(2,3)--[[2-[C]Methoxy-5-[5-(trifluoromethyl)tetrazol-1-yl]phenyl]methyl]-2-phenyl-piperidin-3-amine

(2,3)--[[2-[C]Methoxy-5-[5-(trifluoromethyl)tetrazol-1-yl]phenyl]methyl]-2-phenyl-piperidin-3-amine ([C]GR205171) is a radioligand developed for positron emission tomography (PET) imaging of NK receptors (substance P (SP) receptors) in the central nervous system (CNS) (1). Tachykinins are peptides comprising 10 to12 amino acids that share a common carboxy-terminal sequence “Phe-X-Gly-Leu-Met-amide” where “X” is different but always a hydrophobic residue that is either an aromatic or a beta-branched aliphatic (2-4). This peptide family consists of SP, neurokinin A (NK), and neurokinin B (NK). The tachykinin peptides mediate their effects by specific G protein-coupled receptors. These receptors are divided into three subtypes: neurokinin 1 (NK, formerly the SP receptor), neurokinin 2 (NK, formerly the substance K/substance E receptor/NK receptor), and neurokinin 3 (NK, formerly the NK receptor). The effects of SP are mediated primarily the NK receptor subtypes. There is evidence that SP behaves like a neurotransmitter involved in regulation of emotional and behavioral responses to a range of noxious and stressful stimuli (5). SP may also play a role in neurogenic inflammation, vasomotor control, and many gastrointestinal functions. Studies in the brain have shown that in the brain SP is found in the neocortex, in limbic areas, habenula, periaqueductal gray matter, midbrain nuclei, and is especially enriched in the basal ganglia. There is little SP in the cerebellum. The distribution of the NK receptors in the brain generally corresponds to that of SP. SP-NK receptor pathways are found in both the CNS and the peripheral nervous system. The CNS pathways have been implicated in the pathophysiology of pain, nausea/emesis, and depression disorders (6). PET and single-photon emission tomography of radioligands targeting NK receptors can visualize and allow the study of CNS NK receptors in normal and pathologic states. These studies can identify the degree of receptor occupancy in patients with depression and the change in response to therapy (6). A number of NK selective agonists and antagonists have been successfully labeled, but they failed to provide a specific signal (6, 7). Solin et al. (7) developed a selective NK receptor antagonist, SPA-RQ, with a high affinity for NK receptor. Gardner et al. (8) reported the discovery of a trifluoromethyl compound, GR205171, as a potent NK receptor antagonist. This compound has a high affinity for the human NK1 receptor and has a high degree of selectivity and specificity. C-labeled GR205171 shows promising potential to be used as a PET ligand to characterize NK-receptor binding (1).