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Radioligands for the trp-m8 receptor and methods therewithRelated Patent Categories: Drug, Bio-affecting And Body Treating Compositions, Radionuclide Or Intended Radionuclide Containing; Adjuvant Or Carrier Compositions; Intermediate Or Preparatory CompositionsRadioligands for the trp-m8 receptor and methods therewith description/claimsThe Patent Description & Claims data below is from USPTO Patent Application 20070053834, Radioligands for the trp-m8 receptor and methods therewith. Brief Patent Description - Full Patent Description - Patent Application Claims
[0001] This application is a continuation-in-part of Ser. No. 10/687,188, filed Oct. 15, 2003, Inventor Wei, entitled "Radioligands for the TRP-M8 Receptor and Methods Therewith", incorporated by reference. BACKGROUND OF THE INVENTION [0002] 1. Field of the Invention [0003] This invention generally relates to chemicals that bind to receptors in the TRP (transient receptor potential) ion channel family, more particularly to the subgroup of long TRP (or TRPM) channels, and most particularly to those that specifically bind to the TRP channel called TRP-M8 (trp-p8, CMR.sub.1); TRP-M8 receptors are present in sensory nerves and activation of these receptors is associated with cool and cold sensations. These receptors are also at elevated levels in the tissues of certain cancers, such as prostate and breast cancer. This invention more particularly relates to TRP binding compositions containing radioisotopes such as radioactive fluorine and iodine .sup.18F, .sup.123I, .sup.125I, or .sup.131I, within the molecular structure, said compositions being useful, for example, in radioreceptor, diagnostic imaging, and radiotherapeutic applications. [0004] 2. Description of Related Art [0005] About two decades ago a group of scientists discovered novel compounds that have a physiological cooling action on the skin. These were described in U.S. Pat. No. 4,193,936 (Watson et al., Mar. 18, 1980), U.S. Pat. No. 4,248,859 (Rowsell et al, Feb. 3, 1981) and U.S. Pat No. 4,318,900 (Rowsell, Mar. 9, 1982). Much more recently a new physiological receptor was discovered. This 1104-amino acid protein, deciphered from the cDNA sequence, was named trp-p8 because of its structural homology to receptors of the transient receptor potential (TRP) family. The mRNA for the synthesis of this specific protein was also detected in samples of malignant prostate, mammary gland cells, melanoma, and colorectal cancer cells. The functional role, if any, of TRP-M8 receptors on malignant cells is not known. [0006] The TRP-M8 sequence of the gene/protein was published in Cancer Research (vol. 61, pg. 3760-3769, May 1, 2001. L. Tsavaler, M. H. Shapero, S. Morkowski, and R. Laus: "Trp-p8, a novel prostate-specific gene, is up-regulated in prostate cancer and other malignancies and shares high homology with transient receptor potential calcium channel proteins"). Soon afterwards it was discovered that this receptor was present in sensory neurons and transduced the sensations of cold temperatures (McKemy et al. "Identification of a cold receptor reveals a general role for TRP channels in thermosensation". Nature 416: 52-58, March 2002). Chemicals that elicit sensations of cold, such as menthol and icilin, bind to and activate the cold receptor, as measured by binding constants and by calcium influxes into the cells. [0007] A nomenclature panel composed of experts in the field has recommended the TRP-M8 designation for the cold/prostate receptor because of its structural homology to other protein receptors in this family. However, some still call this receptor trp-p8 or CMR.sub.1 (cold-menthol receptor). The tags for the TRP-M8 sequences in the NicePro TrEMBL Database are Q8R405 (mouse TRP-M8), Q8R444 (rat TRP-M8 or CMR.sub.1) and Q8TAC3 (human TRP-M8, or trp-p8). The corresponding identity tags in the GenBank are AF4811480 and AY095352 (mouse), AY072788 (rat) and AY090109 (humans). [0008] Various radioactive fluorine and iodine compounds are used in clinical oncology. For example, .sup.18F and .sup.123I are used in positron emission tomography (PET) and single-photon emission computed tomography (SPECT), respectively, for the imaging, diagnosis and staging of neoplastic disease. .sup.125I and .sup.131I are used for the treatment of cancer, especially thyroid cancer. Radioiodine compounds in thyroid therapy are remarkably effective because iodine is incorporated specifically into the thyroid hormones (thyroxin and tri-iodothyronine). Hence, the malignant cells are selectively and specifically targeted, with minimal damage to normal cells and adverse side effects. [0009] Prostate cancer is the most common cancer among men in the United States. There is no universally agreed-upon strategic plan for its diagnosis and management. Brachytherapy, a treatment well known in the art, involves the implantation of radioactive seeds directly into the prostate gland. The radioactive seeds used in brachytherapy may include iodine-125, iodine-131, palladium, radium, iridium, or cesium. Another common cancer is bladder malignancy, which will be diagnosed in an estimated 44,640 men and 15,600 women in the United State in 2004, with about 13,000 deaths from this disease. [0010] The