus monkeys are assumed to have no amyloid deposits in their brains, thus this study should reflect brain entry and clearance from normal brain tissue. The time activity curves of compound FZ 2-110 is shown in Figure 1 , indicating that compounds easily penetrate the blood-brain barrier after intraveneous injection.

[0055] As an example of this procedure, FZ 2-110 was tested and has a Ki = 0.53 nM v. [3H]-PIB, and a logP of 2.96. Figure 1 shows SUV v. time in various portions of the brain.

[0056] The studies described above indicate that the compounds disclosed are excellent imaging agents for amyloid plaques. The inventive compounds can readily penetrate the intact blood-brain barrier and be retained in the brain sufficiently long enough for imaging. These compounds exhibit specific brain uptake over other tissues in vivo. The skilled artisan can evaluate a compound of the invention as an imaging agent for amyloid plaques by various art-known methods and assays as disclosed herein. For example, a given compound can be tested for binding specificity and selectivity for amyloid deposits in an in vitro competitive binding assay using suitable cells, tissues or beta amyloid peptides, along with a known imaging agent as a control, as described in the present application. If the compound shows desired binding characteristics for amyloid plaques, it can then be further evaluated in vivo, i.e., for brain uptake, selective and specific binding for amyloid deposits, by measuring distribution in various tissues after administration into an animal (e.g. rhesus monkey).

Example 3: Synthesis

[0057] Those skilled in the art can synthesize any compound of the invention according to the description provided herein, combined with the knowledge readily available in the art without undue experimentation.

[0058] The schemes below provide exemplary synthesis methods for compounds of the invention. It is recognized that one of ordinary skill in the art can use the provided synthesis methods and other methods known in the art to synthesize all compounds of the invention. Scheme 1

I

I

Scheme 2

Scheme 3

9-BBN, NaOH, H₂O,

Kryptofi ^x

Scheme 4

X = F₁CI, Br, I

Scheme 5

Y

O EtOH, H₂SO₄ O MeI, K₂CO₃

HO ^{^}Λ /r^NH> reflux EtO- -NH₂ DMSO 10O⁰C

EtO

reflux

= 3-F = 2-F

= 3-F X = F, Cl, Br, I = 2-F Y=F, Cl, OCH₃

= 3-CI

Scheme 6

Scheme 7

Scheme 8

[0059] When the compounds of the invention are to be used as imaging agents, they must be labeled with suitable radioactive halogen isotopes such as ¹²³I, ¹³¹I, ¹⁸F, ⁷⁶Br, and ⁷⁷Br. The radiohalogenated compounds of this invention can easily be provided in kits with materials necessary for imaging amyloid deposits. For example, a kit can contain a final product labeled with an appropriate isotope ready to use for imaging or a penultimate product (e.g. compounds of formula I-V having Sn(alkyl)₃ at the X position) and a label (e.g. K[¹⁸F]F) with reagents such that a final product can be made at the site or time of use.

Example 4. Imaging

[0060] As described herein, compounds of the invention are useful in imaging. In embodiments, the compounds are useful for in vivo imaging. In embodiments, the compounds are useful for in vitro imaging. In an exemplary protocol, a radiolabled compound of Formula I-V is introduced into a tissue or a patient in a detectable quantity. The compound is typically part of a pharmaceutical composition and is administered to the tissue or the patient by methods well known to those skilled in the art. For example, the compound can be administered either orally, rectally, parenterally (intravenous, by intramuscularly or subcutaneously), intracistemally, intravaginally, intraperitoneal^, intravesically, locally (powders, ointments or drops), or as a buccal or nasal spray. After sufficient time has passed for the compound to become associated with the desired tissue, the labeled compound is detected noninvasively inside the patient.

