4-(2´-Methoxyphenyl)-1-[2´-(N-2´´-1,3 pyrimidino)- p-[18F]fluorobenzamido]ethylpiperazine

Excerpt

4-(2´-Methoxyphenyl)-1-[2´-(N-2´´-1,3 pyrimidino)-p-[¹⁸F]fluorobenzamido]ethylpiperazine ([¹⁸F]FPWAY) is a radioligand developed for positron emission tomography (PET) imaging of serotonin-1A (5-HT_1A) receptors in the central nervous system (1, 2). It is a selective 5-HT_1A antagonist labeled with ¹⁸F, a positron emitter with a physical t_½ of 109.7 min (3, 4).

The serotonin (5-hydroxytryptamine (5-HT)) neurotransmission system consists mainly of neurons in the brainstem, with nerve tracts extending from these neurons to many areas of the brain and spinal cord. During firing, the neurons 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. 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. 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 and septum). 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. 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. Various compounds have been radiolabeled for visualization and quantification of these receptors. 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. The short t_½ of ¹¹C also presents some challenges in clinical application of the radiotracer. A radioligand with slower metabolism and labeled with a longer-lived radioisotope would be a better agent for quantitative PET studies. A number of fluorinated derivatives of WAY 100635 have been developed. In 2000, Lang et al. (5) synthesized [¹⁸F]FPWAY with labeling at the carboxamide moiety to minimize metabolites that cross the blood-brain barrier (BBB). [¹⁸F]FPWAY appears to be an intermediate-affinity antagonist of the 5-HT_1A receptors and may be more sensitive to transient changes in endogenous 5-HT_1A levels than high-affinity analogs (6). In this WAY 100635 analog, the pyridine ring is replaced by pyrimidine and the cyclohexane ring is replaced by fluorobenzyl. With ¹⁸F in the 4 position of the benzamide, [¹⁸F]FPWAY is a very different compound from another WAY 100635 analog with a similar abbreviation, [¹⁸F]6FPWAY, which was synthesized by Marchais et al. (7). [¹⁸F]6FPWAY contains a N-pyridine with ¹⁸F in the 6 position of the pyridine moiety.