[C]-[-Methyl]3-[(3-fluorophenyl)sulfonyl]-8-(4-methyl-1-piperazinyl)quinoline

Serotonin (5-hydroxytryptamine; 5-HT), a derivative of the tryptophan amino acid, is a low molecular weight neurotransmitter that plays an important role in the functioning of different physiological, cognitive, and emotional processes. Impairment of the serotonergic system is associated with psychiatric disorders, such as anxiety and depression, and neurological afflictions, such as Parkinson’s disease, Alzheimer’s disease, and epilepsy (1). The 5-HT mediates its biological activity through a group of seven receptors (5-HTR) that are further classified into 14 distinct subtypes on the basis of their structure and pharmacological activity. Except for the 5-HTR, which is a ligand-gated ion channel, all other 5-HTRs belong to the family of G-protein–coupled seven-transmembrane receptors (2). Radiolabeled tracers have been developed for use with positron emission tomography (PET) to study the different 5-HTR subtypes, and much information is available regarding only the 5-HTR, 5-HTR, 5-HTR, and 5-HTR subtypes (3). Compared to the discovery of the other 5-HTR subtypes, the identification of 5-HTR is fairly recent, and this receptor is located mostly in the limbic and cortical regions of the mammalian central nervous system (4). Although the exact mechanism of action of the 5-HTR is not clear, there are indications that antagonists of this receptor reverse amnesia and improve cognitive and memory functions in individuals suffering from schizophrenia, Parkinson's disease, or Alzheimer’s disease (5). Therefore, it was imperative to develop a ligand that could be used to study the biological characteristics of this receptor. Radioiodinated SB-258585 ([I]-SB258585), a selective antagonist of the 5-HTR, has been shown to have a high affinity for this receptor in membranes derived from rat or pig striatum and human caudate putamen (6). Autoradiography of rat brain sections exposed to [I]-SB258585 revealed that the 5-HTR was located primarily in the striatum, followed by the cerebral cortex; accumulation was lowest in the cerebellum of these animals. From this observation, the investigators concluded that the receptor was probably involved in cognition, memory, and locomotor control functions in the animals (7). In another study, [-methyl]3-[(3-fluorophenyl)sulfonyl]-8-(4-methyl-1-piperazinyl)quinoline (GSK215083) was reported to have a 5-fold and >55-fold higher subnanomolar concentration affinity for the 5-HTR compared to the concentrations required for the 5-HTR and the other 5-HTRs, respectively (3). In addition, the lipophilicity of GSK215083 was determined to be suitable for crossing the blood–brain barrier and penetration into the brain. On the basis of these observations, [C]-GSK215083 was evaluated as a 5-HTR ligand in pigs, non-human primates, and humans (3).