WO2011110511A1

WO2011110511A1 - Spect imaging agents of amyloid plaques

Info

Publication number: WO2011110511A1
Application number: PCT/EP2011/053353
Authority: WO
Inventors: Heribert Schmitt-Willich; Tobias Heinrich; Damian Brockschnieder
Original assignee: Bayer Pharma Aktiengesellschaft
Priority date: 2010-03-11
Filing date: 2011-03-07
Publication date: 2011-09-15
Also published as: TW201134492A; AR080497A1

Abstract

The invention relates to novel iodine -radiolabeled compounds useful for diagnosing Alzheimer's desease, to respective novel precursors for the synthesis of such compounds, and to the process of manufacturing said imaging agent of the following Formula (I), wherein Q is a six membered aromatic ring, either carbocycle or heterocycle with one N- atom, wherein X₁, X₂, X₃, X₄ and X₅ are independently selected from N or C, and wherein zero or one of X₁ ( X₂, X₃, X₄ or X₅ is N and the remaining ones are C; A is either Sn(alkyl)3, I, l-123, l-124, l-125, l-131, Br; wherein alkyl comprises methyl, ethyl, propyl, butyl, pentyl and hexyl, Y is C or N; with the proviso that if X₁ ( X₂, X₃, X₄ or X₅ has the meaning of N, substitution by A in that position is excluded; or a pharmaceutically acceptable salt thereof.

Description

SPECT imaging agents of amyloid plaques

Background of the Invention The invention relates to novel iodine-radiolabeled compounds useful for diagnosing Alzheimer's disease, to respective novel precursors for the synthesis of such compounds, and to the process of manufacturing said imaging agent.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder marked by loss of memory, cognition, and behavioral stability. AD is defined pathologically by extracellular senile plaques comprised of fibrillar deposits of the beta-amyloid peptide (Αβ) and neurofibrillary tangles comprised of paired helical filaments of hyperphosphorylated tau protein. The 39 to 43 amino acids comprising Αβ peptides are derived from the larger amyloid precursor protein (APP). In the amyloidogenic pathway, Αβ peptides are cleaved from APP by the sequen- tial proteolysis by β- and γ-secretases. Αβ peptides are released as soluble proteins and can be detected at low levels in the cerebrospinal fluid (CSF) in normal aging brains. During the progress of AD the Αβ peptides aggregate and form amyloid deposits in the parenchyma and vasculature of the brain, which can be detected post mortem as diffuse and senile plaques and vascular amyloid during histological examination (for a recent review see: Blennow et al., Lancet. 2006 Jul 29;368(9533):387-403).

Alzheimer's disease is becoming a great health and social economical problem all over the world. There are great efforts being made to develop techniques and methods for the early detection and effective treatment of the disease. Currently, diagnosis of AD in an academic setting of memory-disorder clinics is approximately 85-90% accurate (Petrella JR et al., Ra- diology. 2003 226:315-36). It is based on the exclusion of a variety of diseases causing similar symptoms and the careful neurological and psychiatric examination, as well as neuropsychological testing. However, post mortem histological examination of the brain is still the only definite diagnosis of this disease. Thus the in vivo detection of one pathological feature of the disease - the deposition of amyloid aggregates in the brain - is thought to have a big impact on the early detection of AD and differentiation from other dementias. Additionally, most disease modifying therapies that are under development are aiming at lowering the amyloid load in the brain. Thus imaging the amyloid load in the brain may provide an essential tool for patient stratification and treatment monitoring. In addition, amyloid deposits are also known to play a role in amyloidosis, in which amyloidogenic proteins are abnormally deposited in different organs and/or tissues, causing disease. For a recent review see Chiti et al., Annu Rev Biochem. 2006;75:333-66. Potential ligands for visualizing amyloid aggregates in the brain must show a high binding affinity to amyloid and must cross the blood brain barrier. Moreover they must carry a suitable label which can be detected by imaging modalities such as positron emission tomography (PET) or single photon emission computed tomography (SPECT). PET tracers that have been already investigated in humans regarding their binding patterns in brains of AD patients are e.g. [F-18]FDDNP (Shoghi-Jadid et al., Am J Geriatr Psychiatry 2002; 10:24-35), [C- 1 1]PIB (Klunk et al., Ann Neurol. 2004 55:306-319), [C-1 1]SB-13 (Verhoeff et al., Am J Geriatr Psychiatry 2004; 12:584-595), [F-18]Bay 94-9172 (Rowe et al. Lancet Neurol 2008, 7:129-135), [C-1 1]BF227 (Kudo et al., J Nucl. Med 2007; 49:554-561 ), and [F-18]PIB (Farrar et al. Turku PET Symposium 2007, Abstract 49). For recent reviews see Lockhardt, Drug Discov Today, 2006 1 1 : 1093-1099, Henriksen et al., Eur J Nucl Med Mol Imaging. 2008 Mar;35 Suppl 1 :S75-81 , Cohen, Mol. Imaging Biol. 2007 9:204-216, Nordberg, Curr. Opin Biol. 2007, 20:398-402, Small et al., Neurology 2008 7:161-172, Nordberg, Eur. J. Nucl. Med. Mol. Imaging 2008, 35, S46-S50.

In contrast, SPECT tracers are less advanced in development (Ono et al., Chem Pharm Bull (Tokyo). 2009 Oct;57(10):1029-39). Human studies have been published for [l-123]IMPY (Newberg et al., J. Nucl. Med.2006, 47, 748-754; Newberg et al., J. Nucl. Med.2006, 47, p. 78 Abstract # 220), however the target-to-background ratio was not as good as for advanced PET tracers. Generally, SPECT bears certain advantages over PET as SPECT cameras a more widespread available and compound logistics are facilitated by the longer decay times of SPECT isotopes compared to the relatively short-lived PET isotopes.

The preferred radionuclides for PET are ¹⁸F (T_{1 2} = 1 10 min) and ¹¹C (T_{1 2} = 20 min): These isotopes have relatively short half-lifes that do not really allow complicated long synthesis routes and purification procedures. Compared to these PET isotopes single photon emitters like ^99mTc (T_{1 2} = 6.05 hr) or ¹²³l (T_{1 2} = 13.30 hr) have significantly longer half-lives, thus can lead to certain advantages. These include the ability to utilize radiopharmaceuticals that have the ability to produce the radiopharmaceuticals offsite for distribution to the clinic. In addition, in research a longer half-life makes radiopharmaceutical development more convenient. The simultaneous use of different energy single photon emitters (small animal SPECT imaging or cut and count biodistribution) allows the study of multiple parameters in parallel.

The problem underlying the present invention was to provide novel compounds for SPECT imaging with high affinity for amyloid β, ability to cross the blood brain barrier and successive rapid elimination of the unspecifically bound radioactivity from the brain, in order to obtain a favorable signal to background ratio.