[0061] In another embodiment of the invention, a labeled compound of the invention is introduced into a patient, sufficient time is allowed for the compound to become associated with amyloid deposits, and then a sample of tissue from the patient is removed and the labeled compound in the tissue is detected apart from the patient. Alternatively, a tissue sample is removed from a patient and a labeled compound of the invention is introduced into the tissue sample. After a sufficient amount of time for the compound to become bound to amyloid deposits, the compound is detected. The term "tissue" means a part of a patient's body. Examples of tissues include the brain, heart, liver, blood vessels, and arteries. A detectable quantity is a quantity of labeled compound necessary to be detected by the detection method chosen. The amount of a labeled compound to be introduced into a patient in order to provide for detection can readily be determined by those skilled in the art. For example, increasing amounts of the labeled compound can be given to a patient until the compound is detected by the detection method of choice. A label is introduced into the compounds to provide for detection of the compounds. As used herein, a "patient" is any organism to which a compound of the invention is desired to be administrated. In embodiments, a patient is a mammal. In embodiments, a patient is a human.

[0062] The administration of the labeled compound to a patient can be by a general or local administration route. For example, the labeled compound may be administered to the patient such that it is delivered throughout the body. Alternatively, the labeled compound can be administered to a specific organ or tissue of interest. For example, it is desirable to locate and quantitate amyloid deposits in the brain in order to diagnose or monitor the progress of Alzheimer's disease in a patient.

[0063] Those skilled in the art are familiar with determining the amount of time sufficient for a compound to become associated with amyloid deposits. The amount of time necessary can easily be determined by introducing a detectable amount of a labeled compound of the invention into a patient and then detecting the labeled compound at various times after administration.

[0064] Those skilled in the art are familiar with the various ways to detect labeled compounds. For example, magnetic resonance imaging (MRI), positron emission tomography (PET), or single photon emission computed tomography (SPECT) can be used to detect radiolabeled compounds. The label that is introduced into the compound will depend on the detection method desired. For example, if PET is selected as a detection method, the compound must possess a positron-emitting atom, such as 11 C or 18F.

[0065] Fluorine-18 is currently the most desirable positron emitting radioelement because its 110 minute half life allows sufficient time for radiosynthesis, purification of the final product and transportation to hospitals or other sites from the cyclotron or radiopharmacy. Also, fluorine-18 can be prepared in curie quantities as fluoride ion which can be used for automated radiosynthetic procedures (see Applied Radiation and Isotopes 58:657 (2003)). Radiopharmaceuticals of very high specific activity can be obtained in a theoretical, 1.7 Ci/nmol specific activity that can be calculated for a no-carrier-added fluorine-18 fluoride ion nucleophilic substitution reaction. Fluorine-18 is the lowest energy positron emitter (0.635 MeV, 2.4 mm positron range) which affords the highest spatial resolution in PET images. Other radioisotope labels are also useful.

[0066] The cyclic and non-cyclic compounds of the invention, can be labeled with Technetium to produce Tc-complexed compounds. Technetium-99m is known to be useful radionuclides for SPECT imaging. The compounds of the invention are joined to a Tc-99m metal cluster through a 4-6 carbon chain which can be saturated or possess a double or triple bond. The Tc-99m metal cluster can be, for example, an alkylthiolato complex, a cytectrene or a hydrazino nicotinamide complex (HYNIC), a cyclopentadienetricarbonyl or an N287 chelate. The linking structure can be R₅ where R₅ is Z-(CH₂)_a-CH_b-CH, where a is 1 , 2 or 3, b is 0, 1 or 2, and Z is an alkylthiolato-Tc complex, a Tc-cytectrene or a Tc-HYNIC complex or other Tc chelate as known in the art. The synthesis and use of Tc-99m complexes of compounds of the invention are known in the art.

[0067] The radioactive diagnostic agent should have sufficient radioactivity and radioactivity concentration which can assure reliable diagnosis. For instance, in case of the radioactive metal being technetium-99m ("Tc-99m complexed compounds"), it may be included usually in an amount of 0.1 to 50 mCi in about 0.5 to 5.0 ml at the time of administration. The amount of a compound of Formula I-V may be such as sufficient to form a stable chelate compound with the radioactive metal.

