Novel imaging agents for detecting neurological dysfunction   

The present application is a National Stage entry of PCT/US09/00961, filed Feb. 17, 2009, which claims the priority of U.S. provisional application No. 60/066,101, filed Feb. 14, 2008. PCT/US09/00961 and U.S. provisional application No. 60/066,101 are incorporated herein by reference.

Alzheimer\'s disease (AD), a leading cause of dementia, develops in one percent of the population between the ages 65 and 69, and increasing to 40-50% in those 95 years and older. AD patients exhibit telltale clinical symptoms that include cognitive impairment and deficits in memory function. In these patients, heavy senile plaque burden found in the cerebral cortex, verified by post mortem histopathological examination, confirms the presence of AD. The mature senile plaques consist of intracellular neurofibrillary tangles (NFT) derived from filaments of hyperphosphorylated tau proteins, and extracellular β-amyloid peptides derived from enzymatic processing of amyloid precursor protein. Interestingly, despite the development and presence of senile plaques in elderly persons with normal cognitive function, the severity of NFT and senile plaque deposition purportedly correlates with a loss of cognitive function and neuronal circuitry deterioration.

Despite Alzheimer\'s disease being the fourth leading cause of death in the United States, pharmaceutical intervention has yet to commercialize a curative therapy. Instead, clinicians currently prescribe cholinesterase inhibitors to cognitively impaired patients. Rivastigmine, a therapeutic treatment for both AD and Parkinson disease patients, inhibits both acetylcholinesterase and butyrylcholinesterase, preventing the breakdown of acetyl- and butyrylcholine. Galantamine, a naturally derived acetylcholinesterase inhibitor, increases nicotinic cholinergic receptors to release acetylcholine into the brain. As a final example, the acetylcholinesterase inhibitor Aricept slows progression of AD in patients by inhibiting acetylcholinesterase and thus increasing cortical acetylcholine. In a recent clinical trial, Aricept\'s effectiveness slowed AD progression in patients but the therapeutic effects disappeared after 36 months. The effect of treating AD patients with a therapeutic combination of both Aricept and memantine caused an increased cognitive function in those AD patients relative to those who just received only Aricept. Despite the usefulness of cholinesterase inhibitors, the current array of AD therapeutics can only delay full-onset AD by approximately two to three years, after which they are therapeutically ineffective in inhibiting cognitive decline. It has been reported that delaying AD onset by five years is sufficient to reduce the number of AD cases in half and, given the current shortcomings of cholinesterase inhibitors, further research efforts are required to meet that goal.

Neurological imaging of AD has seen the emergence of imaging tracers that appear to confirm the presence of AD based on plaque and fibril mediated tracer uptake and, subsequently, are currently undergoing extensive clinical examination. Many of these tracers contain chemotypes that derive from fluorescent dyes (Table 1). For example, increased uptake and binding of the napthylaniline derivative 18F-FDDNP in living brains correlates well with the presence of AD when compared to cognitively functional normals of similar age. [Liu, J., et al., High-Yield, Automated Radiosynthesis of 2-(1-{6-[18F]Fluorethyl)(methyl)amino]-2-naphthyl}ethylidene)malonitrile ([18F]FDDNP) Ready for Animal or Human Administration. Molecular Imaging and Biology, 2007. 9: p. 6-16.] A competing compound, 11C-PIB, shows enhanced uptake in frontotemporal and hippocampal brain regions in AD patients when compared to healthy normals.

There are several issues, however, that question the validity of imaging senile plaques and tangles. First, the current array of AD imaging agents can only confirm the well-established manifestation of AD and this late stage diagnosis offers little defense against further disease progression past 36 months. Secondly, the detection of senile plaques and tangles may not correlate to development of the early stages of AD. Recent data suggests that the amyloid cascade model [Hardy, J. and D. Selkoe, The Amyloid Hypothesis of Alzheimer\'s Disease: Progress and Problems on the Road to Therapeutics. Science, 2002. 297: p. 353-356] does not accurately depict the primary factors leading to cognitive decline in AD patients and that other contributing factors, such as neuorotoxic soluble oligomers and aggregates may play a contributory role in neurodegeneration. [Talaga, P., Inhibitors of beta-amyloid aggregation: still an issue of structure and function? Drug Discovery Today: Therapeutic Strategies, 2004. 1: p. 7-12]. To date, FDDNP and PIB are not known to bind to neurotoxic soluble oligomers and aggregates and thus are not expected to differentiate accurately between the early stages of AD from the advanced stages of AD in patients.

As summarized from a recent discussion group on Dec. 5, 2006, (Biochemical Pharmacology Discussion Group, cosponsored by the American Chemical Society\'s New York section), researchers are now focusing on methods that target AD precursors by blocking either β-amyloid protein (BAP) production or by controlling mutant tau protein formation. Clearly, this focused research effort aims to control the formation of AD precursors that potentially lead to AD and this new strategy might delay full-onset AD more effectively that current therapeutics. In parallel, neurological imaging must mirror the therapeutic trend by identifying AD precursors in a duel effort to compliment both AD therapeutic development and, in addition, identify presymptomatic at-risk AD patients.

A number of medical diagnostic procedures, including PET and SPECT utilize radiolabeled compounds, are well known in the art. PET and SPECT are very sensitive techniques and require small quantities of radiolabeled compounds, called tracers. The labeled compounds are transported, accumulated and converted in vivo in exactly the same way as the corresponding non-radioactively compound. Tracers, or probes, can be radiolabeled with a radionuclide useful for PET imaging, such as 11C, 13N, 15O, 18F, 64Cu and 124I, or with a radionuclide useful for SPECT imaging, such as 99Tc, 77Br, 61Cu, 153Gd, 123I, 125I, 131I and 32P.

PET creates images based on the distribution of molecular imaging tracers carrying positron-emitting isotopes in the tissue of the patient. The PET method has the potential to detect malfunction on a cellular level in the investigated tissues or organs. PET has been used in clinical oncology, such as for the imaging of tumors and metastases, and has been used for diagnosis of certain brain diseases, as well as mapping brain and heart function. Similarly, SPECT can be used to complement any gamma imaging study, where a true 3D representation can be helpful, for example, imaging tumor, infection (leukocyte), thyroid or bones.

SUMMARY

In one embodiment, there is provided a radiolabeled compound of the Formula I to Formula VI:

wherein:

A is N or CR1; B is N or CR2; J is N or CR3; K is N or CR4; L is N or CR5; M is N or CR6; P is N or CR7; and Q is N or CR8, provided that no more than two of A, B, J, K, L, M, P and Q can be N;

X is a bond or is selected from the group consisting of C1-6alkylenyl, —C(O)—, —C(S)—, —C(O)O—, —C(S)O—, —N(R10)C(O)—, —N(R10)C(S)—, —S(O)N(R10)— and —N(R10)S(O)2—;

R1, R2, R3, R4, R5, R6, R7 and R8 are each independently hydrogen or are each independently selected from the group consisting of amino, halo, cyano, nitro, hydroxyl, —SR10, —C(O)NH2, —C(S)NH2, halo-C1-6alkyl, perhaloC1-6alkyl, C1-6alkyl, C3-6cycloalkyl, C3-12cycloalkylC1-5alkyl, C6-14aryl, C6-10arylC1-4alkyl, heteroaryl, C1-5alkoxy, H(OCH2CH2)1-6O—, C1-3alkyl(OCH2CH2)1-6O—, halo-C1-5alkoxy, halo-C1-3alkyl(OCH2CH2)1-6O—, halo-CH2CH2O—, C3-6cycloalkoxy, C3-12cycloalkylC1-5alkoxy, heteroarylC2-5alkoxy, C6-14aryloxy, C6-10arylC1-4alkoxy, heteroaryloxy, C1-5alkylNR10C(O)—, (C1-6alkyl)2NC(O)CH(C1-5alkyl)-, halo-C1-6alkylNR10C(O)CH(C1-5alkyl)-, halo-C1-6alkylOC(O)CH(C1-5alkyl)-, halo-C1-5alkylNR10C(O)—, C1-5alkylNR10C(O)O—, C1-5alkylC(O)—, C1-5alkylC(O)O—, C6-10arylC(O)— and C6-10arylC(O)O—; or at least one of R1 and R2, R2 and R3, R3 and R4, R5 and R6, R6 and R7, or R7 and R8 together with the carbon atoms to which they are attached to, form a substituted or unsubstituted aromatic or non-aromatic carbocyclic or heterocyclic ring;

provided that at least any two of R1, R2, R3, R4, R5, R6, R7 and R8 are hydrogens;