The problem has been solved by the provision of the compounds of the invention. Description of the Invention

The invention relates to a compound having the formula (formula I)

, wherein

- Q is a six membered aromatic ring, either carbocycle or heterocycle with one N- atom, wherein X₂, X3, X4 and X₅ are independently selected from N or C, and wherein zero or one of , X₂, X3, X4 or X₅ is N and the remaining ones are C;

- A is either Sn(alkyl)₃, I, 1-123, 1-124, 1-125, 1-131 , Br;

wherein alkyl comprises methyl, ethyl, propyl, butyl, pentyl and hexyl,

- Y is C or N; with the proviso that if X^ X₂, X3, X4 or X₅ has the meaning of N, substitution by A in that position is excluded; or a pharmaceutically acceptable salt thereof.

In the context of the present invention, pharmaceutically acceptable salts of the compounds according to the invention are pharmaceutically acceptable salts for imaging tracer such as SPECT or PET tracers. These salts also comprise salts which for their part are not suitable for other pharmaceutical applications, but which can be used, for example, for isolating or purifying the compounds according to the invention.

Pharmaceutically acceptable salts of the compounds according to the invention include acid addition salts of mineral acids, carboxylic acids and sulphonic acids, for example salts of hy- drochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonic acid, ethanesulphonic acid, toluenesulphonic acid, benzenesulphonic acid, naphthalene disul- phonic acid, acetic acid, trifluoroacetic acid, propionic acid, lactic acid, tartaric acid, malic acid, citric acid, fumaric acid, maleic acid and benzoic acid. The invention relates further to compounds having the formula (formu

, wherein

- A is either Sn(alkyl)₃, I, 1-123, 1-124, 1-125, 1-131 , Br;

wherein alkyl comprises methyl, ethyl, propyl, butyl, pentyl and hexyl,

- Y is C or N; or a pharmaceutically acceptable salt thereof.

The invention relates in one embodiment to a compound having the formula (formula I)

, wherein

- A is either Sn(alkyl)₃, I, Br;

wherein alkyl comprises methyl, ethyl, propyl, butyl, pentyl and hexyl,

The invention relates further to compounds having the formula (formula II)

wherein

- A is either Sn(alkyl)₃, I, Br;

wherein alkyl comprises methyl, ethyl, propyl, butyl, pentyl and hexyl,

- Y is C or N; or a pharmaceutically acceptable salt thereof. A preferred embodiment of the invention is a compound selected from the group of compounds consisting of -(2-{4-[5-(benzyloxy)pyridin-2-yl]piperazin-1 -yl}-2-oxoethyl)-2-iodopyridine-4-carboxamide

or a pharmaceutically acceptable salt thereof; -(2-{4-[5-(benzyloxy)pyridin-2-yl]piperazin-1 -yl}-2-oxoethyl)-2-bromopyridine-4-carboxamide

or a pharmaceutically acceptable salt thereof; -{2-[4-(5-Benzyloxy-pyridin-2-yl)-piperazin-1 -yl]-2-oxo-ethyl}-3-iodo-benzamide

or a pharmaceutically acceptable salt thereof; -{2-[4-(5-Benzyloxy-pyridin-2-yl)-piperazin-1 -yl]-2-oxo-ethyl}-3-tributylstannanyl-benzami

or a pharmaceutically acceptable salt thereof;

N-{2-[4-(5-Benzyloxy-pyridin-2-yl)-piperazin-1 -yl]-2-oxo-ethyl}-4-iodo-benzarnide

or a pharmaceutically acceptable salt thereof;

N-{2-[4-(5-Benzyloxy^yrimidin-2-yl)-piperazin-1 -yl]-2-oxo-ethyl}-2-iodopyridine-4-

or a pharmaceutically acceptable salt thereof;

-{2-[4-(5-Benzyloxy-pyridin-2-yl)-piperazin-1-yl]-2-oxo-ethyl}-2-iodo-benzamide

or a pharmaceutically acceptable salt thereof;

N-{2-[4-(5-Benzyloxy^yridin-2-yl)-piperazin-1-yl]-2-oxo-ethyl}-3-[¹²⁵l]iodo-benzamide

or a pharmaceutically acceptable salt thereof;

or such a compound, wherein 1-125 is replaced by 1-123, 1-124, or 1-131 ,

or a pharmaceutically acceptable salt thereof;

N-{2-[4-(5-Benzyloxy-pyridin-2-yl)-piperazin-1 -yl]-2-oxo-ethyl}-5-iodo-nicotinamide

or a pharmaceutically acceptable salt thereof;

6-lodo-pyridine-2-carboxylic acid {2-[4-(5-benzyloxy-pyridin-2-yl)-piperazin-1 -yl]-2-oxo-ethyl}- amide

or a pharmaceutically acceptable salt thereof;

N-{2-[4-(5-Benzyloxy-pyridin-2-yl)-piperazin-1-yl]-2-oxo-ethyl}-3-iodo-isonicotinamide

or a pharmaceutically acceptable salt thereof; -{2-[4-(5-Benzyloxy-pyridin-2-yl)-piperazin-1 -yl]-2-oxo-ethyl}-4-tributylstannanyl-benzamide

or a pharmaceutically acceptable salt thereof;

The invention also relates to a compound according to formula I or II as defined above, wherein A is selected from the group consisting of 1-123, 1-124, 1-125, 1-131 ; as a diagnostic compound.

A preferred embodiment of the invention is the compound

N-{2-[4-(5-Benzyloxy-pyridin-2-yl)-piperazin-1-yl]-2-oxo-ethyl}-3-[¹²⁵l]iodo-benzamide

or a pharmaceutically acceptable salt thereof as a diagnostic compound.

A preferred embodiment of the invention is the compound

wherein 1-125 is replaced by 1-123, 1-124, or 1-131 ,

or a pharmaceutically acceptable salt thereof as a diagnostic compound. pound as disclosed above, preferably

as a diagnostic compound for SPECT imaging of Alzheimer's disease. pound as disclosed above, preferably

wherein 1-125 is replaced by 1-123, 1-124, or 1-131 ,

as a diagnostic compound for SPECT imaging of Alzheimer's disease.

A further embodiment is diagnostic composition comprising a radiolabeled compound as de- scribed, preferably

A further embodiment is diagnostic composition comprising a radiolabeled compound as described, preferably

, wherein 1-125 is replaced by 1-123, 1-124, or 1-131

The diagnostic compositions of the invention are preferably diagnostic compositions for diagnosing an amyloidosis, more preferably Alzheimer's disease.

The invention further relates to the use of such a radiolabeled compound, preferably

in the preparation of a diagnostic composition for SPECT imaging of Alzheimer's disease. aration of a compound having the formula

aration of a compound having the formula

wherein 1-125 is replaced by 1-123, 1-124, or 1-131

Furthermore, a method for the preparation of a radiolabeled compound of the invention, comprising the steps of reacting a suitable precursor molecule compound with a Iodine containing moiety wherein the Iodine is ¹²³l' ¹²⁴l' ¹²⁵l, or ¹³¹l,

optionally removing protecting group(s) and

- optionally converting obtained compound into an acceptable salts of inorganic or organic acids thereof, hydrates, complexes, esters, amides, and solvates, Is part of the invention. tion the compound having the formula

wherein 1-125 may be replaced by 1-123, 1-124, or 1-131 ,

, comprising the steps of reacting a suitable precursor molecule compound with a Iodine containing moiety wherein the Iodine is ¹²³|· ¹²⁴Ι' ¹²⁵l, or ¹³¹l,

optionally removing protecting group(s) and optionally converting obtained compound into an acceptable salts of inorganic or organic acids thereof, hydrates, complexes, esters, amides, and solvates thereof. aration the compound having the formula

, comprising the steps of reacting a suitable precursor molecule compound with a Iodine containing moiety wherein the Iodine is ¹²⁵l,

optionally removing protecting group(s) and

optionally converting obtained compound into an acceptable salts of inorganic or organic acids thereof, hydrates, complexes, esters, amides, and solvates thereof.

is

or a pharmaceutically acceptable salt thereof.