[0068] The inventive compound as a radioactive diagnostic agent is sufficiently stable, and therefore it may be immediately administered as such or stored until its use. When desired, the radioactive diagnostic agent may contain any additive such as pH controlling agents (e.g., acids, bases, buffers), stabilizers (e.g., ascorbic acid) or isotonizing agents (e.g., sodium chloride). The imaging of amyloid deposits can also be carried out quantitatively so that the amount of amyloid deposits can be determined.

[0069] Preferred compounds f IUolr U iml Ida(gJliInl(gJ I iMnUcIlUuUdte! d a I r daUdIiUoIiSsUotLUoμpte! S sUuUchI d abs ' I,

124 Iι, 1 ^m31l ■, 1¹⁰8Fr-, 7 '⁰6B_Dr-, 7 "7B_Dr or 1 "1C/ .

[0070] The inventive compounds are particularly useful for imaging amyloid deposits in vivo. One of the key prerequisites for an in vivo imaging agent of the brain is the ability to cross the intact blood-brain barrier after a bolus intravenous injection. The compounds disclosed herein possess a core ring system comprised of various substituted, fused 5- and 6-member aromatic rings. Several compounds of this invention contain a thiazolopyridine core. These compounds contain no quaternary ammonium ion, therefore, they are relatively small in size, neutral and lipophilic.

[0071] Another aspect of the invention is a method of inhibiting amyloid plaque aggregation. The present invention also provides a method of inhibiting the aggregation of amyloid proteins to form amyloid deposits, by administering to a patient an amyloid inhibiting amount of a compound of the invention. Those skilled in the art understand how to determine an amyloid inhibiting amount by simply administering a compound of the invention to a patient in increasing amounts until the growth of amyloid deposits is decreased or stopped. The rate of growth can be assessed using imaging as described above or by taking a tissue sample from a patient and observing the amyloid deposits therein. The compounds of the present invention can be administered to a patient at dosage levels in the range of about 0.1 to about 1 ,000 mg per day. For a normal human adult having a body weight of about 70 kg, a dosage in the range of about 0.01 to about 100 mg per kilogram of body weight per day is sufficient. The specific dosage used, however, can vary. For example, the dosage can depend on a number of factors including the requirements of the patient, the severity of the condition being treated, and the pharmacological activity of the compound being used. The determination of optimum dosages for a particular patient is well known to those skilled in the art.

[0072] The foregoing exemplary descriptions and the illustrative preferred embodiments of the present invention have been explained in the drawings and described in detail, with varying modifications and alternative embodiments being taught. While the invention has been so shown, described and illustrated, it should be understood by those skilled in the art that equivalent changes in form and detail may be made therein without departing from the true spirit and scope of the invention, and that the scope of the invention is to be limited only to the claims except as precluded by the prior art. Moreover, the invention as disclosed herein, may be suitably practiced in the absence of the specific elements which are disclosed herein. [0073] When a group of substituents is disclosed herein, it is understood that all individual members of that group and all subgroups, including any isomers and enantiomers of the group members and classes of compounds that can be formed using the substituents are disclosed separately. When a Markush group or other grouping is used herein, all individual members of the group and all combinations and subcombinations possible of the group are intended to be individually included in the disclosure. When a compound is described herein such that a particular isomer or enantiomer of the compound is not specified, for example, in a formula or in a chemical name, that description is intended to include each isomers and enantiomer of the compound described individual or in any combination. Additionally, unless otherwise specified, all isotopic variants of compounds disclosed herein are intended to be encompassed by the disclosure. For example, it will be understood that any one or more hydrogens in a molecule disclosed can be replaced with deuterium or tritium. Isotopic variants of a molecule are generally useful as standards in assays for the molecule and in chemical and biological research related to the molecule or its use. Specific names of compounds are intended to be exemplary, as it is known that one of ordinary skill in the art can name the same compounds differently.

[0074] Many of the molecules disclosed herein contain one or more ionizable groups [groups from which a proton can be removed (e.g., -COOH) or added (e.g., amines) or which can be quaternized (e.g., amines)]. All possible ionic forms of such molecules and salts thereof are intended to be included individually in the disclosure herein. With regard to salts of the compounds herein, one of ordinary skill in the art can select from among a wide variety of available countehons those that are appropriate for preparation of salts of this invention for a given application.

