(+)-(2 S,3 S)-3-(2-[11C]Methoxybenzylamino)-2-phenylpiperidine

Excerpt

(+)-(2S,3S)-3-(2-[¹¹C}Methoxybenzylamino)-2-phenylpiperidine ([¹¹C]CP-99,994) 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 an aromatic or a 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) receptors. 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 that target NK₁ receptors can visualize and allow the study of the 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).

Snider et al. (7) developed CP-96,345, a potent nonpeptide antagonist of the NK₁ receptor, and showed that ³H-labeled CP-96,345 distributed in a similar CNS pattern similar to ³H-labeled SP in guinea pigs. Desai et al. (8) proposed that the position of the inner phenyl ring of the benzhydryl group relative to the C-3 benzylamino group in CP-96,345 was important for activity. On the basis of this observation, they synthesized CP-99,994, a similar nonpeptide compound with better CNS penetration. Livni et al. (1) first described the CP-99,994 radiolabeled with ¹¹C as a potential PET imaging agent and evaluated its in vivo biodistribution in hamsters.