Further part of the invention is a method of diagnosing Alzheimer's disease in a patient comprising the steps of administering a radiolabeled compound as described above to said patient and performing SPECT analysis.

Preferred is such a method, wherein the compound for performing this method is

wherein 1-125 may be replaced by 1-123, 1-124, or 1-131. he compound for performing this method is

is

Also part of the invention is a kit comprising a compound of formula I or II in a sealed container.

, wherein

- Q is a six membered aromatic ring, either carbocycle or heterocycle with one N- atom, wherein Xi, X₂, X3, X4 and X₅are independently selected from N or C, and wherein zero or one of , X₂, X3, X4 or X₅ is N and the remaining ones are C;

- A is either Sn(alkyl)₃, I, Br;

wherein alkyl comprises methyl, ethyl, propyl, butyl, pentyl and hexyl, - Y is C or N; with the proviso that if X₂, X3, X4 or X₅ has the meaning of N, substitution by A in that position is excluded; or a pharmaceutically acceptable salt thereof.

An even more preferred kit comprises the compound

or a pharmaceutically acceptable salt thereof.

The kits of the invention may comprise a sealed vial containing a predetermined quantity of a compound as defined in the foregoing, and pharmaceutically suitable salts of inorganic or organic acids thereof, hydrates, complexes, esters, amides, and solvates thereof. Optionally the kit comprises a pharmaceutically acceptable carrier, diluent, excipient or adjuvant.

The invention further relates to a method for the preparation of the compound having the

This method may comprise reacting the compound having the formula

with 1 , 1 , 1 ,2,2,2, -hexabutyl-distannane, optionally in the presence of tetrakis(triphenyl- phosphine)palladium(O). Another aspect of the invention is the use of the lodine-radiolabeled compound as described above and herein for diagnosing Alzheimer's disease and/or amyloidoses in a patient, in particular in a mammal, such as a human.

Preferably, the use of the the lodine-radiolabeled compound of the invention in the diagnosis is performed using SPECT.

Another aspect of the invention is directed to a method of imaging amyloid deposits. Such a method comprises a) administering to a mammal the the lodine-radiolabeled compound as described above and herein, and b) detecting the signal stemming from the compound that is specifically bound to the amyloid deposits. The specific binding is a result of the high binding affinity of the compounds of the present invention to the amyloid deposits.

In a further aspect, the invention is directed to a method of diagnosing a patient with Alzheimer's disease or amyloidoses. This method comprises a) administering to a human in need of such diagnosis the lodine-radiolabeled labeled compound of the invention for detecting the compound in the human as described above and herein, and b) measuring the signal from the detectable label arising from the administration of the compound to the human, by SPECT. A further embodiment of the invention includes a diagnostic method for other neurological disorders as Alzheimer's disease comprising the exclusion of Alzheimer's disease in a patient, that method comprising administering the lodine-radiolabeled compound of the invention to a patient and applying an imaging method of the invention.

The diagnostic methods of the invention can also be used as post-mortem diagnostic meth- Furthermore, the diagnostic methods of the invention by using the lodine-radiolabeled compound of the invention can also be used for monitoring the therapy of Alzheimer's disease, a neurodegenerative disorder or an amyloidoses. Furthermore, the diagnostic methods of the invention using the lodine-radiolabeled compound of the invention can also be used in diagnosing neurological disorders other than Alzheimer's disease by excluding Alzheimer's disease.

Furthermore, the compounds of the invention can also be used as tools in screening, for ex- ample high throughput screening methods and in vitro assays.

The invention further relates to a method for diagnosing a disease in a mammal selected from the group consisting of Alzheimer's disease, a neurodegenerative disorder, or an amyloidosis, this method comprising administering to said mammal the lodine- radiolabeled compound of the invention. Furthermore, this method may comprise imaging of said mammal and detecting the imaging signal. Additionally, said imaging may be performed using SPECT. Furthermore, this method may be used to monitor the effect of a therapy. Furthermore, the invention relates to a method for diagnosing or therapy monitoring of a disease selected from the group consisting of Alzheimer's disease, a neurodegenerative disorder, or an amyloidosis in a mammal, said method comprising analyzing in vitro a sample of said mammal, wherein said mammal or sample has been treated with the lodine-radiolabeled compound of the invention. This sample can be cerebrospinal fluid.

The diagnostic methods and the novel SPECT tracer of the invention may also be used for the stratification of AD patients. General synthesis of radioiodo compounds: aryl-l and (hetero)aryl-l

SPECT detectable radio iodo isotopes can be introduced into compounds by the following published methods.

The radioiodination reaction can be carried out, for example in a typical reaction vessel (e.g. Wheaton vial, Eppendorf vial, lodogen tube etc.) which is known to someone skilled in the art or in a microreactor. Typically the reactions are carried out at room temperature in aqueous solutions. These aqueous solutions can contain but are not limited to acids and buffers. If necessary for a quicker conversion the reactions (e.g. radioiodo-dehalogenations or ra- dioiodo-detriazenation) can be carried out in a sealed vial under elevated temperatures . Therefore the vial can be heated by typical methods, e.g. oil bath, heating block or microwave. In the case of electrophilic radioiodination substitution reactions the generation of an electrophilic iodine species is carried out in-situ by the addition of a suitable oxidizing agent. These oxidizing agents can be taken from but are not limited to the group of N-chloramides, hydrogen peroxide, lodogen, N-halosuccinimides and peracids. These in situ oxidations can e.g. be used for direct iodo-deprotonations, iodo-demetallations or indirect iodinations with heterobifunctional reagents like 4-hydroxyphenyl succinimidyl esters (Bolton and Hunter reagent; Bioc em. J. 1973, 133, 529). Organic solvents can be involved in such a reaction as co-solvent. The radioiodination reactions are conducted for one to 60 minutes. This and other conditions for such radioiodinations are known to experts (Eisenhut M., Mier W., Radioiodination Chemistry and Radioiodinated Compounds (2003) in: Vertes A., Nagy S., Klenscar Z., (eds.) Rosch F. (volume ed.), Handbook of Nuclear Chemistry, 4, pp. 257-278 and Coenen H.H., Mertens J., Maziere B., Radioiodination Reactions for Pharmaceuticals, pp. 29-72).

A method of the invention is an iodine-labeling method.

