title: Characterization of radioactive metabolites of 5-HT2A receptor PET ligand [18F]altanserin in human and rodent.
abstract: This study was performed to identify and characterize the radiometabolites of the serotonin 5-HT2A receptor ligand [18F]altanserin in supporting quantification of the target receptors by positron emission tomography. In analogy to its analog ketanserin, we postulated 4-(4-fluorobenzoyl)piperidine (FBP) and altanserinol for the previously observed two polar radiometabolites, corresponding to dealkylation at the piperidine nitrogen and reduction at the ketone, respectively. To test this hypothesis and characterize the in vivo and in vitro behavior of the radiometabolites, we synthesized nonradioactive authentic compounds altanserinol, 1-(4-fluorophenyl)-1-(piperidin-4-yl)methanol (FBPOH), and isolated nonradioactive FBP metabolite from monkey plasma. [18F]Altanserinol was obtained by NaBH4 reduction of [18F]altanserin, followed by acid hydrolysis. Identification of radiometabolites was carried out by high performance liquid chromatography and thin layer chromatography comparison of the radioactive plasma after injection of tracers with five authentic compounds. Human studies revealed that at least four radiometabolites, one identified as [18F]altanserinol, resulted from reduction of the ketone functionality. The N-dealkylation product [18F]FBP was not detectable; however, a radiometabolite of FBP was present in plasma after administration of [18F]altanserin. Monkey studies showed nonradioactive FBP was converted rapidly to a less polar metabolite. In rat, altanserin and altanserinol were converted to each other in vivo, and all the radiometabolites likely penetrated the blood-brain barrier and entered the brain. Displacement binding of altanserin to cloned serotonin 5-HT2A, 5-HT2C, 5-HT6, and 5-HT7 receptors showed Ki values of 0.3, 6.0, 1,756, and 15 nM; the binding of FBP and altanserinol to these four 5-HT subtypes was negligible. We conclude from these studies that the radiometabolites of [18F]altanserin from N-dealkylation and ketone reduction should not interfere with specific receptor quantification in an equilibrium paradigm.
authors.affiliation: Yale University School of Medicine, Yale-VA Pet Center, West Haven, Connecticut 06511, USA. Tan@orpheus.med.yale.edu
authors.forename: P Z
authors.initials: PZ
authors.lastname: Tan
authors.forename: R M
authors.initials: RM
authors.lastname: Baldwin
authors.forename: C H
authors.initials: CH
authors.lastname: Van Dyck
authors.forename: M
authors.initials: M
authors.lastname: Al-Tikriti
authors.forename: B
authors.initials: B
authors.lastname: Roth
authors.forename: N
authors.initials: N
authors.lastname: Khan
authors.forename: D S
authors.initials: DS
authors.lastname: Charney
authors.forename: R B
authors.initials: RB
authors.lastname: Innis
mesh_terms: D000818:Animals; D001711:Biotransformation; D001921:Brain / Q000378:metabolism; D005260:Female; D005462:Fluorine Radioisotopes / Q000493:pharmacokinetics*; D006801:Humans; D007650:Ketanserin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000493:pharmacokinetics; D010052:Ovariectomy; D010215:Papio; D019275:Radiopharmaceuticals / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D044402:Receptor, Serotonin, 5-HT2A; D011985:Receptors, Serotonin / Q000032:analysis / Q000378:metabolism*; D014018:Tissue Distribution; D014055:Tomography, Emission-Computed
chemical_list: D005462:Fluorine Radioisotopes; D019275:Radiopharmaceuticals; D044402:Receptor, Serotonin, 5-HT2A; D011985:Receptors, Serotonin; C071983:altanserin; D007650:Ketanserin