Novel oxorhenium and oxotechnetium MO(NS)(S) 2 complexes in the development of 5-HT 1A receptor imaging agents

Abstract

The [NS][S] 2 mixed-ligand system was applied to synthesize oxorhenium and oxotechnetium complexes of the general formula MO( o-CH 3OC 6H 4N(CH 2CH 2) 2NCH 2CH 2S)( p-CH 3C 6H 4S) 2 (M=Re in 1, M= 99Tc in 2, and M= 99mTc in 3). The bidentate [NS] ligand includes the 1-(2-methoxyphenyl)piperazine moiety which is a fragment of the true 5-HT 1A antagonist WAY 100635. The oxorhenium complex 1 was prepared by a ligand exchange reaction using ReOCl 3(PPh 3) 2 as precursor while [Bu 4N][ 99TcOCl 4] and 99Tc-gluconate were used as precursors in the synthesis of the oxotechnetium-99 complex 2. Both complexes were characterized by elemental analysis and spectroscopic methods. Crystallographic analysis of 1 showed that the rhenium coordination geometry is trigonal bipyramidal. The basal plane of the trigonal bipyramid is defined by the oxo group and two sulphur atoms, one belonging to the [NS] ligand and the other to an aromatic thiol, while the apical positions are occupied by the nitrogen of the [NS] ligand and the sulphur of the second aromatic thiol. The oxotechnetium-99 complex 2 has almost identical unit cell parameters to those of the oxorhenium complex 1 indicating, in combination with the other analytical data, that the complexes are isostructural. The binding affinity of the oxorhenium complex 1 for the 5-HT 1A receptor subtype was determined in rat brain hippocampal preparations (IC 50=106 nM). The oxotechnetium-99m complex 3 was prepared by a ligand exchange reaction using 99mTc-glucoheptonate as the precursor. Its structure was established by comparative HPLC studies using the oxotechnetium-99 complex 2 as a reference. Complex 3 was administered by intravenous injection in rats. At 2 min post injection, 0.153% of the injected dose per gram of tissue was measured in rat brain.