[0075] Every formulation or combination of components described or exemplified herein can be used to practice the invention, unless otherwise stated.

[0076] Whenever a range is given in the specification, for example, a temperature range, a time range, or a composition or concentration range, all intermediate ranges and subranges, as well as all individual values included in the ranges given are intended to be included in the disclosure. [0077] All patents and publications mentioned in the specification are indicative of the levels of skill of those skilled in the art to which the invention pertains. References cited herein are incorporated by reference herein in their entirety to indicate the state of the art as of their filing date and it is intended that this information can be employed herein, if needed, to exclude specific embodiments that are in the prior art. For example, when a compound is claimed, it should be understood that compounds known and available in the art prior to Applicant's invention, including compounds for which an enabling disclosure is provided in the references cited herein, are not intended to be included in the composition of matter claims herein.

[0078] As used herein, "comprising" is synonymous with "including," "containing," or "characterized by," and is inclusive or open-ended and does not exclude additional, unrecited elements or method steps. As used herein, "consisting of" excludes any element, step, or ingredient not specified in the claim element. As used herein, "consisting essentially of does not exclude materials or steps that do not materially affect the basic and novel characteristics of the claim. In each instance herein any of the terms "comprising", "consisting essentially of and "consisting of may be replaced with either of the other two terms. The invention illustratively described herein suitably may be practiced in the absence of any element or elements, limitation or limitations which is not specifically disclosed herein.

[0079] One of ordinary skill in the art will appreciate that starting materials, reagents, solid substrates, synthetic methods, purification methods, and analytical methods other than those specifically exemplified can be employed in the practice of the invention without resort to undue experimentation. All art-known functional equivalents, of any such materials and methods are intended to be included in this invention. The terms and expressions which have been employed are used as terms of description and not of limitation, and there is no intention that in the use of such terms and expressions of excluding any equivalents of the features shown and described or portions thereof, but it is recognized that various modifications are possible within the scope of the invention claimed. Thus, it should be understood that although the present invention has been specifically disclosed by preferred embodiments and optional features, modification and variation of the concepts herein disclosed may be resorted to by those skilled in the art, and that such modifications and variations are considered to be within the scope of this invention as defined by the appended claims.

[0080] The exact formulation, route of administration and dosage can be chosen by the individual physician in view of the patient's condition (see e.g. Fingl et. al., in The Pharmacological Basis of Therapeutics, 1975, Ch. 1 p. 1 ).

[0081] It should be noted that the attending physician would know how to and when to terminate, interrupt, or adjust administration due to toxicity, or to organ dysfunctions, or other adverse reactions. Conversely, the attending physician would also know to adjust treatment to higher levels if the clinical response were not adequate (precluding toxicity). The magnitude of an administered dose in the management of the disorder of interest will vary with the severity of the condition to be treated and to the route of administration. The severity of the condition may, for example, be evaluated, in part, by standard prognostic evaluation methods. Further, the dose and perhaps dose frequency, will also vary according to the age, body weight, and response of the individual patient. A program comparable to that discussed above also may be used in veterinary medicine.

[0082] Depending on the specific conditions being treated and the targeting method selected, such agents may be formulated and administered systemically or locally. Techniques for formulation and administration may be found in Alfonso and Gennaro (1995). Suitable routes may include, for example, oral, rectal, transdermal, vaginal, transmucosal, or intestinal administration; parenteral delivery, including intramuscular, subcutaneous, or intramedullary injections, as well as intrathecal, intravenous, or intraperitoneal injections.

[0083] For injection, the agents of the invention may be formulated in aqueous solutions, preferably in physiologically compatible buffers such as Hanks' solution, Ringer's solution, or physiological saline buffer. For transmucosal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art. [0084] Use of pharmaceutically acceptable carriers to formulate the compounds herein disclosed for the practice of the invention into dosages suitable for systemic administration is within the scope of the invention. With proper choice of carrier and suitable manufacturing practice, the compositions of the present invention, in particular those formulated as solutions, may be administered parenterally, such as by intravenous injection. Appropriate compounds can be formulated readily using pharmaceutically acceptable carriers well known in the art into dosages suitable for oral administration. Such carriers enable the compounds of the invention to be formulated as tablets, pills, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a patient to be treated.