Preferably, the iodine-labeling method concerns a method for labeling invention compounds with Iodine containing moiety wherein the Iodine containing moiety preferably comprises ¹²³l' ¹²V²⁵l, ¹²⁷l or ¹³¹ l.

More preferably, Iodine containing moiety comprises ¹²³l_, ¹²⁴l, ¹²⁵l or ¹³¹1.

Preferably, the lodine-labeling method is a lodine-radiolabeling method.

Under the present invention, the lodine-labeling method is a direct or an indirect labeling method for obtaining radiolabeled compounds of formula I or II or mixtures thereof.

The reagents, solvents and conditions which are used for this iodination are common and well- known to the skilled person in the field.

Preferably, the solvents used in the present method is water, aqueous buffer, DMF, DMSO, acetonitrile, DMA, or mixtures thereof, preferably the solvent is water, aqueous buffer or ace- tonitrile.

The invention also relates to the therapeutic use of compounds of the invention for the therapy of amyloidoses, preferably for the therapy of Alzheimer's disease. A preferred therapy is radiotherapy. Therapeutic compounds, compositions and uses thereof are described in the following.

In particular, the invention relates to a compound having the formula

. wherein

- Q is a six membered aromatic ring, either carbocycle or heterocycle with one N- atom, wherein X₂, X3, X4 and X₅ are independently selected from N or C, and wherein zero or one of , X₂, X3, X4 or X₅ is N and the remaining ones are C; - A is either I, 1-123, 1-124, 1-125, 1-131 , Br;

- Y is C or N; with the proviso that if X^ X₂, X3, X4 or X₅ has the meaning of N, substitution by A in that posi- tion is excluded; or a pharmaceutically acceptable salt thereof as a medicament. rding having the formula

, whereii

- A is either I, 1-123, 1-124, 1-125, 1-131 , Br; preferred wherein A is selected from the group consisting of 1-123, 1-124, 1-125, 1-131 ; in an even more preferred embodiment A is 1-131 - Y is C or N; or a pharmaceutically acceptable salt thereof as a medicament.

More preferred, the invention relates to a compound selected from the group of compounds consisting of

N-(2-{4-[5-(benzyloxy)pyridin-2-yl]piperazin-1 -yl}-2-oxoethyl)-2-iodopyridine-4-carboxamide

or a pharmaceutically acceptable salt thereof,

-(2-{4-[5-(benzyloxy)pyridin-2-yl]piperazin-1-yl}-2-oxoethyl)-2-bromopyridine-4-carboxamide

or a pharmaceutically acceptable salt thereof, -{2-[4-(5-Benzyloxy-pyridin-2-yl)-piperazin-1 -yl]-2-oxo-ethyl}-3-iodo-benzamide

or a pharmaceutically acceptable salt thereof,

N-{2-[4-(5-Benzyloxy-pyridin-2-yl)-piperazin-1 -yl]-2-oxo-ethyl}-4-iodo-benzamide

or a pharmaceutically acceptable salt thereof, N-{2-[4-(5-Benzyloxy^yrimidin-2-yl)-piperazin-1 -yl]-2-oxo-ethyl}-2-iodopyridine-4-

or a pharmaceutically acceptable salt thereof, -{2-[4-(5-Benzyloxy^yridin-2-yl)-piperazin-1 -yl]-2-oxo-ethyl}-2-iodo-benzarnide

or a pharmaceutically acceptable salt thereof,

N-{2-[4-(5-Benzyloxy^yridin-2-yl)-piperazin-1 -yl]-2-oxo-ethyl}-5-iodo-nicotinamide

or a pharmaceutically acceptable salt thereof;

or a pharmaceutically acceptable salt thereof;

N-{2-[4-(5-Benzyloxy^yridin-2-yl)-piperazin-1-yl]-2-oxo-ethyl}-3-iodo-isonicotinamide

or a pharmaceutically acceptable salt thereof; -{2-[4-(5-Benzyloxy-pyridin-2-yl)-piperaz

or a pharmaceutically acceptable salt thereof;

or a pharmaceutically acceptable salt thereof;

or such a wherein 1-125 is replaced by 1-123, 1-124, or 1-131 ,

or a pharmaceutically acceptable salt thereof;

as a medicament.

Even more preferred is a compound of the therapeutic compounds described above as a medicament for treating amyloidoses, especially Alzheimer's disease.

Also part of the invention is a therapeutic composition comprising a therapeutic compound as described above.

Furthermore part of the invention is the use of a therapeutic compound as described above in the preparation of a therapeutic composition for the treatment of amyloidoses, preferably Alzheimer's disease.

Also part of the invention is a method of treatment of amyloidoses, preferably Alzheimer's disease, this method comprising administering to a patient in need thereof a therapeutically effective amount of a therapeutic compound of the invention. In the context of the current application the symbol for carbon C has the meaning of C-H if not defined to be substituted.

Brief description of the figures

Figure 1 : Preparative HPLC for the compound of Example 8.

Figure 2: Analytical HPLC for the compound of Example 8 (gamma detection).

Figure 3: Analytical HPLC for the compound of Example 8 (UV detection).

Figure 4: Autoradiographical analysis of binding of compound 8 to brain sections from cortex of Alzheimer^'s disease patients (AD) with amyloid beta plaques. Control sections without amyloid beta pathology stem from healthy volunteers (HC) and fronto-temporal dementia (FTD) patients. Blocking of specific signals was performed with an excess of cold compound. Arrows point to plaque-specific signals. Examples

A method for synthesizing and labeling is exemplified in the following Examples. These Examples illustrate certain aspects of the above-described method and advantageous results and are shown by way of illustration and not by way of limitation.

Example 1

N-(2-{4-[5-(benzyloxy)pyridin-2-yl]piperazin-1 -yl}-2-oxoethyl)-2-iodopyridine-4-carboxamide -Benzyloxy-2-bromo-pyridine

To a solution of 1 0.0 g (57.47 mmol) of 2-bromo-5-hydroxypyridine in 400 mL N,N- dimethylformamide (DMF) was added 14.75 g (86.21 mmol) of benzyl bromide and 23.82 g (172.4 mmol) of potassium carbonate. The mixture was stirred for 6 h at 60°C and overnight at room temperature. The suspension was filtered off and after evaporation of the solvent the residue was chromatographed on silica gel using a dichloromethane/methanol gradient. Yield: 14.82 g (96.7 %). MS (ESIpos): m/z = 264, 266 [M+H]⁺

¹H-NMR (300MHz, CHLOROFORM-d): δ [ppm]

6H), 8.14 (d, 1 H).

-(5-Benzyloxy-pyridin-2-yl)-piperazine

All glassware was dried at 100°C. To a solution of 5.27 g (61.22 mmol) of piperazine in 180 ml. toluene was added 561 mg (0.61 mmol) of tris(dibenzylidene acetone) dipalladium(O) and 520 mg (0.83 mmol) of BINAP (2,2'-bis(diphenylphosphino)-1 , 1 -binaphthyl). Then, a solution of 14.7 g (55.66 mmol) of 5-benzyloxy-2-bromo-pyridine (example 1a) in tetrahydrofuran (THF) was added followed by a suspension of 8.02 g (83.48 mmol) of sodium t-butylate in THF.