R9 is hydrogen or is selected from the group consisting of halo, C1-6alkyl, C3-6cycloalkyl, C3-12cycloalkylC1-5alkyl, C6-14aryl, C6-10arylC1-4alkyl, heteroaryl, halo-(CH2CH2)1-6—; halo-CH2CH2—(OCH2CH2)1-6—, halo-CH2CH2—(OCH2CH2)1-6O(CO)— and halo-CH2CH2—(OCH2CH2)1-6(CO)—;

each R10 is independently H or C1-6alkyl;

provided that the compound of Formula I is not a compound selected from the group consisting of 2-fluoroethyl 6-fluoro-4-methoxy-9H-pyrido[3,4-b]indole-3-carboxylate, 2-fluoropropyl 6-fluoro-4-methoxy-9H-pyrido[3,4-b]indole-3-carboxylate, 9H-pyrido[3,4-b]indole-3-carboxylate, 9H-pyrido[3,4-b]indole-3-thiocarboxylate, 9H-pyrido[3,4-b]indole-3-carboxamide, 9H-pyrido[3,4-b]indole-3-carbimidate, β-carboline-3-carboxylate, β-carboline-3-thiocarboxylate, β-carboline-3-carboxamide, β-carboline-3-carbimidate; (S)-4-(3-(3-(2′-18F]-fluoroethylamino)-2-hydroxypropoxy)-carbazol, R, S, SS and SR-1′-[18F]-fluorocarazolol (FCAR) and [11C]-carazolol (CAR), (S)-(−)-4-(2-hydroxy-3-(1′-[18]fluoroisopropyl)-aminopropoxy)carbazole, 7-(2-fluoroethoxy)-1-methyl-9H-β-carboline, 7-(2-fluoropropoxy)-1-methyl-9H-β-carboline, 7-[2-(2-fluoroethoxy)ethoxy]-1-methyl-9H-β-carboline, 7-{2-[2-(2-fluoroethoxy)ethoxy]ethoxy}-1-methyl-9H-β-carboline and carbazolyl-(4)-oxypropanolamine and their derivatives;

wherein the radiolabel comprises a radionuclide selected from the group consisting of 11C, 13N, 15O, 18F, 123I, 124I, 125I, 131I and 77Br;

and pharmaceutically acceptable salts thereof;

X is a bond or is selected from the group consisting of C1-6alkylenyl, —C(O)—, —C(S)—, —C(O)O—, —C(S)O—, —N(R10)C(O)—, —N(R10)C(S)—, —S(O)N(R10)— and —N(R10)S(O)2—;

R1, R2, R3, R4, R5, R6, R7 and R8 are each independently hydrogen or are each independently selected from the group consisting of amino, halo, cyano, nitro, hydroxyl, —SR10, —C(O)NH2, —C(S)NH2, halo-C1-6alkyl, perhaloC1-6alkyl, C1-6alkyl, C3-6cycloalkyl, C3-12cycloalkylC1-5alkyl, C6-14aryl, C6-10arylC1-4alkyl, heteroaryl, C1-5alkoxy, H(OCH2CH2)1-6O—, C1-3alkyl(OCH2CH2)1-6O—, halo-C1-5alkoxy, halo-C1-3alkyl(OCH2CH2)1-6O—, halo-CH2CH2O—, C3-6cycloalkoxy, C3-12cycloalkylC1-5alkoxy, heteroarylC2-5alkoxy, C6-14aryloxy, C6-10arylC1-4alkoxy, heteroaryloxy, C1-5alkylNR10C(O)—, (C1-6alkyl)2NC(O)CH(C1-5alkyl)-, halo-C1-6alkylNR10C(O)CH(C1-5alkyl)-, halo-C1-6alkylOC(O)CH(C1-5alkyl)-, halo-C1-5alkylNR10C(O)—, C1-5alkylNR10C(O)O—, C1-5alkylC(O)—, C1-5alkylC(O)O—, C6-10arylC(O)— and C6-10arylC(O)O—; or at least one of R1 and R2, R2 and R3, R3 and R4, R5 and R6, R6 and R7, or R7 and R8 together with the carbon atoms to which they are attached to, form a substituted or unsubstituted aromatic or non-aromatic carbocyclic or heterocyclic ring;

provided that at least any two of R1, R2, R3, R4, R5, R6, R7 and R8 are hydrogens;

R9 is hydrogen or is selected from the group consisting of halo, C1-6alkyl, C3-6cycloalkyl, C3-12cycloalkylC1-5alkyl, C6-14aryl, C6-10arylC1-4alkyl, heteroaryl, halo-(CH2CH2)1-6—; halo-CH2CH2—(OCH2CH2)1-6, halo-CH2CH2—(OCH2CH2)1-6O(CO)— and halo-CH2CH2—(OCH2CH2)1-6(CO)—;

each R10 is independently H or C1-6alkyl;

wherein the radiolabel comprises a radionuclide selected from the group consisting of 11C, 13N, 15O, 18F, 123I, 124I, 125I, 131I and 77Br;

and pharmaceutically acceptable salts thereof;

Y and Y′ are each independently a bond or are each independently selected from the group consisting of amino, halo, cyano, nitro, hydroxyl, —SR10, —C(O)NH2, —C(S)NH2, haloC1-6alkyl, perhaloC1-6alkyl, C1-6alkyl, C3-6cycloalkyl, C3-12cycloalkylC1-5alkyl, C6-14aryl, C6-10arylC1-4alkyl, heteroaryl, C1-5alkoxy, H(OCH2CH2)1-6O—, C1-3alkyl(OCH2CH2)1-6O—, halo-C1-5alkoxy, halo-C1-3alkyl(OCH2CH2)1-6O—, halo-CH2CH2O—, C3-6cycloalkoxy, C3-12cycloalkylC1-5alkoxy, heteroarylC2-5alkoxy, C6-14aryloxy, C6-10arylC1-4alkoxy and heteroaryloxy when R11 and R12 are absent;

R5, R6, R7 and R8 are each independently hydrogen or are each independently selected from the group consisting of amino, halo, cyano, nitro, hydroxyl, —SR10, —C(O)NH2, —C(S)NH2, halo-C1-6alkyl, perhaloC1-6alkyl, C1-6alkyl, C3-6cycloalkyl, C3-12cycloalkylC1-5alkyl, C6-14aryl, C6-10arylC1-4alkyl, heteroaryl, C1-5alkoxy, H(OCH2CH2)1-6O—, C1-3alkyl(OCH2CH2)1-6O—, halo-C1-5alkoxy, halo-C1-3alkyl(OCH2CH2)1-6O—, halo-CH2CH2O—, C3-6cycloalkoxy, C3-12cycloalkylC1-5alkoxy, heteroarylC2-5alkoxy, C6-14aryloxy, C6-10arylC1-4alkoxy, heteroaryloxy, C1-5alkylNR10C(O)—, (C1-6alkyl)2NC(O)CH(C1-5alkyl)-, halo-C1-6alkylNR10C(O)CH(C1-5alkyl)-, halo-C1-6alkylOC(O)CH(C1-5alkyl)-, halo-C1-5alkylNR10C(O)—, C1-5alkylNR10C(O)O—, C1-5alkylC(O)—, C1-5alkylC(O)O—, C6-10arylC(O)— and C6-10arylC(O)O—; or at least one of R5 and R6, R6 and R7 or R7 and R8 together with the carbon atoms to which they are attached to, form a substituted or unsubstituted aromatic or non-aromatic carbocyclic or heterocyclic ring;

provided that at least one of R5, R6, R7 and R8 is a hydrogen;

each R10 is independently H or C1-6alkyl;

R11 and R12 are each independently absent, a hydrogen or are each independently selected from the group consisting of halo, C1-6alkyl, C3-6cycloalkyl, C3-12cycloalkylC1-5alkyl, C6-14aryl, C6-10arylC1-4alkyl, heteroaryl, halo-(CH2CH2)1-6—, halo-CH2CH2—(OCH2CH2)1-6—, halo-CH2CH2—(OCH2CH2)1-6O(CO)— and halo-CH2CH2—(OCH2CH2)1-6(CO)—;

wherein the radiolabel comprises a radionuclide selected from the group consisting of 11C, 13N, 15O, 18F, 123I, 124I, 125I, 131I and 77Br;

and pharmaceutically acceptable salts thereof;

W is O or N—X—R9;

X is a bond or is selected from the group consisting of C1-6alkylenyl, —C(O)—, —C(S)—, —C(O)O—, —C(S)O—, —N(R10)C(O)—, —N(R10)C(S)—, —S(O)N(R10)— and —N(R10)S(O)2—;

Y and Y′ are each independently a bond or are each independently selected from the group consisting of amino, halo, cyano, nitro, hydroxyl, —SR10, —C(O)NH2, —C(S)NH2, halo-C1-6alkyl, perhaloC1-6alkyl, C1-6alkyl, C3-6cycloalkyl, C3-12cycloalkylC1-5alkyl, C6-14aryl, C6-10arylC1-4alkyl, heteroaryl, C1-5alkoxy, H(OCH2CH2)1-6O—, C1-3alkyl(OCH2CH2)1-6O—, halo-C1-5alkoxy, halo-C1-3alkyl(OCH2CH2)1-6O—, halo-CH2CH2O—, C3-6cycloalkoxy, C3-12cycloalkylC1-5 alkoxy, heteroarylC2-5alkoxy, C6-14aryloxy, C6-10arylC1-4alkoxy and heteroaryloxy when R11 and R12 are absent; or Y is

and R12 is absent;