[0085] Agents intended to be administered intracellular^ may be administered using techniques well known to those of ordinary skill in the art. For example, such agents may be encapsulated into liposomes, then administered as described above. Liposomes are spherical lipid bilayers with aqueous interiors. All molecules present in an aqueous solution at the time of liposome formation are incorporated into the aqueous interior. The liposomal contents are both protected from the external microenvironment and, because liposomes fuse with cell membranes, are efficiently delivered into the cell cytoplasm. Additionally, due to their hydrophobicity, small organic molecules may be directly administered intracellular^.

[0086] Pharmaceutical compositions suitable for use in the present invention include compositions wherein the active ingredients are contained in an effective amount to achieve the intended purpose. Determination of the effective amounts is well within the capability of those skilled in the art, especially in light of the detailed disclosure provided herein.

[0087] In addition to the active ingredients, these pharmaceutical compositions may contain suitable pharmaceutically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically. The preparations formulated for oral administration may be in the form of tablets, dragees, capsules, or solutions, including those formulated for delayed release or only to be released when the pharmaceutical reaches the small or large intestine. [0088] The pharmaceutical compositions of the present invention may be manufactured in a manner that is itself known, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levitating, emulsifying, encapsulating, entrapping or lyophilizing processes.

[0089] Pharmaceutical formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form. Additionally, suspensions of the active compounds may be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.

[0090] Pharmaceutical preparations for oral use can be obtained by combining the active compounds with solid excipient, optionally grinding a resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores. Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and/or polyvinylpyrrolidone (PVP). If desired, disintegrating agents may be added, such as the cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.

[0091] Dragee cores are provided with suitable coatings. For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses. [0092] Pharmaceutical preparations which can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. The push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In addition, stabilizers may be added.

[0093] Although the description herein contains many specificifies, these should not be construed as limiting the scope of the invention, but as merely providing illustrations of some of the embodiments of the invention. Thus, additional embodiments are within the scope of the invention and within the following claims. All references cited herein are hereby incorporated by reference to the extent that there is no inconsistency with the disclosure of this specification. Some references provided herein are incorporated by reference to provide details concerning sources of starting materials, additional starting materials, additional reagents, additional methods of synthesis, additional methods of analysis and additional uses of the invention.

Claims

CLAIMSWe claim:

1. A compound of formula I:

where Z is O, S or NH;

R2 and R3 are each independently H, C1-4 aminoalkyl, C1-4 haloalkyl or C1-C4 alkyl;

A, B and D are each independently N, NH, C-Y or C=O, provided that at least one of A, B and D is not CH; each Y is independently selected from the group consisting of: H, X,

CH2(CH2)nX, CH2CH=CH(CH2)nX, O(CH2)nX, OCH2CH=CH(CH2)nX,

(OCH₂CH₂)_nX, S(CH2)nX, SCH2CH=CH(CH2)nX, (SCH₂CH₂)_nX, and Tc-99m complexed compounds; each n is independently an integer from O to 7; each X is independently I, F, Br or Cl;

R4 and Rs are each independently selected from the group consisting of: H, X,

OH, C1 -C4 alkyl, 0-(C1 -C4 alkyl), CH2(CH₂)nX, CH₂CH=CH(CH2)nX,

OCH2(CH₂)nX, OCH₂CH=CH(CH2)nX, (OCH₂CH₂)_nX, S(CH₂)nX,

SCH2CH=CH(CH2)nX, and (SCH₂CH₂)_nX; where each n is independently an integer from O to 7; and

E and G are independently C, CH, or N.

