(2 S,3 S)-(2-[11C]Methoxy-5-tetrazol-1-ylbenzyl)(2-phenylpiperidin-3-yl)amine

Excerpt

(2S,3S)-(2-[¹¹C]Methoxy-5-tetrazol-1-ylbenzyl)(2-phenylpiperidin-3-yl)amine ([¹¹C]GR203040) is a radioligand developed for positron emission tomography (PET) imaging of neurokinin 1 (NK₁) receptors [substance P (SP) receptors] in the central nervous system (CNS) (1).

Tachykinins are peptides comprising 10−12 amino acids that share a common carboxy-terminal sequence “Phe-X-Gly-Leu-Met-amide” where “X” may vary but is always a hydrophobic residue that is either aromatic or β-branched aliphatic (2-4). This peptide family consists of SP, neurokinin A (NK_A), and neurokinin B (NK_B). The tachykinin peptides mediate their effects by specific G protein−coupled receptors. These receptors are divided into three subtypes: NK₁, (formerly the SP receptor), NK₂ (formerly the substance K/substance E receptor/NK_A receptor), and NK₃ (formerly the NK_B receptor). The effects of SP are mediated primarily via the NK₁ 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 SP is found in the neocortex, 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 NK₁ receptors in the brain generally corresponds to that of SP.

SP-NK₁ 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 computed tomography of radioligands targeting NK₁ receptors can visualize and allow the study of CNS NK₁ 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 NK₁ selective agonists and antagonists have been successfully labeled, but they failed to provide a specific signal in vivo (6, 7). Ward et al. (8) reported the antiemetic, pharmacokinetic, and metabolic profile of the potent NK₁ receptor antagonist CP-99,994. They also reported that a tetrazolyl-substituted analog, GR203040, had high metabolic stability, low lipophilicity, and high NK₁ receptor affinity. ¹¹C-labeled GR205171 and its trifluoromethyl analog, [¹¹C]GR205171, were studied to be used as a PET ligand to characterize NK₁ receptor binding (1).