The reaction mixture was refluxed for 6 h and stirred at room temperature overnight. After evaporation of the solvents the residue was chromatographed on silica gel using a dichloro- methane/methanol gradient.

Yield: 7.12 g (47.0 %).

MS (ESIpos): m/z = 270 [M+H]⁺

1H-NMR (300MHz, CHLOROFORM-d): δ [ppm]= 2.97 - 3.07 (m, 4H), 3.36 - 3.46 (m, 4H), 5.04 (s, 2H), 6.63 (d, 1 H), 7.21 (dd, 1 H), 7.29 - 7.48 (m, 5H), 8.00 (d, 1 H). zin-1 -yl}-2-oxoethyl)carbamate

To a solution of 4.63 g (26.43 mmol) i-Butoxycarbonyl-glycine (Aldrich) in 500 ml. THF and 5 ml. triethyl amine (35.87 mmol) at -15°C, 3.43 ml. (26.43 mmol) isobutyl chloroformate were added dropwise and the solution was maintained at this temperature for another 15 min. Then, 7.12 g of 1 -(5-Benzyloxy-pyridin-2-yl)-piperazine (1 b) and 18 ml. triethyl amine (129 mmol) in 200 ml. THF/dichloromethane (1 :1 ) were added slowly to this cold solution, the temperature was kept below -10°C for another 15 min and was then allowed to reach room temperature. After stirring overnight the solvent was evaporated and the residue was taken up in ethyl acetate. This solution was washed successively with aqueous sodium carbonate, water, 1 M aqueous hydrochloric acid (HCI) solution, saturated aqueous sodium chloride solution, finally dried over magnesium sulfate and then evaporated. This residue was chroma- tographed on silica gel using a hexane/ethyl acetate gradient.

Yield: 8.04 g (70.6 %).

MS (ESIpos): m/z = 427 [M+H]⁺

¹H-NMR (300MHz, CHLOROFORM-d): δ [ppm]= 1.46 (s, 9H), 3.36 - 3.45 (m, 2H), 3.51 (br. s., 4H), 3.70 - 3.81 (m, 2H), 4.02 (d, 2H), 5.05 (s, 2H), 5.53 (br. s., 1 H), 6.65 (d, 1 H), 7.23 (dd, 1 H), 7.30 - 7.48 (m, 5H), 8.00 (d, 1 H).

d) N-(2-{4-[5-(benzyloxy)pyridin-2-yl]piperazin-1-yl}-2-oxoethyl)-2-iodopyridine-4-

8.0 g (1 8.76 mmol) of tert-butyl (2-{4-[5-(benzyloxy)pyridin-2-yl]piperazin-1-yl}-2-oxoethyl) carbamate (1 c) were suspended in 160 mL 2N HCI in diethyl ether and stirred overnight at room temperature. The precipitate was filtered off and washed with ether and dried at 40°C in vacuo.

Yield: 7.4 g (quantitative). The product was used in the next step without further purification. MS (ESIpos): m/z = 327 [M+H]⁺

To a solution of 274 mg (1.10 mmol) of 2-iodopyridine-4-carboxylic acid (Alfa Aesar) and 363 mg (1.0 mmol) of hydrochloride prepared above in 15 mL DMF were added 624 mg (1 .2 mmol) Benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyBOP) and 0.70 mL (4 mmol) N-ethyl-N,N-diisopropylamine and the reaction mixture was stirred overnight at room temperature. After evaporation of the solvent the residue was taken up in ethyl acetate. This solution was washed with water and saturated aqueous sodium chloride solution, dried over sodium sulfate and then evaporated. This residue was chromatographed on silica gel using an dichloromethane/methanol gradient and the appropriate fractions were combined and concentrated.

Yield: 320 mg (53.8 %).

MS (ESIpos): m/z = 558 [M+H] ¹H-NMR (600MHz, DMSO-d₆): δ [ppm]= 2.52 (m, 2H), 2.60 (m, 2H), 2.74-2.76 (m, 4H), 3.36- 3.37 (m, 2H), 4.24 (s, 2H), 6.02 (d, 1 H), 6.46-6.62 (m, 6H), 6.96 (d, 1 H), 7.12 (d, 1 H), 7.38 (d, 1 H), 7.69 (d, 1 H), 8.17-8.22 (m, 1 H).

Example 2 -(2-{4-[5-(benzyloxy)pyridin-2-yl]piperazi

8.0 g (18.76 mmol) of tert-butyl (2-{4-[5-(benzyloxy)pyridin-2-yl]piperazin-1 -yl}-2-oxoethyl) carbamate (1 c) were suspended in 160 mL 2N HCI in diethyl ether and stirred overnight at room temperature. The precipitate was filtered off and washed with ether and dried at 40°C in vacuo.

To a solution of 1.01 g (5.01 mmol) of 2-bromopyridine-4-carboxylic acid (Alfa) and 2.0 g (5.51 mmol) of hydrochloride prepared above in 160 mL DMF were added 3.13 g (6.0 mmol) PyBOP (Benzotriazol-l-yloxy)tripyrrolidinophosphonium hexafluorophosphate) and 2.75 mL (16 mmol) N-ethyl-N,N-diisopropylamine and the reaction mixture was stirred overnight at room temperature. After evaporation of the solvent the residue was taken up in dichloro- methane. This solution was washed with water and saturated aqueous sodium chloride solution, dried over sodium sulfate and then evaporated. This residue was chromatographed on silica gel using an ethyl acetate/ethanol gradient and the appropriate fractions were com- bined and concentrated.

Yield: 1 .91 g (70.7 %).

MS (ESIpos): m/z = 509, 51 1 [M+H]⁺

¹H-NMR (400MHz, DMSO-d₆): δ [ppm]= 3.86 - 3.44 (m, 4H), 3.59 (m, 4H), 4.20 (m, 2H), 5.08 (s, 2H), 6.83 - 6.88 (m, 1 H), 7.32 - 7.44 (m, 6H), 7.82 - 7.84 (m, 1 H), 7.95 (s, 1 H), 8.02 - 8.03 (m, 1 H), 8.54 - 8.57 (m, 1 H), 9.02 - 9.07 (m, 1 H). Example 3 -{2-[4-(5-Benzyloxy^yridin-2-yl)-piperazin-1 -yl]-2-oxo-ethyl}-3-iodo-benzamide

8.0 g (18.76 mmol) of tert-butyl (2-{4-[5-(benzyloxy)pyridin-2-yl]piperazin-1-yl}-2-oxoethyl) carbamate (1 c) were suspended in 160 ml. 2N HCI in diethyl ether and stirred overnight at room temperature. The precipitate was filtered off and washed with ether and dried at 40°C in vacuo.

To a solution of 136 mg (0.55 mmol) of 3-iodobenzoic acid (Aldrich) and 200 mg (0.55 mmol) of hydrochloride prepared above in 5 ml. DMF were added 286 mg (0.55 mmol) Benzotriazol-1 -yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyBOP) and 0.15 ml_ (1.1 mmol) N-ethyl-N,N-diisopropylamine and the reaction mixture was stirred overnight at room temperature. After evaporation of the solvent the residue was taken up in ethyl acetate. This solution was washed with water and saturated aqueous sodium chloride solution, dried over sodium sulfate and then evaporated. This residue was chromatographed on silica gel using an dichloromethane/methanol gradient and the appropriate fractions were combined and concentrated.

Yield: 252 mg (82.7 %).

MS (ESIpos): m/z = 556 [M+H]⁺

¹H-NMR (400MHz, DMSO-d₆): δ [ppm]= 3.36 (s, 2H), 3.43 (s, 2H), 3.59 (s, 4H), 4.17 (d, 2H), 5.08 (s, 2H), 6.85 (d, 1 H), 7.26-7.31 (m, 1 H), 7.32-7.46 (m, 6H), 7.85-7.92 (m, 2H), 7.95 (d, 1 H), 8.23 (t, 1 H), 8.71 (t, 1 H).

Example 4

N-{2-[4-(5-Benzyloxy-pyridin-2-yl)-piperazin-1 -yl]-2-oxo-ethyl}-3-tributylstannanyl-benzamide

41 mg (0.074 mmol) of N-{2-[4-(5-Benzyloxy-pyridin-2-yl)-piperazin-1 -yl]-2-oxo-ethyl}-3-iodo- benzamide (example 3), 121 mg (0.21 mmol) of 1 , 1 ,1 ,2,2,2-hexabutyl-distannane and 1 mg (0.001 mmol) of tetrakis(triphenylphosphine)palladium(0) were stirred in 2 mL toluene for 3d under nitrogen atmosphere at 60°C. After evaporation of the solvent the residue was chro- matographed on silica gel RP-18 using an acetonitrile/water gradient and the appropriate fractions were combined and concentrated.

Yield: 14 mg (26.4 %). MS (ESIpos): m/z = 721 [M+H]⁺

¹H-NMR (400MHz, CHLOROFORM-d): δ [ppm]= 0.90 (t, 9H), 1 .08-1 .12 (m, 6H), 1 .31 -1.37 (m, 6H), 1.51 -1.57 (m, 6H), 3.46 (s, 2H), 3.51-3.56 (m, 2H), 3.59-3.64 (m, 2H), 3.80-3.84 (m, 2H), 4.32 (d, 2H), 5.06 (s, 2H), 6.65 (s, 1 H), 7.22-7.26 (m, 1 H), 7.29-7.44 (m, 7H), 7.60 (s, 1 H), 7.72-7.75 (m, 1 H), 7.94 (s, 1 H), 8.02 (d, 1 H).

Example 5 -{2-[4-(5-Benzyloxy-pyridin-2-yl)-piperazin-1 -yl]-2-oxo-ethyl}-4-iodo-benzamide

To a solution of 136 mg (0.55 mmol) of 4-iodobenzoic acid (Aldrich) and 200 mg (0.55 mmol) of hydrochloride prepared above in 5 mL DMF were added 286 mg (0.55 mmol) PyBOP and 0.15 mL (1.1 mmol) N-ethyl-N,N-diisopropylamine and the reaction mixture was stirred over- night at room temperature. After evaporation of the solvent the residue was taken up in ethyl acetate. This solution was washed with water and saturated aqueous sodium chloride solution, dried over sodium sulfate and then evaporated. This residue was chromatographed on silica gel using an dichloromethane/methanol gradient and the appropriate fractions were combined and concentrated.

Yield: 57 mg (18.6 %).

MS (ESIpos): m/z = 556 [M+H]⁺

¹H-NMR (300MHz, CHLOROFORM-d): δ [ppm]= 3.41 - 3.67 (m, 6H), 3.74 - 3.91 (m, 2H), 4.29 (d, 2H), 5.05 (s, 2H), 6.66 (d, 1 H), 7.20 - 7.26 (m, 1 H), 7.29 - 7.49 (m, 6H), 7.54 - 7.64 (m, 2H), 7.76 - 7.87 (m, 2H), 8.01 (d, 1 H).

Example 6 N-{2-[4-(5-Benzyloxy-pyrimidin-2-yl)-piperazin-1 -yl]-2-oxo-ethyl}-2-iodopyridine-4- carboxamide -(5-Benzyloxy-pyridimin-2-yl)-piperazine

76.2 mg (0.4 mmol) of copper(l) iodide and 1.955 g (6 mmol) of cesium carbonate were dried overnight at 120°C in vacuo and suspended in 4.12 mL (40 mmol) of benzyl alcohol and 5 mL of toluene. 972.45 mg (4 mmol) of 5-bromo-2-(piperazin-1-yl)pyrimidine (Scientific Frontier) and 144 mg (0.8 mmol) of 1 ,10-phenanthroline were added and the mixture was stirred under nitrogen at 1 10°C for 24h. After the insoluble salts were filtered off, the solution was evaporated and the residue taken up in 20 mL ethyl acetate. The precipitate was collected and dried in vacuo.

Yield: 460 mg (42.5 %).

MS (ESIpos): m/z = 271

b) ierf-Butyl (2-{4-[5-(benzyloxy)pyrimidin-2-yl]piperazin-1 -yl}-2-oxoethyl)carbamate

To a solution of 219 mg (1 .25 mmol) i-Butoxycarbonyl-glycine (Aldrich) in 15 mL THF and 0.7 mL (5.0 mmol) triethyl amine at -15°C, 0.18 mL (1 .36 mmol) isobutyl chloroformate were added dropwise and the solution was maintained at this temperature for another 15 min. Then, 340 mg (1 .26 mmol) of 1 -(5-Benzyloxy-pyridimin-2-yl)-piperazine (6a) and 0.17 mL triethyl amine (1 .24 mmol) in 20 mL THF were added slowly to this cold solution, the temperature was kept below -10°C for another 15 min and was then allowed to reach room temperature. After stirring overnight the solvent was evaporated and the residue was taken up in ethyl acetate. This solution was washed successively with aqueous sodium carbonate, water, 1 M aqueous hydrochloric acid (HCI) solution, saturated aqueous sodium chloride solution, finally dried over magnesium sulfate and then evaporated. This residue was chromatogra- phed on silica gel using a hexane/ethyl acetate gradient.

Yield: 156 mg (29.0 %).

MS (ESIpos): m/z = 428 [M+H]⁺

c) N-{2-[4-(5-Benzyloxy-pyrimidin-2-yl)-piperazin-1 -yl]-2-oxo-ethyl}-2-iodopyridine-4-

120 mg (0.28 mmol) of ierf-Butyl (2-{4-[5-(benzyloxy)pyrimidin-2-yl]piperazin-1 -yl}-2-oxo- ethyl)carbamate (6b) were suspended in 10 mL 2N HCI in diethyl ether and stirred overnight at room temperature. The precipitate was filtered off and washed with ether and dried at 40°C in vacuo.

Yield: 57 mg (55.8%). The product was used in the next step without further purification. MS (ESIpos): m/z = 328 [M+H]⁺

To a solution of 41 .1 mg (0.157 mmol) of 2-iodopyridine-4-carboxylic acid (Alfa Aesar) and 57 mg (0.157 mmol) of hydrochloride prepared above in 3 mL DMF were added 81 .6 mg (0.157 mmol) PyBOP and 104 microL (0.597 mmol) N-ethyl-N,N-diisopropylamine and the reaction mixture was stirred overnight at room temperature. After evaporation of the solvent the residue was taken up in ethyl acetate. This solution was washed with water and saturated aqueous sodium chloride solution, dried over sodium sulfate and then evaporated. This residue was chromatographed on silica gel using an dichloromethane/methanol gradient and the appropriate fractions were combined and concentrated.

Yield: 88 mg (quantitative). MS (ESIpos): m/z = 558 [M+H]⁺

¹H-NMR (400MHz, DMSO-d₆): δ [ppm]= 3.50-3.75 (m, 8H), 4.20 (d, 2H), 5.1 1 (s, 2H), 7.29- 7.48 (m, 5H), 7.79 (dd, 1 H), 8.21 (s, 1 H), 8.28 (s, 2H), 8.52 (d, 1 H), 9.00 (t, 1 H).

Example 7 -{2-[4-(5-Benzyloxy^yridin-2-yl)-piperazin-1 -yl]-2-oxo-ethyl}-2-iodo-benzamide

To a solution of 136 mg (0.55 mmol) of 2-iodobenzoic acid (Aldrich) and 200 mg (0.55 mmol) of hydrochloride prepared above in 5 mL DMF were added 286 mg (0.55 mmol) PyBOP and 0.15 mL (1 .1 mmol) N-ethyl-N,N-diisopropylamine and the reaction mixture was stirred over- night at room temperature. After evaporation of the solvent the residue was taken up in ethyl acetate. This solution was washed with water and saturated aqueous sodium chloride solution, dried over sodium sulfate and then evaporated. This residue was chromatographed on silica gel using an dichloromethane/methanol gradient and the appropriate fractions were combined and concentrated.

Yield: 199 mg (64.9 %).

MS (ESIpos): m/z = 556 [M+H]⁺

¹H-NMR (400MHz, DMSO-d₆): δ [ppm]= 3.34 - 3.48 (m, 4H), 3.59 (br. s., 4H), 4.15 (d, 2H), 5.08 (s, 2H), 6.86 (d,1 H), 7.18 (m, 1 H), 7.29 - 7.49 (m, 8H), 7.88 (d, 1 H), 7.95 (d, 1 H), 8.43 (t, 1 H). Example 8 -{2-[4-(5-Benzyloxy^yridin-2-yl)-piperazin-1-yl]-2-oxo-ethyl}-3-[¹²⁵l]iodo-benzam

2 μΙ_ of a solution of [¹²⁵l]Nal (85 MBq) in 0.1 N NaOH were given into a 4 mL vial , 50 μΙ_ 0.1 M HCI, 75 it precursor-solution (1 mg 4 / mL DMF) and 50 μΙ_ H₂0₂-solution (6%) were added sequentially. The vial was incubated and shaked for 15 min at room temperature. After incubation 100 μΙ_ of a saturated sodium thiosulfate solution and 100 μΙ_ of a saturated sodium hydrogencarbonate were added sequentially. The crude product solution was ana- lyzed by HPLC and diluted with 4.6 mL acetonitrile/water (1 :1 v/v) +0.1 % trifluoroacetic acid and was subsequently transferred to the preparative HPLC using a Agilent Zorbax Bonus-RP C18, 5μιτι; 250x9.4 mm column. The eluent was acetonitrile/water with 0.1 % trifluoroacetic acid at a flow rate of 5 mL/min. For the preparative purification (Fig. 1 ) a linear gradient from 20 to 30 % acetonitrile within 20 min, 30 to 35% acetonitrile in 10 more minutes was used. The HPLC fraction containing the product peak (t_R= 19.9 min) was diluted with water and transferred onto a tC18 Plus short cartridge which was washed with 5 mL water. The final product was eluted from the cartridge with 1 mL ethanol to give 54 MBq of 8 in a radiochemical yield of 64 % (99% radiochemical purity) after a synthesis time of 60 min.

The desired 1-125 labeled product 8 (t_R=4.0 min, Fig. 2) was analyzed using analytical HPLC: ACE3-C18 50 mm x 4,6 mm; solvent gradient: start 5 % acetonitrile - 95 % acetonitrile in 0.1 % trifluoroacetic acid in 7 min., flow: 2mL/min and confirmed by co-injection with the corresponding non-radioactive lodo-standard 3 on the analytical HPLC (t_R=3.8 min, Fig. 3).

Example 9

Binding studies using human brain homoqenate

A competition assay with a tritiated amyloid ligand was performed in 96-well plates (Greiner bio-one; Cat. 651201 ; Lot. 06260130) using brain homogenate from AD patients.

Homogenates were prepared by homogenizing (Ultra-Turrax, setting 2, 30 s, 24000 rpm) dissected frontal cortex containing grey matter and white matter from AD patients in phosphate buffered saline (PBS, pH 7.4). The homogenate with a concentration of 100 mg wet tissue/ml was divided into aliquots of 300 μΙ and stored at -80°C.

Varying concentrations of the unlabeled test substances were incubated with 100 μg/ml homogenate and 10 nM of the tritiated ligand in PBS, 0.1 % BSA (final volume 200 μΙ) for 3 h at room temperature. Subsequently the binding mixture was filtered through Whatman GF/B filters (wetted with PBS, 0.1 % BSA) using a Filtermate 196 harvester (Packard). Filters were then washed twice with PBS, 0.1 %BSA and 40 μΙ scintillator was added to each well before the bound radioactivity was measured in a TopCount devise (Perkin Elmer). Non-specific binding was assessed by adding an excess of 1000x of the tritiated ligand to the reaction mixture. Finally IC50 values were calculated with the help of appropriate analysis software.

Table 1 : Binding affinity of compounds towards human AD brain homogenate (ADH)

Compound IC50 human ADH

(Example) [nM]

1 d 13

5 13

3 27

7 236

6c 63

Autoradiographical analysis

Fresh frozen as well as paraffin embedded sections of the frontal lobe from Alzheimer's dementia patients, frontotemporal dementia patients and age matched controls were used for the study.

Frozen sections, sliced at 18 μιτι thickness on a cryostate (Leica, Germany) and paraffin sections, sliced on a sliding microtom (Leica) at a thickness of 6 μιτι, were mounted onto glass slides (Superfrost Plus, Fa.Menzel, Braunschweig Germany). Frozen sections were allowed to adhere to the slides for several nights at -20°C. The paraffin sections were deparaffinized using routine histological methods. For binding studies sections were incubated with the [I- 125] labeled test compound at 10 Bq/μΙ diluted in 25mM Hepes buffer, pH 7.4, 0, 1 % BSA (200-300 μΙ/slide) for 1 ,5 hour at room temperature in a humidified chamber. For blocking experiments an excess of the unlabeled test substance was added to the incubation mixture. After hybridization, sections were washed four times with Hepes buffer, 0.1 % BSA (or alternatively two times with 40% ethanol) and finally dipped two times into water for 10 sec. The air-dried sections were exposed to imaging plates and signals were detected by a phosphoi- mager device (Fuji BAS5000).

Fig. 4: Autoradiographical analysis of binding of compound 8 to brain sections from cortex of Alzheimer^'s disease patients (AD) with amyloid beta plaques. Control sections without amy- loid beta pathology stem from healthy volunteers (HC) and fronto-temporal dementia (FTD) patients. Blocking of specific signals was performed with an excess of cold compound. Arrows point to plaque-specific signals.

Biodistribution

Biodistribution and excretion studies were performed in male NMRI mice (body weight app. 30 g; 3 animals per time point). The animals were kept under normal laboratory conditions at a temperature of 22 ± 2°C and a dark/light rhythm of 12 hours. Food and water were provided ad libitium. During an acclimation period of at least 3 days before the beginning of the study animals were clinically examined to ascertain the absence of abnormal clinical signs. At 2 min, 5 min, 15 min, 30 min, 1 h, 4 h, 24 h post intravenous injection via the tail vein of ca. 185 kBq of the test compound, urine and feces were quantitatively collected. At the same time points, animals were sacrificed by decapitation under isoflurane anaesthesia and organs and tissues of interest were removed for the determination of radioactivity using a gamma- counter. For analysis the decay corrected percentage of the injected dose per tissue weight (%ID/g ± standard deviation) was calculated.

Table 2: Brain uptake and brain wash-out of compound 8 expressed as percentage of injected dose per gram tissue [%ID/g]. The [1-125] signal was detected at 2 min and 30 min af- ter compound administration to mice. Note the favourable high brain uptake and fast washout from healthy mouse brain, which is devoid of plaques.

4.01 0.40 10

The tracer 8 shows an advantageous rapid elimination of the radioactive background signal from the brain.

The studies described above indicate that iodine radiolabeled compounds of the invention are useful as imaging agents for amyloid beta plaques. They can penetrate the intact blood- brain barrier and bind specifically to amyloid beta deposits.

Claims

1.

, wherein

- Q is a six membered aromatic ring, either carbocycle or heterocycle with one N- atom, wherein X₂, X3, X4 and X₅ are independently selected from N or C, and wherein zero or one of , X₂, X3, X4 or X₅ is N and the remaining ones are C; - A is either Sn(alkyl)₃, I, 1-123, 1-124, 1-125, 1-131 , Br;

wherein alkyl comprises methyl, ethyl, propyl, butyl, pentyl and hexyl,

- Y is C or N; with the proviso that if Xi , X₂, X3, X4 or X₅ has the meaning of N, substitution by A in that position is excluded; or a pharmaceutically acceptable salt thereof.

wherein

- A is either Sn(alkyl)₃, I, 1-123, 1-124, 1-125, 1-131 , Br;

wherein alkyl comprises methyl, ethyl, propyl, butyl, pentyl and hexyl,

- Y is C or N; or a pharmaceutically acceptable salt thereof.

3. A compound according to claim 1 selected from the group of compounds consisting of -(2-{4-[5-(benzyloxy)pyridin-2-yl]piperazin-1 -yl}-2-oxoethyl)-2-iodopyridine-4-carboxam

-[5-(benzyloxy)pyridin-2-yl]piperazin-1-yl}-2-oxoethyl)-2-bromopyridine-4-carboxamide

-oxo-ethyl}-3-iodo-benzarriide

-{2-[4-( -Benzyloxy-pyridin-2-yl)-piperazin-1 -yl]-2-oxo-ethyl}-3-tributylstannanyl-benzamide

N-{2-[4-(5-Benzyloxy-pyrimidin-2-yl)-piperazin-1 -yl]-2-oxo-ethyl}-2-iodopyridine-4- carboxamide

-{2-[4-(5-Benzyloxy^yridin-2-yl)-piperazin-1 -yl]-2-oxo-ethyl}-2-iodo-benzamide

N-{2-[4-(5-Benzyloxy^yridin-2-yl)-piperazin-1-yl]-2-oxo-ethyl}-5-iodo-nicotinamide

-{2-[4-(5-Benzyloxy-pyridin-2-yl)-piperazin-1 -yl]-2-oxo-ethyl}-4 ributylstannanyl-benzamide

N-{2-[4-(5-Benzyloxy^yridin-2-yl)-piperazin-1-yl]-2-oxo-ethyl}-3-[¹²⁵l]iodo-benzam

or such a compound wherein 1-125 is replaced by 1-123, 1-124, or 1-131 ;

or a pharmaceutically acceptable salt therepf.

4. A compound according to claim 1 or 2 ,

wherein A is selected from the group consisting of 1-123, 1-124, 1-125, 1-131 ; as a diagnostic compound.

5. The compound

or a pharmaceutically acceptable salt thereof as a diagnostic compound. 6. A compound according to claim 4 or 5 as a diagnostic compound for SPECT imaging of Alzheimer's disease.

7. A diagnostic composition comprising a compound according claims 4 or 5. 8. Use of a compound according to claims 4 or 5 in the preparation of a diagnostic composition for SPECT imaging of Alzheimer's disease.

9. A method for the preparation of a compound having the formula

or of such a compound wherein 1-125 is replaced by 1-123, 1-124, or 1-131

10. A method for the preparation of a compound according to claims 4 or 5, comprising the steps of reacting a suitable precursor molecule compound with a Iodine containing moiety wherein the Iodine is ¹²³l' ¹²⁴l' ¹²⁵l, or ¹³¹l,

optionally removing protecting group(s) and

- optionally converting obtained compound into an acceptable salts of inorganic or organic acids thereof, hydrates, complexes, esters, amides, and solvates.

1 1. A method for the preparation of a compound according to claim 10, the compound having t

or of such a compound wherein 1-125 is replaced by 1-123, 1-124, or 1-131

, comprising the steps of reacting a suitable precursor molecule compound with a Iodine containing moiety wherein the Iodine is ¹²³l' ¹²⁴l' ¹²⁵l, or ¹³¹l,

optionally removing protecting group(s) and

12. A method according to claim 1 1 , wherein the precursor molecule is

or a pharmaceutically acceptable salt thereof.

13. A method of diagnosing Alzheimer's disease in a patient comprising the steps of adminis- tering a compound according to claims 4 or 5 to said patient and performing SPECT analysis. e compound is

or such a compound wherein 1-125 is replaced by 1-123, 1-124, or 1-131

15. A kit comprising a compound according to claims 1 - 3 in a sealed container. has the formula

, wherein

- A is either Sn(alkyl)₃, I, Br;

wherein alkyl comprises methyl, ethyl, propyl, butyl, pentyl and hexyl,

- Y is C or N; with the proviso that if X₂, X3, X4 or X₅ has the meaning of N, substitution by A in that position is excluded;

or a pharmaceutically acceptable salt thereof.

or a pharmaceutically acceptable salt thereof.