[ O-methyl-11C]2-{4-[4-(7-Methoxynaphthalen-1-yl)piperazin-1-yl]butyl}-4-methyl-2 H-[1,2,4]triazine-3,5-dione

Excerpt

[O-methyl-¹¹C]2-{4-[4-(7-Methoxynaphthalen-1-yl)piperazin-1-yl]butyl}-4-methyl-2H-[1,2,4]triazine-3,5-dione ([¹¹C]MPT) is a radioligand developed for positron emission tomography (PET) imaging of serotonin-1A (5-hydroxytryptamine 1A (5-HT_1A)) receptors in the central nervous system (1). It is a selective 5-HT_1A agonist labeled with ¹¹C, a positron emitter with a physical half-life (t_½) of 20.4 min (1, 2).

The 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). 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 (4). 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 it 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). 5-HT_1A receptors appear to exist in the high (HA) and low (LA) agonist affinity states. Antagonist ligands bind to both the HA and LA conformations, whereas agonist ligands bind to the HA state, which is coupled to G-protein. WAY 100635 was developed as a highly selective, silent antagonist (possessing no intrinsic agonist activity) of 5-HT_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 WAY 100635 that bear bulkier cycloalkylcarbonyl groups appear to be more resistant to amide hydrolysis. However, the added lipophilicity also reduces receptor affinity (8). Although 5-HT_1A receptor agonist ligands can elicit pharmacologic effects, there are some distinct potential applications of radiolabeled 5-HT_1A receptor agonist ligands because they behave like serotonin, which binds preferentially to the HA sites (1, 9). Kumar et al. (1) selected MPT for development as a radiolabeled 5-HT_1A receptor agonist probe because of its high affinity (pK_i = 10.49) and favorable calculated lipophilicity (clogP = 1.8) (10, 11)