pharmacological strategy, to bring radio-labeled compounds to specific targets in malignant cells, to improve diagnosis, or to treat certain cancers, is called targeted radiodiagnostics and targeted radiotherapy. New radiofluorinated and radioiodinated compounds useful for these applications are being sought. BRIEF SUMMARY OF THE INVENTION [0011] The present discovery provides carboxamide ligands that are usefully labeled with various radionuclides, and which have a high affinity to TRP-M8 receptors in cells and tissues. Formula 1 illustrates carboxamide ligands of this discovery. R--(C.dbd.O)--N(H or CH.sub.3)--R'--Y Formula 1 [0012] where (a) R is a branched hydrophobic carbon unit with 5 to about 14 carbon atoms, and is preferably a cycloalkane radical with one to three C.sub.1 to C.sub.5 normal or branched alkyl substituents, [0013] (b) R' is an optional carbon bridge having C.sub.1-C.sub.3 carbons which may include a hydroxy group, and [0014] (c) Y is an aromatic radical containing at least one substituent selected from R.sub.1 and R.sub.2, and at least one substituent X, wherein [0015] R.sub.1, is selected from the group hydrogen, hydroxyl, C.sub.1-C.sub.5 alkyl, C.sub.1-C.sub.3 alkoxy, C.sub.1-C.sub.3 carboxyalkyl, C.sub.1-C.sub.4 carbonylalkylester, C.sub.1-C.sub.3 oxycarbonylalkyl, C.sub.1-C.sub.3 hydroxyalkyl, [0016] R.sub.2 is selected from the group --SO.sub.2NH-pyrimidine, --SO.sub.3--(H, Me or Et), or --CH.sub.2--SO.sub.3--(H, Me or Et), acetyl, C.sub.1-C.sub.3 hydroxyalkyl, trifluoromethyl, nitro, cyano, halo, and [0017] X is selected from the group [.sup.18F]--, [.sup.123I]--, [.sup.125I]--, [.sup.131I]--[.sup.76Br]--[.sup.77Br]-- and [.sup.211At]--. [0018] In one aspect of the present invention, N-radiohaloaryl-alkylcarboxamide radioligand embodiments with specific affinity for the TRP-M8 receptor are provided (where there is no carbon bridge, R', of Formula 1). These radioactive ligands are useful to study receptor binding (and to identify new drugs that activate the TRP-M8 receptor), to conduct radioimaging and radiodiagnostics, and should be useful as radioligands for therapy. The radionuclides preferred are .sup.18F, .sup.123I 125I, or .sup.131I. The inventive [.sup.125I]-compounds are useful for laboratory tests, called radioreceptor assays. The inventive [.sup.18F], [.sup.123I], [.sup.131I]-compounds are useful for imaging of the tumor cells in vivo bearing this receptor marker, and the [.sup.125I] or [.sup.131I]-compounds are further believed potentially useful for targeted radiotherapy. [0019] Among particularly preferred compositions of this first embodiment are those including [.sup.123, 125, or .sup.131I]--N-(4'-iodo-2'-methylphenyl)-2-isopropyl-5-methylcyclohexaneca- rboxamide illustrated below as Structure 1. [0020] Also among particularly preferred compositions of the first embodiment are those that include [.sup.18F]--N-(4'-fluoro-2'-hydroxyphenyl)-2-isopropyl-2,3-dimethylbutyra- mide illustrated as Structure 2. [0021] In another aspect of this invention, N-radioisotope-labelled aryl-alkyl-alkylcarboxamide radioligands with specific affinity for the TRP-M8 receptor are provided (where the carbon bridge of R' has one, two or three carbons). Among particularly preferred compositions of the second embodiment are those that include the compound illustrated by Structure 3. [0022] In this Structure 3 compound, R' is hydroxyethyl, R.sub.1 is acetyl or --SO.sub.2NH-pyrimidine, and R.sub.2 is hydroxyl or hydroxymethyl, and X is selected from the group [.sup.18F]--, [.sup.123I]--, [.sup.125I]--, [.sup.131I]-- [.sup.76Br]-- [.sup.77Br]-- and [.sup.211At]-- [0023] In yet another aspect of the present invention, methods are provided in which a Formula 1 compound having a determinable binding for the TRP-M8 receptor and having a specific activity of about 20 Ci/mmol or greater is exposed to or contacted with a plurality of TRP-M8 receptors under conditions sufficient to permit specific binding therebetween. These methods include radioreceptor assays, diagnostic imaging and radiotherapy, particularly for the diagnosis, monitoring and potential therapy of prostate cancer. [0024] Other advantages and aspects of the present invention will be understood by reading the following detailed description and the accompanying claims. DETAILED DESCRIPTION OF THE INVENTION [0025] With reference generally to Formula 1 below, radioligands of the invention have a) a hydrogen bonding site, as exemplified by the CO and NH groups of a carboxamide, b) a hydrophobic group, as exemplified by cycloalkyl or branched aliphatic groups, and c) an aryl group that can be halogenated with radioisotopes. The hydrogen bond/hydrophobic carbon units optimize docking into the TRP-M8 binding site, and the aryl ring permits delivery of the isotope. [0026] The selected isotopes, preferably from the group .sup.18F, .sup.123I, .sup.125I, and .sup.131I, serve to either mark the location or quantity of the TRP-M8 receptor or to deliver radiation to the TRP-M8 bearing cell. [0027] Embodiments of the present invention can function as ligands for the TRP-M8 receptor and preferably have high affinity to TRP-M8 sites in cells and tissues and a specific activity of about 20 Ci/mmol or greater. 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