[2-[18F]Fluoromethoxy-5-(5-trifluoromethyl-tetrazol-1-yl)-benzyl]([2 S,3 S]2-phenyl-piperidin-3-yl)-amine

Excerpt

[2-[¹⁸F]Fluoromethoxy-5-(5-trifluoromethyl-tetrazol-1-yl)-benzyl]([2S,3S]2-phenyl-piperidin-3-yl)-amine ([¹⁸F]SPA-RQ) is a radioligand developed for positron emission tomography (PET) imaging of NK₁ receptors (SP receptors) in the central nervous system (CNS) (1).

Tachykinins are 10-12 amino acid peptides 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 substance P (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: neurokinin 1 (NK₁, formerly the SP receptor), neurokinin 2 (NK₂, formerly the substance K/substance E receptor/NK-A receptor), and neurokinin 3 (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 have shown that in the brain SP is found throughout the neocortex, in limbic areas, habenula, periaqueductal gray, midbrain nuclei, and 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 CNS and 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 NK₁ receptors can visualize and study 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). A number of NK₁ selective agonists and antagonists have been successfully labeled, but they failed to provide a specific signal in vivo (1, 6). Solin et al (1). developed a selective NK₁ receptor antagonist, SPA-RQ, with a high affinity for NK₁ receptor (IC₅₀ = 67 pM) and moderate lipophilicity (logP = 1.8).