title: Synthesis and autoradiographic evaluation of a novel high-affinity Tc-99m ligand for the 5-HT2A receptor.
abstract: The synthesis and in vitro autoradiography of a novel Tc-99m ligand with subnanomolar affinity to the 5-HT2A receptor is reported. The complex combines the 4-(4-fluoro)-benzoyl piperidine portion derived from the 5-HT2A receptor antagonist ketanserin with a neutral oxotechnetium(V) chelate in form of a mixed ligand "3 + 1" unit containing the SNS/S donor set. The analogous rhenium compound has been synthesized as a surrogate for the Tc-99m complex for use in receptor binding assays and for complete structural characterization. In competition experiments the Tc-99 complex as well as its Re analogue display subnanomolar affinity toward the 5-HT2A receptor (Ki 0.44 nM for Tc, 0.25 nM for Re). The subnanomolar 5-HT2A receptor binding of the Re complex was confirmed by functional in vitro antagonism of contractile effects evoked by 5-HT in rat arterial tissue. Re 1 inhibited 5-HT-induced, 5-HT2A receptor-mediated contractions of isolated rat tail artery in a competitive fashion and possessed nanomolar affinity (pA2 = 9.08, pA2 representing the negative decadic logarithm of the Re 1/5-HT2A-receptor dissociation constant [mol/L]). Like ketanserin, Re 1 displayed moderate affinity for adrenergic alpha1D (pA2 = 8.23) and histamine H1 receptors (pA2 = 8.00), and was >600-fold up to 10,700-fold less active at several neurotransmitter receptor subtypes. In vitro autoradiographic studies clearly indicate the accumulation of the Tc-99m compound in 5-HT2A-receptor-rich areas of the brain. This enrichment can be blocked by 5-HT2A receptor antagonists such as mianserin and ketanserin and is therefore specific.
authors.affiliation: Forschungszentrum Rossendorf, Institut für Bioanorganische und Radiopharmazeutiscihe Chemie, Dresden, Germany.
authors.forename: H J
authors.initials: HJ
authors.lastname: Pietzsch
authors.forename: M
authors.initials: M
authors.lastname: Scheunemann
authors.forename: M
authors.initials: M
authors.lastname: Kretzschmar
authors.forename: S
authors.initials: S
authors.lastname: Elz
authors.forename: H H
authors.initials: HH
authors.lastname: Pertz
authors.forename: S
authors.initials: S
authors.lastname: Seifert
authors.forename: P
authors.initials: P
authors.lastname: Brust
authors.forename: H
authors.initials: H
authors.lastname: Spies
authors.forename: R
authors.initials: R
authors.lastname: Syhre
authors.forename: B
authors.initials: B
authors.lastname: Johannsen
mesh_terms: D000818:Animals; D001345:Autoradiography; D001921:Brain / Q000033:anatomy & histology / Q000378:metabolism; D007650:Ketanserin / Q000031:analogs & derivatives / Q000494:pharmacology; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D019275:Radiopharmaceuticals / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D051381:Rats; D017208:Rats, Wistar; D044402:Receptor, Serotonin, 5-HT2A; D011954:Receptors, Dopamine / Q000187:drug effects; D011985:Receptors, Serotonin / Q000187:drug effects*; D012702:Serotonin Antagonists / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D013667:Technetium / Q000737:chemistry; D014018:Tissue Distribution
chemical_list: D008024:Ligands; D019275:Radiopharmaceuticals; D044402:Receptor, Serotonin, 5-HT2A; D011954:Receptors, Dopamine; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D013667:Technetium; D007650:Ketanserin