R1, R2, R3 and R4 are each independently hydrogen or are each independently selected from the group consisting of amino, halo, cyano, nitro, hydroxyl, —SR10, —C(O)NH2, —C(S)NH2, halo-C1-6alkyl, perhaloC1-6alkyl, C1-6alkyl, C3-6cycloalkyl, C3-12cycloalkylC1-5alkyl, C6-14aryl, C6-10arylC1-4alkyl, heteroaryl, C1-5alkoxy, H(OCH2CH2)1-6O—, C1-3alkyl(OCH2CH2)1-6O—, halo-C1-5alkoxy, halo-C1-3alkyl(OCH2CH2)1-6O—, halo-CH2CH2O—, C3-6cycloalkoxy, C3-12cycloalkylC1-5alkoxy, heteroarylC2-5alkoxy, C6-14aryloxy, C6-10arylC1-4alkoxy, heteroaryloxy, C1-5alkylNR10C(O)—, (C1-6alkyl)2NC(O)CH(C1-5alkyl)-, halo-C1-6alkylNR10C(O)CH(C1-5alkyl)-, halo-C1-6alkylOC(O)CH(C1-5alkyl)-, halo-C1-5alkylNR10C(O)—, C1-5alkylNR10C(O)O—, C1-5alkylC(O)—, C1-5alkylC(O)O—, C6-10arylC(O)— and C6-10arylC(O)O—; or at least one of R5 and R6, R6 and R7 or R7 and R8 together with the carbon atoms to which they are attached to, form a substituted or unsubstituted aromatic or non-aromatic carbocyclic or heterocyclic ring;

provided that at least one of R1, R2, R3 and R4 is a hydrogen;

R5, R6, R7, R8 and Ro are each independently hydrogen or are each independently selected from the group consisting of amino, halo, cyano, nitro, hydroxyl, —SR10, —C(O)NH2, —C(S)NH2, halo-C1-6alkyl, perhaloC1-6alkyl, C1-6alkyl, C3-6cycloalkyl, C3-12cycloalkylC1-5alkyl, C6-14aryl, C6-10arylC1-4alkyl, heteroaryl, C1-5alkoxy, H(OCH2CH2)1-6O—, C1-3alkyl(OCH2CH2)1-6O—, halo-C1-5alkoxy, halo-C1-3alkyl(OCH2CH2)1-6O—, halo-CH2CH2O—, C3-6cycloalkoxy, C3-12cycloalkylC1-5alkoxy, heteroarylC2-5alkoxy, C6-14aryloxy, C6-10arylC1-4alkoxy, heteroaryloxy, C1-5alkylNR10C(O)—, (C1-6alkyl)2NC(O)CH(C1-5alkyl)-, halo-C1-6alkylNR10C(O)CH(C1-5alkyl)-, halo-C1-6alkylOC(O)CH(C1-5alkyl)-, halo-C1-5alkylNR10C(O)—, C1-5alkylNR10C(O)O—, C1-5alkylC(O)—, C1-5alkylC(O)O—, C6-10arylC(O)— and C6-10arylC(O)O—;

R9 is hydrogen or is selected from the group consisting of halo, C1-6alkyl, C3-6cycloalkyl, C3-12cycloalkylC1-5alkyl, C6-14aryl, C6-10arylC1-4alkyl, heteroaryl, halo-(CH2CH2)1-6—; halo-CH2CH2—(OCH2CH2)1-6—, halo-CH2CH2—(OCH2CH2)1-6O(CO)— and halo-CH2CH2—(OCH2CH2)1-6(CO)—;

each R10 is independently H or C1-6alkyl;

R11 and R12 are each independently absent, a hydrogen or are each independently selected from the group consisting of halo, C1-6alkyl, C3-6cycloalkyl, C3-12cycloalkylC1-5alkyl, C6-14aryl, C6-10arylC1-4alkyl, heteroaryl, halo-(CH2CH2)1-6—; halo-CH2CH2—(OCH2CH2)1-6—, halo-CH2CH2—(OCH2CH2)1-6O(CO)— and halo-CH2CH2—(OCH2CH2)1-6(CO)—;

wherein the radiolabel comprises a radionuclide selected from the group consisting of 11C, 13N, 15O, 18F, 123I, 124I, 125I, 131I and 77Br;

and pharmaceutically acceptable salts thereof;

X is a bond or is selected from the group consisting of C1-6alkylenyl, —C(O)—, —C(S)—, —C(O)O—, —C(S)O—, —N(R10)C(O)—, —N(R10)C(S)—, —S(O)N(R10)— and —N(R10)S(O)2—;

R5 and R6 are each independently hydrogen or are each independently selected from the group consisting of amino, halo, cyano, nitro, hydroxyl, —SR10, —C(O)NH2, —C(S)NH2, halo-C2-6alkyl, perhaloC1-6alkyl, C1-6alkyl, C3-6cycloalkyl, C3-12cycloalkylC1-5alkyl, C6-14aryl, C6-10arylC1-4alkyl, heteroaryl, C1-5alkoxy, H(OCH2CH2)1-6O—, C1-3alkyl(OCH2CH2)1-6O—, halo-C1-5alkoxy, halo-C1-3alkyl(OCH2CH2)1-6O—, halo-CH2CH2O—, C3-6cycloalkoxy, C3-12cycloalkylC1-5alkoxy, heteroarylC2-5alkoxy, C6-14aryloxy, C6-10arylC1-4alkoxy, heteroaryloxy, C1-5alkylNR10C(O)—, (C1-6alkyl)2NC(O)CH(C1-5alkyl)-, halo-C1-6alkylNR10C(O)CH(C1-5alkyl)-, halo-C1-6alkylOC(O)CH(C1-5alkyl)-, halo-C1-5alkylNR10C(O)—, C1-5alkylNR10C(O)O—, C1-5alkylC(O)—, C1-5alkylC(O)O—, C6-10arylC(O)— and C6-10arylC(O)O—; or R5 and R6 together with the carbon atoms to which they are attached to, form a substituted or unsubstituted aromatic or non-aromatic carbocyclic or heterocyclic ring;

R9 is hydrogen or is selected from the group consisting of halo, C1-6alkyl, C3-6cycloalkyl, C3-12cycloalkylC1-5alkyl, C6-14aryl, C6-10arylC1-4alkyl, heteroaryl, halo-(CH2CH2)1-6—; halo-CH2CH2—(OCH2CH2)1-6—, halo-CH2CH2—(OCH2CH2)1-6O(CO)— and halo-CH2CH2—(OCH2CH2)1-6(CO)—;

each R10 is independently H or C1-6alkyl;

wherein the radiolabel comprises a radionuclide selected from the group consisting of 11C, 13N, 15O, 18F, 123I, 124I, 125I, 131I and 77Br;

and pharmaceutically acceptable salts thereof;

X is a bond or is selected from the group consisting of C1-6alkylenyl, —C(O)—, —C(S)—, —C(O)O—, —C(S)O—, —N(R10)C(O)—, —N(R10)C(S)—, —S(O)N(R10)— and —N(R10)S(O)2—;

Y is a bond or is selected from the group consisting of amino, halo, cyano, nitro, hydroxyl, —SR10, —C(O)NH2, —C(S)NH2, halo-C1-6alkyl, perhaloC1-6alkyl, C1-6alkyl, C3-6cycloalkyl, C3-12cycloalkylC1-5alkyl, C6-14aryl, C6-10arylC1-4alkyl, heteroaryl, C1-5alkoxy, H(OCH2CH2)1-6O—, C1-3alkyl(OCH2CH2)1-6O—, halo-C1-5alkoxy, halo-C1-3alkyl(OCH2CH2)1-6O—, halo-CH2CH2O—, C3-6cycloalkoxy, C3-12cycloalkylC1-5alkoxy, heteroarylC2-5alkoxy, C6-14aryloxy, C6-10arylC1-4alkoxy and heteroaryloxy;

R5 and R6 are each independently hydrogen or are each independently selected from the group consisting of amino, halo, cyano, nitro, hydroxyl, —SR10, —C(O)NH2, —C(S)NH2, haloC1-6alkyl, perhaloC1-6alkyl, C1-6alkyl, C3-6cycloalkyl, C3-12cycloalkylC1-5alkyl, C6-14aryl, C6-10arylC1-4alkyl, heteroaryl, C1-5alkoxy, H(OCH2CH2)1-6O—, C1-3alkyl(OCH2CH2)1-6O—, halo-C1-5alkoxy, halo-C1-3alkyl(OCH2CH2)1-6O—, halo-CH2CH2O—, C3-6cycloalkoxy, C3-12cycloalkylC1-5alkoxy, heteroarylC2-5alkoxy, C6-14aryloxy, C6-10arylC1-4alkoxy, heteroaryloxy, C1-5alkylNR10C(O)—, (C1-6alkyl)2NC(O)CH(C1-5alkyl)-, halo-C1-6alkylNR10C(O)CH(C1-5alkyl)-, halo-C1-6alkylOC(O)CH(C1-5alkyl)-, halo-C1-5alkylNR10C(O)—, C1-5alkylNR10C(O)O—, C1-5alkylC(O)—, C1-5alkylC(O)O—, C6-10arylC(O)— and C6-10arylC(O)O—; or R5 and R6 together with the carbon atoms to which they are attached to, form a substituted or unsubstituted aromatic or non-aromatic carbocyclic or heterocyclic ring;

