[ carbonyl-11C](R, S)-(N-(2-(1-(4-(2-Methoxyphenyl)piperazinyl)(2-methylethyl)))- N-pyridinyl)cyclohexanecarboxamide

Excerpt

[carbonyl-¹¹C](R,S)-(N-(2-(1-(4-(2-Methoxyphenyl)piperazinyl)(2-methylethyl)))-N-pyridinyl)cyclohexanecarboxamide ([carbonyl-¹¹C](R,S)-JWAY) is a radioligand developed for positron emission tomography (PET) imaging of serotonin-1A (5-HT_1A) receptors in the central nervous system (1). It is a selective 5-HT_1A antagonist labeled with ¹¹C, a positron emitter with a physical t_½ of 20.4 min (2).

The serotonin (5-hydroxytryptamine (5-HT)) neurotransmission system comprises mainly neurons in the brainstem, with nerve tracts extending from these neurons to many areas of the brain and spinal cord (3). When neurons fire, they release 5-HT, a neurotransmitter that is involved in the modulation of various important physiologic functions and behavior, such as thermoregulation, cardiovascular function, aggressive and sexual behavior, mood, appetite, and the sleep–wake cycle (4). The effects of 5-HT are mediated by as many as seven classes of receptor populations (5-HT₁ to 5-HT₇), many of which also contain several subtypes (5). There are five receptor subtypes within the G protein-coupled 5-HT₁ receptor family, with the 5-HT_1A subtype located primarily in the limbic forebrain (the hippocampus, entorhinal cortex ,septum, and raphe) (4, 5). 5-HT_1A receptors appear to function both as presynaptic (somatodendritic) autoreceptors in the raphe nuclei and as postsynaptic receptors in the terminal fields. This receptor subtype is involved in the modulation of emotion and the function of the hypothalamus, and is implicated in the pathogenesis of anxiety, depression, hallucinogenic behavior, motion sickness, dementia, schizophrenia, and eating disorders (6). A radioligand that can be used to assess the in vivo densities of 5-HT_1A receptors and their changes may facilitate investigation of the relationship of these receptors to various neuropsychiatric diseases and aid in the design of novel drugs for their treatment.

Many psychiatric drugs modulate serotonergic transmission or specifically target the 5-HT_1A receptors (2). Various compounds have been radiolabeled for visualization and quantification of these receptors (7). WAY 100635 was developed as a highly selective, silent antagonist (possessing no intrinsic agonist activity) of 5HT_1A receptors at both pre- and postsynaptic sites. WAY 100635 radiolabeled with ¹¹C at the carbonyl position is an effective radioligand but it is rapidly cleared and metabolized. Analogs of WAY100635 bearing bulkier cycloalkylcarbonyl groups appear to be more resistant to amide hydrolysis. However, the added lipophilicity also reduces receptor affinity (8). McCarron et al. (1) proposed adding a smaller group to WAY-100635 for less impact on lipophilicity and receptor affinity. They synthesized (R,S)-JWAY by adding a methyl group (α-carbon position to the carbonyl group) on the ethyl side chain of WAY100635. This WAY-100635 analog was radiolabeled with ¹¹C and evaluated with PET in a monkey. The radioligand gave a high 5-HT_1A receptor-selective PET signal, but the added methyl group did not appear to have the desired influence on the rate of metabolism.