2. The compound of claim 1 wherein Z is S.

3. The compound of claim 1 wherein Z is NH.

4. The compound of claim 1 wherein Z is S, B is N, A is C-Y, and D is CH, where Y is a halogen.

5. The compound of claim 1 wherein Z is S, A is CH, B is N, and D is C-Y where Y is a halogen.

6. A compound of formula II:

where R₂ and R₃ are each independently H, Ci_-4 aminoalkyl, Ci_-4 haloalkyl or

CrC₄ alkyl;

A is C-Y or C=O;

Y is selected from the group consisting of: X, CH₂(CH₂)_nX,

CH₂CH=CH(CH₂)_nX, O(CH₂)_nX, OCH₂CH=CH(CH₂)_nX, (OCH₂CH₂)_nX,

S(CH₂)_nX, SCH₂CH=CH(CH₂)_nX , and (SCH₂CH₂)_nX where each n is independently an integer from 0 to 7, and Tc-99m complexed compounds;

X is I, F, Br or Cl;

R₄ and R₅ are each independently selected from the group consisting of: H, X, OH, C1 -C4 alkyl, O-(C1 -C4 alkyl), CH₂(CH₂)_nX,

CH₂CH=CH(CH₂)_nX, OCH₂(CH₂)_nX, OCH₂CH=CH(CH₂)_nX,

(OCH₂CH₂)_nX, S(CH₂)_nX, SCH₂CH=CH(CH₂)_nX, and (SCH₂CH₂)_nX, where each n is independently an integer from O to 7.

7. The compound of any of claims 1 -6, which is isotopically labeled.

8. The compound of any of claims 1 -7 wherein one or more carbon atoms or oxygen atoms in R₂ or R₃ is isotopically labeled.

9. The compound of any of claims 1 -8 wherein one or more carbon atoms in R₂ Or R₃ is ¹¹C.

10. The compound of any of claims 1 -9, wherein one or more oxygen atoms in R₂ or R₃ is ¹⁵O or ¹⁸O.

11. The compound of any of claims 1 -10, wherein R₂ and R₃ are each independently H or C1-C4 alkyl.

12. The compound of any of claims 1 -11 , wherein X is selected from the group consisting of: I, F, Br and Cl.

13. The compound of any of claims 1 -12, wherein R₄ and R5 are each independently selected from the group consisting of: H; X; OH; C1 -C4 alkyl; O-(C1 -C4 alkyl).

14. The compound of any of claims 1 -13 which is radiolabeled.

15. The compound of any of claims 1 -14, wherein any X is ¹²⁴I, ¹²⁵I, ¹³¹1, ¹²³1, ⁷⁶Br, 7⁷Br₁ ⁸²Br₁ ¹⁸F₁ Or ³²CI.

16. The compound of any of claims 1 -15, wherein one of R₂ and R₃ is hydrogen and the other of R2 and R3 is C1 -C4 alkyl.

17. The compound of any of claims 1 -16, wherein both of R₂ and R₃ are C1 -C4 alkyl.

18. The compound of claim any of claims 1 -17, wherein both of R₂ and R₃ are hydrogen.

19. The compound of claim 1 , having one of the formulas below:

20. The compound of claim 19, which is radiolabeled.

21. The compound of claim 1 , having one of the formulas below:

22. The compound of claim 21 , which is radiolabeled.

23. The compound of claim 1 , having one of the formulas below:

24. A pharmaceutical composition comprising a compound of any of claims 1 -23 and a pharmaceutically acceptable carrier.

25. A diagnostic composition for imaging amyloid deposits, comprising a radiolabeled compound of any of claims 1 -24.

26. A method of inhibiting amyloid plaque aggregation in a mammal, comprising administering the composition of any of claims 1 -25 in an amount effective to inhibit amyloid plaque aggregation.

27. A method of imaging amyloid deposits, comprising: a) introducing into a mammal a detectable quantity of a diagnostic composition of any of claims 1 - 25; b) allowing sufficient time for the labeled compound to become associated with amyloid deposits; and c) detecting the labeled compound associated with one or more amyloid deposits.

28. The method of claim 27, wherein the detecting is performed using PET or SPECT imaging.

29. The compound having any of the formulas: