Synthesis and autoradiographic evaluation of a novel high-affinity Tc-99m ligand for the 5-HT2A receptor

The synthesis and in vitro autoradiography of a novel Tc-99m ligand with su bnanomolar affinity to the 5-HT2A receptor is reported. The complex combine s the 4-(4-fluoro)-benzoyl piperidine portion derived from the 5-HT-induced , 5-HT2A receptor antagonist ketanserin with a neutral oxotechnetium(V) che late 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 structu ral characterization. In competition experiments the Tc-99 complex as well as its Re analogue display subnanomolar affinity toward the 5-HT2A receptor (K-i 0.44 nM for Tc, 0.25 nM for Re). The subnanomolar 5-HT2A receptor bin ding of the Re complex was confirmed by functional in vitro antagonism of c ontractile effects evoked by 5-HT in rat arterial tissue. Re 1 inhibited 5- HT-induced, 5-HT2A receptor-mediated contractions of isolated rat tail arte ry in a competitive fashion and possessed nanomolar affinity (pA(2) = 9.08, pA(2) representing the negative decadic logarithm of the Re 1/5-HT2A-recep tor dissociation constant [mol/L]). Like ketanserin, Re 1 displayed moderat e affinity for adrenergic alpha(1D) (pA(2) = 8.23) and histamine H-1 recept ors (pA(2) = 8.00), and was >600-fold up to 10,700 fold less active at seve ral neurotransmitter receptor subtypes. In vitro autoradiographic studies c learly 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. (C) 2000 Elsevier Science Inc. All rights reserved.