R9 is hydrogen or is selected from the group consisting of halo, C1-6alkyl, C3-6cycloalkyl, C3-12cycloalkylC1-5alkyl, C6-14aryl, C6-10arylC1-4alkyl, heteroaryl, halo-(CH2CH2)1-6—; halo-CH2CH2—(OCH2CH2)1-6—, halo-CH2CH2—(OCH2CH2)1-6O(CO)— and halo-CH2CH2—(OCH2CH2)1-6(CO)—;

each R10 is independently H or C1-6alkyl; R11 is a hydrogen or is selected from the group consisting of halo, C1-6alkyl, C3-6cycloalkyl, C3-12cycloalkylC1-5alkyl, C6-14aryl, C6-10arylC1-4alkyl, heteroaryl, halo-(CH2CH2)1-6—; halo-CH2CH2—(OCH2CH2)1-6—, halo-CH2CH2—(OCH2CH2)1-6O(CO)— and halo-CH2CH2—(OCH2CH2)1-6(CO)—;

provided that at least one of R1 to R12 comprises a radiolabel, as defined herein;

wherein the radiolabel comprises a radionuclide selected from the group consisting of 11C, 13N, 15O, 18F, 123I, 124I, 125I, 131I and 77Br;

and pharmaceutically acceptable salts thereof.

In one variation of the above compound:

A is N or CR1; B is N or CR2; J is N or CR3; K is N or CR4; L is N or CR5; M is N or CR6; P is N; and Q is N or CR8;

X is a bond or is selected from the group consisting of C1-6alkylenyl, —C(O)—, —C(S)—, —C(O)O— and —C(S)O—; and

R1, R2, R3, R4, R5, R6, R7 and R8 are each independently hydrogen or are each independently selected from the group consisting of amino, halo, cyano, nitro, hydroxyl, —SR10, —C(O)NH2, —C(S)NH2, perhaloC1-6alkyl, C1-6alkyl, C3-6cycloalkyl, C3-12cycloalkylC1-5alkyl, C6-14aryl, C6-10arylC1-4alkyl, heteroaryl, C1-5alkoxy, H(OCH2CH2)1-6O—, C1-3alkyl(OCH2CH2)1-6O—, halo-C1-5alkoxy, halo-C1-3alkyl(OCH2CH2)1-6O—, halo-CH2CH2O—, C3-6cycloalkoxy, C3-12cycloalkylC1-5alkoxy, heteroarylC2-5alkoxy, C6-14aryloxy, C6-10arylC1-4alkoxy, heteroaryloxy, C1-5alkylNR10C(O)—, (C1-6alkyl)2NC(O)CH(C1-5alkyl)-, halo-C1-6alkylNR10C(O)CH(C1-5alkyl)-, halo-C1-6alkylOC(O)CH(C1-5alkyl)-, halo-C1-5alkylNR10C(O)—, C1-5alkylNR10C(O)O—, C1-5alkylC(O)—, C1-5alkylC(O)O—, C6-10arylC(O)— and C6-10arylC(O)O—; or at least one of R1 and R2, R2 and R3, R3 and R4, R5 and R6, R6 and R7, or R7 and R8 together with the carbon atoms to which they are attached to, form a substituted or unsubstituted aromatic or non-aromatic carbocyclic or heterocyclic ring;

X is a bond or is selected from the group consisting of C1-6alkylenyl, —C(O)O— and —C(S)O—; and

R1, R2, R3, R4, R5, R6, R7 and R8 are each independently hydrogen or are each independently selected from the group consisting of amino, halo, cyano, nitro, hydroxyl, —SR10, —C(O)NH2, —C(S)NH2, perhaloC1-6alkyl, C1-6alkyl, C3-6cycloalkyl, C3-12cycloalkylC1-5alkyl, C6-14aryl, C6-10arylC1-4alkyl, heteroaryl, C1-5alkoxy, H(OCH2CH2)1-6O—, C1-3alkyl(OCH2CH2)1-6O—, halo-C1-5alkoxy, halo-C1-3alkyl(OCH2CH2)1-6O—, halo-CH2CH2O—, C3-6cycloalkoxy, C3-12cycloalkylC1-5alkoxy, heteroarylC2-5alkoxy, C6-14aryloxy, C6-10arylC1-4alkoxy, heteroaryloxy, C1-5alkylNR10C(O)—, (C1-6alkyl)2NC(O)CH(C1-5alkyl)-, halo-C1-6alkylNR10C(O)CH(C1-5alkyl)-, halo-C1-6alkylOC(O)CH(C1-5alkyl)-, halo-C1-5alkylNR10C(O)—, C1-5alkylNR10C(O)O—, C1-5alkylC(O)—, C1-5alkylC(O)O—, C5-10arylC(O)— and C6-10arylC(O)O—; or at least one of R1 and R2, R2 and R3, R3 and R4, R5 and R6, R6 and R7, or R7 and R8 together with the carbon atoms to which they are attached to, form a substituted or unsubstituted aromatic or non-aromatic carbocyclic or heterocyclic ring;

Y and Y′ are each independently selected from the group consisting of amino, halo, cyano, nitro, hydroxyl, —SR10, —C(O)NH2, —C(S)NH2, halo-C1-6alkyl, perhaloC1-6alkyl, C1-6alkyl, C3-6cycloalkyl, C3-12cycloalkylC1-5alkyl, C6-14aryl, C6-10arylC1-4alkyl, heteroaryl, C1-5alkoxy, H(OCH2CH2)1-6O—, C1-3alkyl(OCH2CH2)1-6O—, halo-C1-3alkyl(OCH2CH2)1-6O—, halo-CH2CH2O—, C3-6cycloalkoxy, C3-12cycloalkylC1-5alkoxy, heteroarylC2-5alkoxy, C6-14aryloxy, C6-10arylC1-4alkoxy and heteroaryloxy when R11 and R12 are absent;

R5, R6, R7 and R8 are each independently hydrogen or are each independently selected from the group consisting of amino, halo, cyano, nitro, hydroxyl, —SR10, —C(O)NH2, —C(S)NH2, perhaloC1-6alkyl, C1-6alkyl, C3-6cycloalkyl, C3-12cycloalkylC1-5alkyl, C6-14aryl, C6-10arylC1-4alkyl, heteroaryl, C1-5alkoxy, H(OCH2CH2)1-6O—, C1-3alkyl(OCH2CH2)1-6O—, halo-C2-5alkoxy, halo-C2-3alkyl(OCH2CH2)1-6O—, halo-CH2CH2O—, C3-6cycloalkoxy, C3-12cycloalkylC1-5alkoxy, heteroarylC2-5alkoxy, C6-14aryloxy, C6-10arylC1-4alkoxy, heteroaryloxy, C1-5alkylNR10C(O)—, (C1-6alkyl)2NC(O)CH(C1-5alkyl)-, halo-C2-6alkylNR10C(O)CH(C1-5alkyl)-, halo-C1-6alkylOC(O)CH(C1-5alkyl)-, halo-C1-5alkylNR10C(O)—, C1-5alkylNR10C(O)O—, C1-5alkylC(O)—, C1-5alkylC(O)O—, C6-10arylC(O)— and C6-10arylC(O)O—; or at least one of R1 and R2, R2 and R3, R3 and R4, R5 and R6, R6 and R7, or R7 and R8 together with the carbon atoms to which they are attached to, form a substituted or unsubstituted aromatic or non-aromatic carbocyclic or heterocyclic ring;

W is O or —N—X—R9;

R1, R2, R3 and R4 are each independently hydrogen or are each independently selected from the group consisting of amino, halo, cyano, nitro, hydroxyl, —SR10, —C(O)NH2, —C(S)NH2, halo-C1-6alkyl, perhaloC1-6alkyl, C1-6alkyl, C3-6cycloalkyl, C3-12cycloalkylC1-5alkyl, C6-14aryl, C6-10arylC1-4alkyl, heteroaryl, C1-5alkoxy, H(OCH2CH2)1-6O—, C1-3alkyl(OCH2CH2)1-6O—, halo-C1-5alkoxy, halo-C1-3alkyl(OCH2CH2)1-6O—, halo-CH2CH2O—, C3-6cycloalkoxy, C3-12cycloalkylC1-5alkoxy, heteroarylC2-5alkoxy, C6-14aryloxy, C6-10arylC1-4alkoxy, heteroaryloxy, C1-5alkylNR10C(O)—, (C1-6alkyl)2NC(O)CH(C1-5alkyl)-, halo-C1-6alkylNR10C(O)CH(C1-5alkyl)-, halo-C1-6alkylOC(O)CH(C1-5alkyl)-, halo-C1-5alkylNR10C(O)—, C1-5alkylNR10C(O)O—, C1-5alkylC(O)—, C1-5alkylC(O)O—, C6-10arylC(O)— and C6-10arylC(O)O—; or at least one of R1 and R2, R2 and R3 or R3 and R4 together with the carbon atoms to which they are attached to, form a substituted or unsubstituted aromatic or non-aromatic carbocyclic or heterocyclic ring;

