Synthesis of novel 6-nitroquipazine analogs for imaging the serotonin transporter by positron emission tomography

A positron emission tomography (PET) imaging agent that can effectively quantify the serotonin transporter (SERT) in brain regions with moderate to low densities of SERT has yet to be identified. The recent literature has suggested that the need for such an agent may be filled by a selective, high affinity SERT ligand that displays extended in vivo kinetic profiles, concurrent with a reduction of in vivo nonspecific binding. Recently, our group has identified 2'-alkyl-6-nitroquipazine analogs as novel SERT ligands displaying very high affinity for SERT (picomolar concentration range). We have utilized the 6-nitroquipazine molecular construct for the development of new SERT PET imaging agents, by generating a series of racemic 2'-alkyl-6-nitroquipazine analogs that can incorporate the carbon-11 or the longer-lived fluorine-18 radionuclides. We expect that the increased SERT affinity of our new ligands will afford more efficacious SERT PET agents that can effectively quantify low density SERT regions in living brain.;A large focus of the present study was to expand our initial racemic lead agents by synthesizing each of them in enantiomerically pure form. Our synthetic strategy utilized an efficient asymmetric synthesis of the piperazine head-group from amino acid starting materials. The syntheses afforded non-radiolabelled target ligands and the appropriate radioligand precursors in good yields. Preliminary pharmacological data suggests a marked difference in binding affinity between the enantiomers of our agents. Furthermore, using racemic amino acids and the same asymmetric synthetic strategy, we were also able to generate novel 2'-aryl-6-nitroquipazine analogs that were not synthetically accessible using our derived methods for the 2'-alkyl agents.;The racemic radiotracer [18F]2'-(3-fluoropropoxymethyl)-6-nitroquipazine agent was synthesized and evaluated in rat for initial radiotracer distribution. The studies in rat have demonstrated favorable accumulation of the tracer in the brain indicating efficient passage through the blood brain barrier. Furthermore, these studies indicate the greatest concentration of radiotracer in regions of the brain with known SERT density. The studies of the initial, racemic tracer have shown that [18F]2'-(3-fluoropropoxymethyl)-6-nitroquipazine demonstrates potential as a new SERT PET imaging agent.