Transient receptor potential (TRP) channels are non-selective cation channels that are activated by a variety of stimuli. Numerous members of the ion channel family have been identified to date, including the cold-menthol receptor, also called TRP M8 (McKemy, D. D., et. al., Nature 2002, 416(6876), 52-58). Collectively, the TRP channels and related TRP-like receptors connote sensory responsivity to the entire continuum of thermal exposure, selectively responding to threshold temperatures ranging from noxious hot through noxious cold as well as to certain chemicals that mimic these sensations. Specifically, TRP M8 is known to be stimulated by cool to cold temperatures as well as by chemical agents such as menthol and icilin, which may be responsible for the therapeutic cooling sensation that these agents provoke.
TRP M8 is located on primary nociceptive neurons (A-delta and C-fibers) and is also modulated by inflammation-mediated second messenger signals (Abe, J., et al., Neurosci Lett 2006, 397(1-2), 140-144; Premkumar, L. S., et al., J. Neurosci, 2005, 25(49), 11322-11329). The localization of TRPM8 on both A-delta and C-fibers may provide a basis for abnormal cold sensitivity in pathologic conditions wherein these neurons are altered, resulting in pain, often of a burning nature (Kobayashi, K., et al., J Comp Neurol, 2005, 493(4), 596-606; Roza, C., et al., Pain, 2006, 120(1-2), 24-35; and Xing, H., et al., J Neurophysiol, 2006, 95(2), 1221-30). Cold intolerance and paradoxical burning sensations induced by chemical or thermal cooling closely parallel symptoms seen in a wide range of clinical disorders and thus provide a strong rationale for the development of TRP M8 modulators as novel antihyperalgesic or antiallodynic agents. TRP M8 is also known to be expressed in the brain, lung, bladder, gastrointestinal tract, blood vessels, prostate and immune cells, thereby providing the possibility for therapeutic modulation in a wide range of maladies.
Non-invasive nuclear imaging techniques can be used to obtain basic and diagnostic information about the physiology and biochemistry of living subjects, including experimental animals, humans and patients. These techniques rely on the use of imaging instruments that can detect radiation emitted from radiotracers administered to the living subjects. The information obtained can be reconstructed to provide planar and tomographic images which reveal the distribution and/or concentration of the radiotracer as a function of time.
Positron emission tomography (PET) is a non-invasive imaging technique that offers the highest spatial and temporal resolution of all the nuclear medicine imaging modalities and has the added advantage that it can allow for true quantitation of tracer concentration in tissues. The technique involves the use of radiotracers, labeled with positron emitting radionuclides. Radiotracers are designed to have in vivo properties which permit measurement of parameters regarding the physiology or biochemistry of a variety of processes in living tissue.
Compounds can be labeled with positron or gamma emitting radionuclides. The most commonly used positron emitting radionuclides are 15O, 13N, 11C and 18F, which are accelerator produced and have half lives of 2, 10, 20 and 110 minutes, respectively. The most widely used gamma emitting radionuclides are 99mTc, 201Tl and 123I.
There remains a need for radiolabelled ligands which bind to the TRP M8 receptor in the central and/or peripheral nervous system, for example in brain and/or spinal cord, of a subject.