X is a bond or is selected from the group consisting of C1-6alkylenyl, —C(O)—, —C(S)—, —C(O)O—, —C(S)O—, —N(R10)C(O)—, —N(R10)C(S)—, —S(O)N(R10)— and —N(R10)S(O)2—;

R5 and R6 are each independently hydrogen or are each independently selected from the group consisting of amino, halo, cyano, nitro, hydroxyl, —SR10, —C(O)NH2, —C(S)NH2, halo-C1-6alkyl, perhaloC1-6alkyl, C1-6alkyl, C3-6cycloalkyl, C3-12cycloalkylC1-5alkyl, C6-14aryl, C6-10arylC1-4alkyl, heteroaryl, C1-5alkoxy, H(OCH2CH2)1-6O—, C1-3alkyl(OCH2CH2)1-6O—, halo-C1-5alkoxy, halo-C1-3alkyl(OCH2CH2)1-6O—, halo-CH2CH2O—, C3-6cycloalkoxy, C3-12cycloalkylC1-5alkoxy, heteroarylC2-5alkoxy, C6-14aryloxy, C6-10arylC1-4alkoxy, heteroaryloxy, C1-5alkylNR10C(O)—, (C1-6alkyl)2NC(O)CH(C1-5alkyl)-, halo-C1-6alkylNR10C(O)CH(C1-5alkyl)-, halo-C1-6alkylOC(O)CH(C1-5alkyl)-, halo-C1-5alkylNR10C(O)—, C1-5alkylNR10C(O)O—, C1-5alkylC(O)—, C1-5alkylC(O)O—, C6-10arylC(O)— and C6-10arylC(O)O—; and

R9 is hydrogen or is selected from the group consisting of halo, C1-6alkyl, C3-6cycloalkyl, C3-12cycloalkylC1-5alkyl, C6-14aryl, C6-10arylC1-4alkyl, heteroaryl, halo-(CH2CH2)1-6—; halo-CH2CH2—(OCH2CH2)1-6—, halo-CH2CH2—(OCH2CH2)1-6O(CO)— and halo-CH2CH2—(OCH2CH2)1-6(CO)—;

X is a bond or is selected from the group consisting of C1-6alkylenyl, —C(O)—, —C(S)—, —C(O)O—, —C(S)O—, —N(R10)C(O)—, —N(R10)C(S)—, —S(O)N(R10)— and —N(R10)S(O)2—;

Y is a bond or is selected from the group consisting of amino, halo, cyano, nitro, hydroxyl, —SR10, —C(O)NH2, —C(S)NH2, haloC1-6alkyl, perhaloC1-6alkyl, C1-6alkyl, C3-6cycloalkyl, C3-12cycloalkylC1-5alkyl, C6-14aryl, C6-10arylC1-4alkyl, heteroaryl, C1-5alkoxy, H(OCH2CH2)1-6O—, C1-3alkyl(OCH2CH2)1-6O—, halo-C1-5alkoxy, halo-C1-3alkyl(OCH2CH2)1-6O—, halo-CH2CH2O—, C3-6cycloalkoxy, C3-12cycloalkylC1-5alkoxy, heteroarylC2-5alkoxy, C6-14aryloxy, C6-10arylC1-4alkoxy and heteroaryloxy;

R5 and R6 are each independently hydrogen or are each independently selected from the group consisting of amino, halo, cyano, nitro, hydroxyl, —SR10, —C(O)NH2, —C(S)NH2, halo-C1-6alkyl, perhaloC1-6alkyl, C1-6alkyl, C3-6cycloalkyl, C3-12cycloalkylC1-5alkyl, C6-14aryl, C6-10arylC1-4alkyl, heteroaryl, C1-5alkoxy, H(OCH2CH2)1-6O—, C1-3alkyl(OCH2CH2)1-6O—, halo-C1-5alkoxy, halo-C1-3alkyl(OCH2CH2)1-6O—, halo-CH2CH2O—, C3-6cycloalkoxy, C3-12cycloalkylC1-5alkoxy, heteroarylC2-5alkoxy, C6-14aryloxy, C6-10arylC1-4alkoxy, heteroaryloxy, C1-5alkylNR10C(O)—, (C1-6alkyl)2NC(O)CH(C1-5alkyl)-, halo-C1-6alkylNR10C(O)CH(C1-5alkyl)-, halo-C1-6alkylOC(O)CH(C1-5alkyl)-, halo-C1-5alkylNR10C(O)—, C1-5alkylNR10C(O)O—, C1-5alkylC(O)—, C1-5alkylC(O)O—, C6-10arylC(O)— and C6-10arylC(O)O—;

R9 is hydrogen or is selected from the group consisting of halo, C1-6alkyl, C3-6cycloalkyl, C3-12cycloalkylC1-5alkyl, C6-14aryl, C6-10arylC1-4alkyl, heteroaryl, halo-(CH2CH2)1-6—; halo-CH2CH2—(OCH2CH2)1-6—, halo-CH2CH2—(OCH2CH2)1-6O(CO)— and halo-CH2CH2—(OCH2CH2)1-6(CO)—; and

R11 is absent, a hydrogen or is selected from the group consisting of halo, C1-6alkyl, C3-6cycloalkyl, C3-12cycloalkylC1-5alkyl, C6-14aryl, C6-10arylC1-4alkyl, heteroaryl, halo-(CH2CH2)1-6—; halo-CH2CH2—(OCH2CH2)1-6—, halo-CH2CH2—(OCH2CH2)1-6O(CO)— and halo-CH2CH2—(OCH2CH2)1-6(CO)—;

wherein the radiolabel comprises a radionuclide selected from the group consisting of 11C, 13N, 15O, 18F, 123I, 124I, 125I, 131I and 77Br;

and pharmaceutically acceptable salts thereof.

In another embodiment, there is provided a radiolabeled compound of the formula IIa:

wherein:

X is a bond or is selected from the group consisting of C1-6alkylenyl, —C(O)—, —C(S)—, —C(O)O—, —C(S)O—, —N(R10)C(O)—, —N(R10)C(S)—, —S(O)N(R10)— and —N(R10)S(O)2;

R2, R3, R4, R6, R7 and R8 are each independently hydrogen or are each independently selected from the group consisting of amino, halo, cyano, nitro, hydroxyl, —SR10, —C(O)NH2, —C(S)NH2, haloC1-6alkyl, perhaloC1-6alkyl, C1-6alkyl, C3-6cycloalkyl, C3-12cycloalkylC1-5alkyl, C6-14aryl, C6-10arylC1-4alkyl, heteroaryl, C1-5alkoxy, H(OCH2CH2)1-6O—, C1-3alkyl(OCH2CH2)1-6O—, halo-C1-5alkoxy, halo-C1-3alkyl(OCH2CH2)1-6O—, halo-CH2CH2—(OCH2CH2)1-6O—, C3-6cycloalkoxy, C3-12cycloalkylC1-5alkoxy, heteroarylC2-5alkoxy, C6-14aryloxy, C6-10arylC1-4alkoxy, heteroaryloxy, C1-5alkylNR10C(O)—, (C1-6alkyl)2NC(O)CH(C1-5alkyl)-, halo-C1-6alkylNR10C(O)CH(C1-5alkyl)-, halo-C1-6alkylOC(O)CH(C1-5alkyl)-, halo-C1-5alkylNR10C(O)—, C1-5alkylNR10C(O)O—, C1-5alkylC(O)—, C1-5alkylC(O)O—, C6-10arylC(O)— and C6-10arylC(O)O—;

provided that at least any two of R2, R3, R4, R6, R7 and R8 are hydrogens, and at least one of R2, R3, R4, R6, R7, R8 and R9 comprises the radiolabel;

R9 is hydrogen or is selected from the group consisting of halo, C1-6alkyl, C3-6cycloalkyl, C3-12cycloalkylC1-5alkyl, C6-14aryl, C6-10arylC1-4alkyl, heteroaryl, halo-(CH2CH2)1-6—; halo-CH2CH2—(OCH2CH2)1-6—, halo-CH2CH2—(OCH2CH2)1-6O(CO)— and halo-CH2CH2—(OCH2CH2)1-6(CO)—;

each R10 is independently H or C1-6alkyl;

wherein the radiolabel comprises a radionuclide selected from the group consisting of 11C, 13N, 15O, 18F, 123I, 124I, 125I, 131I and 77Br;

and pharmaceutically acceptable salts thereof.

In other embodiment, there is provided a radiolabeled compound of the formula III:

wherein:

Y and Y′ are each independently a bond or are each independently selected from the group consisting of amino, halo, cyano, nitro, hydroxyl, —SR10, —C(O)NH2, —C(S)NH2, haloC1-6alkyl, perhaloC1-6alkyl, C1-6alkyl, C3-6cycloalkyl, C3-12cycloalkylC1-5alkyl, C6-14aryl, C6-10arylC1-4alkyl, heteroaryl, C1-5alkoxy, H(OCH2CH2)1-6O—, C1-3alkyl(OCH2CH2)1-6O—, halo-C1-5alkoxy, halo-C1-3alkyl(OCH2CH2)1-6O—, halo-CH2CH2O—, C3-6cycloalkoxy, C3-12cycloalkylC1-5alkoxy, heteroarylC2-5alkoxy, C6-14aryloxy, C6-10arylC1-4alkoxy and heteroaryloxy when R11 and R12 are absent;

R5, R6, R7 and R8 are each independently hydrogen or are each independently selected from the group consisting of amino, halo, cyano, nitro, hydroxyl, —SR10, —C(O)NH2, —C(S)NH2, halo-C1-6alkyl, perhaloC1-6alkyl, C1-6alkyl, C3-6cycloalkyl, C3-12cycloalkylC1-5alkyl, C6-14aryl, C6-10arylC1-4alkyl, heteroaryl, C1-5alkoxy, H(OCH2CH2)1-6O—, C1-3alkyl(OCH2CH2)1-6O—, halo-C1-5alkoxy, halo-C1-3alkyl(OCH2CH2)1-6O—, halo-CH2CH2O—, C3-6cycloalkoxy, C3-12cyoloalkylC1-5alkoxy, heteroarylC2-5alkoxy, C6-14aryloxy, C6-10arylC1-4alkoxy, heteroaryloxy, C1-5alkylNR10C(O)—, (C1-6alkyl)2NC(O)CH(C1-5alkyl)-, halo-C1-6alkylNR10C(O)CH(C1-5alkyl)-, halo-C1-6alkylOC(O)CH(C1-5alkyl)-, halo-C1-5alkylNR10C(O)—, C1-5alkylNR10C(O)O—, C1-5alkylC(O)—, C1-5alkylC(O)O—, C6-10arylC(O)— and C6-10arylC(O)O—; or at least one of R5 and R6, R6 and R7 or R7 and R8 together with the carbon atoms to which they are attached to, form a substituted or unsubstituted aromatic or non-aromatic carbocyclic or heterocyclic ring;

provided that at least one of R5, R6, R7 and R8 is a hydrogen;

each R10 is independently H or C1-6alkyl;

R11 and R12 are each independently absent, a hydrogen or are each independently selected from the group consisting of halo, C1-6alkyl, C3-6cycloalkyl, C3-12cycloalkylC1-5alkyl, C6-14aryl, C6-10arylC1-4alkyl, heteroaryl, halo-(CH2CH2)1-6—, halo-CH2CH2—(OCH2CH2)1-6—, halo-CH2CH2—(OCH2CH2)1-6O(CO)— and halo-CH2CH2—(OCH2CH2)1-6(CO)—;

provided that at least one of R5 to R12 comprises a radiolabel;

wherein the radiolabel comprises a radionuclide selected from the group consisting of 11C, 13N, 15O, 18F, 123I, 124I, 125I, 131 and 77Br;

and pharmaceutically acceptable salts thereof.

In another embodiment, there is provided, a radiolabeled compound of the formula IV:

wherein:

W is O or —N—X—R9;

X is a bond or is selected from the group consisting of C1-6alkylenyl, —C(O)—, —C(S)—, —C(O)O—, —C(S)O—, —N(R10)C(O)—, —N(R10)C(S)—, —S(O)N(R10)— and —N(R10)S(O)2—;

Y and Y′ are each independently a bond or are each independently selected from the group consisting of amino, halo, cyano, nitro, hydroxyl, —SR10, —C(O)NH2, —C(S)NH2, halo-C1-6alkyl, perhaloC1-6alkyl, C1-6alkyl, C3-6cycloalkyl, C3-12cycloalkylC1-5alkyl, C6-14aryl, C6-10arylC3-4alkyl, heteroaryl, C1-5alkoxy, H(OCH2CH2)1-6O—, C1-3alkyl(OCH2CH2)1-6O—, halo-C1-5alkoxy, halo-C1-3alkyl(OCH2CH2)1-6O—, halo-CH2CH2O—, C3-6cycloalkoxy, C3-12cycloalkylC1-5alkoxy, heteroarylC2-5alkoxy, C6-14aryloxy, C6-10arylC1-4alkoxy and heteroaryloxy when R11 and R12 are absent; or Y is

and R12 is absent;

R1, R2, R3 and R4 are each independently hydrogen or are each independently selected from the group consisting of amino, halo, cyano, nitro, hydroxyl, —SR10, —C(O)NH2, —C(S)NH2, halo-C1-6alkyl, perhaloC1-6alkyl, C1-6alkyl, C3-6cycloalkyl, C3-12cycloalkylC1-5alkyl, C6-14aryl, C6-10arylC1-4alkyl, heteroaryl, C1-5alkoxy, H(OCH2CH2)1-6O—, C1-3alkyl(OCH2CH2)1-6O—, halo-C1-5alkoxy, halo-C1-3alkyl(OCH2CH2)1-6O—, halo-CH2CH2O—, C3-6cycloalkoxy, C3-12cycloalkylC1-5alkoxy, heteroarylC2-5alkoxy, C6-14aryloxy, C6-10arylC1-4alkoxy, heteroaryloxy, C1-5alkylNR10C(O)—, (C1-6alkyl)2NC(O)CH(C1-5alkyl)-, halo-C1-6alkylNR10C(O)CH(C1-5alkyl)-, halo-C1-6alkylOC(O)CH(C1-5alkyl)-, halo-C1-5alkylNR10C(O)—, C1-5alkylNR10C(O)O—, C1-5alkylC(O)—, C1-5alkylC(O)O—, C6-10arylC(O)— and C6-10arylC(O)O—; or at least one of R5 and R6, R6 and R7 or R7 and R8 together with the carbon atoms to which they are attached to, form a substituted or unsubstituted aromatic or non-aromatic carbocyclic or heterocyclic ring;

provided that at least one of R1, R2, R3 and R4 is a hydrogen;

R5, R6, R7, R8 and Ro are each independently hydrogen or are each independently selected from the group consisting of amino, halo, cyano, nitro, hydroxyl, —SR10, —C(O)NH2, —C(S)NH2, halo-C1-6alkyl, perhaloC1-6alkyl, C1-6alkyl, C3-6cycloalkyl, C3-12cycloalkylC1-5alkyl, C6-14aryl, C6-10arylC1-4alkyl, heteroaryl, C1-5alkoxy, H(OCH2CH2)1-6O—, C1-3alkyl(OCH2CH2)1-6O—, halo-C1-5alkoxy, halo-C1-3alkyl(OCH2CH2)1-6O—, halo-CH2CH2O—, C3-6cycloalkoxy, C3-12cycloalkylC1-5alkoxy, heteroarylC2-5alkoxy, C6-14aryloxy, C6-10arylC1-4alkoxy, heteroaryloxy, C1-5alkylNR10C(O)—, (C1-6alkyl)2NC(O)CH(C1-5alkyl)-, halo-C1-6alkylNR10C(O)CH(C1-5alkyl)-, halo-C1-6alkylOC(O)CH(C1-5alkyl)-, halo-C1-5alkylNR10C(O)—, C1-5alkylNR10C(O)O—, C1-5alkylC(O)—, C1-5alkylC(O)O—, C6-10arylC(O)— and C6-10arylC(O)O—;

R9 is hydrogen or is selected from the group consisting of halo, C1-6alkyl, C3-6cycloalkyl, C3-12cycloalkylC1-5alkyl, C6-14aryl, C6-10arylC1-4alkyl, heteroaryl, halo-(CH2CH2)1-6—; halo-CH2CH2—(OCH2CH2)1-6—, halo-CH2CH2—(OCH2CH2)1-6O(CO)— and halo-CH2CH2—(OCH2CH2)1-6(CO)—;

each R10 is independently H or C1-6alkyl; and

R11 and R12 are each independently absent, a hydrogen or are each independently selected from the group consisting of halo, C1-6alkyl, C3-6cycloalkyl, C3-12cycloalkylC1-5alkyl, C6-14aryl, C6-10arylC1-4alkyl, heteroaryl, halo-(CH2CH2)1-6—; halo-CH2CH2—(OCH2CH2)1-6—, halo-CH2CH2—(OCH2CH2)1-6O(CO)— and halo-CH2CH2—(OCH2CH2)1-6(CO)—;

provided that at least one of R1 to R12 comprises a radiolabel, as defined herein;

wherein the radiolabel comprises a radionuclide selected from the group consisting of 11C, 13N, 15O, 18F, 123I, 124I, 125I, 131I and 77Br;

and pharmaceutically acceptable salts thereof.

In another embodiment, there is provided a radiolabel compound of the formula VI:

wherein:

X is a bond or is selected from the group consisting of C1-6alkylenyl, —C(O)—, —C(S)—, —C(O)O—, —C(S)O—, —N(R10)C(O)—, —N(R10)C(S)—, —S(O)N(R10)— and —N(R10)S(O)2—;

Y is a bond or is selected from the group consisting of amino, halo, cyano, nitro, hydroxyl, —SR10, —C(O)NH2, —C(S)NH2, halo-C1-6alkyl, perhaloC1-6alkyl, C1-6alkyl, C3-6cycloalkyl, C3-12cycloalkylC1-5alkyl, C6-14aryl, C6-10arylC1-4alkyl, heteroaryl, C1-5alkoxy, H(OCH2CH2)1-6O—, C1-3alkyl(OCH2CH2)1-6O—, halo-C1-5alkoxy, halo-C1-3alkyl(OCH2CH2)1-6O—, halo-CH2CH2O—, C3-6cycloalkoxy, C3-12cycloalkylC1-5alkoxy, heteroarylC2-5alkoxy, C6-14aryloxy, C6-10arylC1-4alkoxy and heteroaryloxy;

R5 and R6 are each independently hydrogen or are each independently selected from the group consisting of amino, halo, cyano, nitro, hydroxyl, —SR10, —C(O)NH2, —C(S)NH2, haloC1-6alkyl, perhaloC1-6alkyl, C1-6alkyl, C3-6cycloalkyl, C3-12cycloalkylC1-5alkyl, C6-14aryl, C6-10arylC1-4alkyl, heteroaryl, C1-5alkoxy, H(OCH2CH2)1-6O—, C1-3alkyl(OCH2CH2)1-6O—, halo-C1-5alkoxy, halo-C1-3alkyl(OCH2CH2)1-6O—, halo-CH2CH2O—, C3-6cycloalkoxy, C3-12cycloalkylC1-5alkoxy, heteroarylC2-5alkoxy, C6-14aryloxy, C6-10arylC1-4alkoxy, heteroaryloxy, C1-5alkylNR10C(O)—, (C1-6alkyl)2NC(O)CH(C1-5alkyl)-, halo-C1-6alkylNR10C(O)CH(C1-5alkyl)-, halo-C1-6alkylOC(O)CH(C1-5alkyl)-, halo-C1-5alkylNR10C(O)—, C1-5alkylNR10C(O)O—, C1-5alkylC(O)—, C1-5alkylC(O)O—, C6-10arylC(O)— and C6-10arylC(O)O—; or R5 and R6 together with the carbon atoms to which they are attached to, form a substituted or unsubstituted aromatic or non-aromatic carbocyclic or heterocyclic ring;

R9 is hydrogen or is selected from the group consisting of halo, C1-6alkyl, C3-6cycloalkyl, C3-12cycloalkylC1-5alkyl, C6-14aryl, C6-10arylC1-4alkyl, heteroaryl, halo-(CH2CH2)1-6—; halo-CH2CH2—(OCH2CH2)1-6—, halo-CH2CH2—(OCH2CH2)1-6O(CO)— and halo-CH2CH2—(OCH2CH2)1-6(CO)—;

each R10 is independently H or C1-6alkyl;

R11 is a hydrogen or is selected from the group consisting of halo, C1-6alkyl, C3-6cycloalkyl, C3-12cycloalkylC1-5alkyl, C6-14aryl, C6-10arylC1-4alkyl, heteroaryl, halo-(CH2CH2)1-6—; halo-CH2CH2—(OCH2CH2)1-6—, halo-CH2CH2—(OCH2CH2)1-6O(CO)— and halo-CH2CH2—(OCH2CH2)1-6(CO)—;

provided that at least one of R1 to R11 comprises a radiolabel, as defined herein;

wherein the radiolabel comprises a radionuclide selected from the group consisting of 11C, 13N, 15O, 18F, 123I, 124I, 125I, 131I and 77Br;

and pharmaceutically acceptable salts thereof.

In another embodiment, there is provided a pharmaceutical composition for in vivo imaging of amyloid deposits.

In another embodiment, there is provided a method of diagnosing Alzheimer\'s Disease or a predisposition thereto in a mammal.

In another embodiment, there is provided a method of diagnosing Alzheimer\'s Disease or a predisposition thereto in a mammal.

In another embodiment, there is provided a method for detecting Alzheimer\'s Disease or a predisposition thereto in a living brain of a mammal.

In another embodiment, there is provided a method for treating a disease or condition, in a mammal in need thereof, selected from the group consisting of anxiety, depression, schizophrenia, Alzheimer\'s Disease, stress-related disease, panic, a phobia, obsessive compulsive disorder, obesity, post-traumatic stress syndrome, or epilepsy.

FIG. 1 shows Biacore binding assay results.

FIG. 2 shows representative scaffolds for compounds found to bind oligomer, polymers and/or fibrils.

FIG. 3A shows UV HPLC analysis of AD-CB-001P-WZ-01019 synthesis of AD-CB-002P-WZ01031.

FIG. 3B shows Gamma HPLC analysis of AD-CB-001P-WZ-01019 synthesis of AD-CB-002P-WZ01031.

FIG. 4 shows immunostaining of brain sections with thioflavin T, thioflavin T with tracer and no thioflavin T.

FIG. 5 shows immunostaining of brain sections with FDDNP, FDDNP with tracer and no FDDNP.

FIG. 6 shows coronal slices of a white rat brain using 1 min framing. After 2 minutes, the tracer concentration reaches a maximum level in the brain and is completely washed out after 7 minutes.

FIG. 7 shows amyloid autoradiography staining (ex vivo) of an AD patient\'s brain with [18F]-CB-001 shows good amyloid binding and little/no white matter binding.

FIG. 8 shows [18F]-CB001 competition studies on AD Brain slices demonstrate reversible plaque binding and competition with PiB, and little/no white matter binding.

FIG. 9 shows the optimal staining and wash protocol indicating tracer specific.

FIG. 10 shows [18F]-CB003 clearly distinguishes between Alzheimer\'s and normal brains.

FIG. 11 shows concentration-dependent blocking of [18F]-PiB tissue binding with PiB and CB003.

FIG. 12 shows surface plasmon resonance assay results of CB003 binding to Aβ42 insoluble aggregates.

FIG. 13 shows surface plasmon resonance assay results of CB003 binding to Aβ42 soluble aggregates.

FIG. 14 shows surface plasmon resonance assay results of PiB binding to Aβ42 insoluble aggregates.

FIG. 15 shows surface plasmon resonance assay results of PiB binding to Aβ42 soluble aggregates.

FIG. 16 shows surface plasmon resonance assay results of CB004 binding to Aβ42 insoluble aggregates.

FIG. 17 shows surface plasmon resonance assay results of CB004 binding to Aβ42 soluble aggregates.

FIG. 18A shows MicroPET imaging, 2 min p.i., with [18F]-CB-001 in App and WT mice demonstrates very good brain uptake.

FIG. 18B shows MicroPET imaging, 20-30 min p.i., with [18F]-CB-001 in App and WT mice demonstrates very good brain uptake.

FIG. 19 shows MicroPET imaging, 10 min, with [18F]-CB003 in WT and App mice.

FIG. 20 left panel shows MicroPET imaging analysis with [18F]-CB003 in individual WT and App mice. Right panel shows combined MicroPET imaging analysis with [18F]-CB003 in WT and App mice.

FIG. 21 shows percent increase of brain/muscle (B/M) ratio for MicroPET imaging analysis with [18F]-CB003 in WT and App mice.

FIG. 22 shows clearance of [18F]PiB in WT and App mice brain.

FIG. 23 shows clearance of [18F]-CB003 in WT and App mice brain indicates that brain clearance of [18F]-CB003 is much faster than with [18F]PiB.

DETAILED DESCRIPTION

The present invention is directed to compounds having the structural Formula I where the radicals have the meanings given above.

“Halogen” or “halo” means F, Cl, Br and I.

“Alkyl” means a saturated monovalent hydrocarbon radical having straight or branched moieties. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl and t-butyl.

“Alkenyl” means an alkyl moieties having at least one carbon-carbon double bond wherein alkyl is as defined above. Examples of alkenyl include, but are not limited to, ethenyl and propenyl,

“Alkynyl” means alkyl moieties having at least one carbon-carbon triple bond wherein alkyl is as defined above. Examples of alkynyl groups include, but are not limited to, ethynyl and 2-propynyl,

“Alkylene” or “alkenylenyl” means a saturated, divalent hydrocarbon radicals i.e., generally present as a bridging or linking group between two other groups, having straight or branched moieties. Examples of alkylene groups include —CH2— (methylene); —CH2CH2— (ethylene); —CH2CH2CH2— (propylene), —CH(CH3)CH2— (isopropylene) etc.

“Amino” means a nitrogen moiety having two further substituents where a hydrogen or carbon atom is attached to the nitrogen. For example, representative amino groups include —NH2, —NHCH3, —N(CH3)2, —N(C2-3-alkyl)2 and the like. Unless indicated otherwise, the compounds of the invention containing amino moieties may include protected derivatives thereof. Suitable protecting groups for amino moieties include acetyl, tert-butoxycarbonyl, benzyloxycarbonyl and the like.

“Aryl” means an organic radical derived from an aromatic hydrocarbon by removal of one hydrogen, such as phenyl, naphthyl, indenyl, indanyl and fluorenyl. “Aryl” encompasses fused ring groups wherein at least one ring is aromatic.

“Cycloalkyl” means non-aromatic saturated cyclic alkyl moieties consisting of one or more rings, wherein said rings (if more than one) share at least one carbon atom, wherein alkyl is as defined above. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclo-[3.1.0]-hexyl, bicyclo-[2.2.1]-hept-1-yl, norbornyl, spiro[4.5]decyl, spiro[4.4]nonyl, spiro[4.3]octyl, spiro[4.2]heptyl and adamantanyl.

“HaloC1-6alkyl” means a C1-6alkyl group that is substituted with at least one halogen atom on a carbon atom of the alkyl group. Non-exclusive, representative examples of such haloC1-6alkyl include F—CH2—, F—CH2CH2—, F—CH2CH2CH2—, CHF2—, CHF2CH2—, CHF2CH2CH2—, Br—CH2—, Br—CH2CH2—, Br—CH2CH2CH2—, CHBr2—, CHBr2CH2—, CHBr2CH2CH2— and the like.

“Heterocyclic” or “hetemcycloalkyl” means a non-aromatic cyclic groups consisting of one or more rings, wherein the rings (if more than one) share one or two atoms and each ring contains up to four heteroatoms (i.e. from zero to four heteroatoms, provided that at least one ring contains at least one heteroatom). The heterocyclic groups of this invention can also include ring systems substituted with one or more O, S(O)0-2, and/or N—R10 as heteroatoms, wherein R10 is as defined herein, and wherein the subscript “0-2” of S(O)0-2 represents an integer of 0, 1 or 2. Thus, S(O)2 represents the group consisting of S, S(═O), and S(O)2. Examples of non-aromatic heterocyclic groups are aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, azepinyl, piperazinyl, 1,2,3,6-tetrahydropyridinyl, oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholino, thiomorpholino, thioxanyl, pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl, quinolizinyl, quinuclidinyl, 1,4-dioxaspiro[4.5]decyl, 1,4-dioxaspiro[4.4]nonyl, 1,4-dioxaspiro[4.3]octyl and 1,4-dioxaspiro[4.2]heptyl.

“Heteroaryl” means an aromatic group containing one or more heteroatoms (O, S, or N), preferably from one to four heteroatoms. A heteroaryl may be a monocyclic or a polycyclic group. Examples of heteroaryl groups are pyridinyl, pyridazinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, quinolyl, isoquinolyl, 1,2,3,4-tetrahydroguinolyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, indolyl, benzimidazolyl, benzofuranyl, indazolyl, indolizinyl, phthalazinyl, triazinyl, 1,3,5-triazinyl, isoindolyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzotriazolyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, dihydroquinolyl, tetrahydroquinolyl, dihydroisoquinolyl, tetrahydroisoquinolyl, benzofuryl, furopyridinyl, pyrolopyrimidinyl and azaindolyl. In certain aspects of the present application, the heteroaryl is a 4-substituted-1H-1,2-3-triazol-1-yl.

As used herein, where a divalent group, such as a linker for example, is represented by a structure -A-B—, as shown below, it is intended to also represent a group that may be attached in both possible permutations, as noted in the two structures below.

For example, when a divalent group such as the group “—N(R10)C(O)—” is provided, for example, the group is intended to also include both the divalent group —N(R10)C(O)— and also the divalent group —C(O)N(R10)—.

The substituents or the groups C1-6alkyl, C3-6cycloalkyl, C3-12cycloalkylC1-5alkyl, C6-14aryl, C6-14aryloxy, C6-10arylC1-4alkyl, heteroaryl, heteroaryloxy etc . . . of the variables R1, R2, R3, R4, R5, R6, R7, R8, R9 and R10 are also optionally further substituted by substituents selected from the group consisting of amino, halo, cyano, nitro, hydroxyl, —SH, —SC1-6alkyl, —C(O)NH2, —C(S)NH2, perhaloC1-6alkyl, C1-6alkyl, C3-6cycloalkyl, C3-12cycloalkyl, C6-14aryl and heteroaryl.

For example, in certain aspect of the present application, the heteroaryl substituent is a 4-substituted-1H-1,2-3-triazol-1-yl. In the radiolabeled compounds of the present application, a radionuclide may be attached to an aryl group of the compound of Formulae I to VI, as in a 2-18F-′carbazole derivative such as the compound represented as:

or a 2-(18F-fluoroethyl)-′carbazole, 2-(18F-fluoromethyl)-′carbazole, a 11C-methoxy- group, for example, and/or the radionuclide may be attached to any one or more of the variables R1, R2, R3, R4, R5, R5, R7, R8, R9 and R10 by way of a 18F-fluoroethyl- group, a 18F-fluoromethyl- group, a 11C-methoxy- group, 4-[(18F-fluoroethyl)-1H-1,2-3-triazol-1-yl]-ethoxy- group, 4-[(18F-fluoroethyl)-1H-1,2-3-triazol-1-yl]-propyloxy- group, a 123I, a 124I, a 125I or a 131I, and the group like. Unless otherwise noted, a compound represented as being substituted by an atom, such as the generic representation by the atom fluorine in F—CH2CH2-(′carbazole) or F—CH2CH2O-(′carbazole), for example, is intended to cover both the naturally occurring element 19F (fluorine-19) as well as the 18F (fluorine-18) isotope(s) of the element itself.

The term “optionally substituted” or “substituted” refers to the specific substituents or groups wherein one to four hydrogen atoms in the group may be replaced by one to four substituents, for example, independently selected from the substituents amino, halo, cyano, nitro, hydroxyl, —SH, —SC1-6alkyl, —C(O)NH2, —C(S)NH2, haloC1-6alkyl, perhaloC1-6alkyl, C1-6alkyl, C3-6cycloalkyl, C3-12cycloalkyl, C6-14aryl and heteroaryl, or as specifically disclosed herein. In addition, the substituents may also include alkyl, aryl, alkylene-aryl, hydroxy, alkoxy, aryloxy, perhaloalkoxy, heterocyclyl, azido, amino, guanidino, amidino, halo, alkylthio, oxo, acylalkyl, carboxy esters, carboxyl, carboxamido, acyloxy, aminoalkyl, alkylaminoaryl, alkylaminoalkyl, alkoxyaryl, arylamino, phosphono, sulfonyl, carboxamidoaryl, hydroxyalkyl, haloalkyl, alkoxyalkyl and perhaloalkyl. In addition, the term “optionally substituted” or “substituted” in reference to the variables R1, R2, R3, R4, R5, R6, R7, R8, R9 and R10, includes groups substituted by one to four substituents, as identified above, that further comprise a positron or gamma emitter. Such positron emitters include, but are not limited to, 11C, 13N, 15O, 18F, 123I, 124I, 125I, 131I and 77Br.

The term “radiolabeled compound” as used herein refers to compounds having an atom or group that may provide a radiolabel or may be converted to a radiolabel, such as from a non-radioactive atom to a radionuclide that is active, such as for example, 11C, 13N, 15O, 18F, 123I, 124I, 125I, 131I and 77Br. In addition, for the purpose of the present application, such “radiolabeled compound” may also refer to an atom or a group, that comprises a non-active nuclide, such as a halogen, such as 19F for example, wherein the compound may be used and administered in a therapeutically effective amount.

Compounds of the Formula I to Formula VI may have optical centers and therefore may occur in different enantiomeric and diastereomeric configurations. The present invention includes all enantiomers, diastereomers, and other stereoisomers of such compounds of the Formula I to Formula VI, as well as racemic compounds and racemic mixtures and other mixtures of stereoisomers thereof. Pharmaceutically acceptable salts of the compounds of Formula I to Formula VI include the acid addition and base salts thereof. Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include, but are not limited to, the acetate, adipate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulphate/sulphate, borate, citrate, formate, fumarate, gluconate, glucuronate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, lactate, malate, maleate, malonate, mesylate, methylsulphate, naphthylate, oxalate, palmitate, phosphate/hydrogen phosphate/dihydrogen phosphate, pyroglutamate, salicylate, stearate, succinate, sulfonate, tartrate, tosylate and trifluoroacetate salts. Suitable base salts are formed from bases which form non-toxic salts. Examples include, but are not limited to, the aluminum, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, potassium, sodium, tromethamine and zinc salts. Hemisalts of acids and bases may also be formed, for example, hemisulphate and hemicalcium salts. For a review on suitable salts, see Handbook of Pharmaceutical Salts: Properties, Selection, and Use by Stahl and Wermuth (Wiley-VCH, 2002). Pharmaceutically acceptable salts of compounds of Formula I to Formula VI may be prepared by one or more of three methods: (i) by reacting the compound of Formula I to Formula VI with the desired acid or base; (ii) by removing an acid- or base-labile protecting group from a suitable precursor of the compound of Formula I to Formula VI; or (iii) by converting one salt of the compound of Formula I to Formula VI to another salt by the reaction with an appropriate acid or base or by means of a suitable ion exchange column.

In one embodiment, there is provided a radiolabeled compound of the Formula I to Formula VI: