Novel mixed ligand technetium complexes as 5-HT1A receptor imaging agents

The synthesis, characterization and biological evaluation of two novel 3 + 1 mixed ligand Tc-99m-complexes, bearing the 1-(2-methoxyphenylpiperazine) moiety, a fragment of the true 5-HT1A antagonist WAY 100635, is reported. Complexes at tracer level ((TcO)-Tc-99m[(CH3CH2)(2)NCH2CH2N(CH2CH2S)(2)][o-CH3OC6H4N(CH2CH2)(2)NCH2CH2S], Tc-99m-1, and ((TcO)-Tc-99m[((CH3)(2)CH)(2)NCH2 CH2N(CH2CH2S)(2)][o-CH3OC6H4N (CH2CH2)(2)NCH2CH2S], Tc-99m-2, were prepared using Tc-99m-glucoheptonate as precursor. For structural characterization, the analogous oxorhenium complexes, Re-1 and Re-2, were prepared by ligand exchange reaction using ReOCl3(PPh3)(2) as precursor, and characterized by elemental analysis and spectroscopic methods. Complex Re-1 was further characterized by crystallographic analysis. Labeling was performed with high yield (>85%) and radiochemical purity (>90%) using very low ligand concentration. The structure of Tc-99m complexes was established by comparative HPLC using the well-characterized oxorhenium analogues as references, In vitro binding assays demonstrated the affinity of these complexes for 5-HT1A receptors (IC50 : 67 and 45 nM for Re-1 and Re-2 respectively). Biological studies in mice showed the ability of Tc-99m-1 and Tc-99m-2 complexes to cross the intact blood-brain barrier (1.4 and 0.9% dose/g, respectively at 1 min post-inj.). The distribution of these complexes in various regions in rat brain is inhomogeneous. The highest ratio between areas reach and poor in 5-HT1A receptors was calculated for complex Tc-1 at 60 min p.i. (hippocampus/cerebellum = 1.7). (C) 2002 Elsevier Science Inc. All rights reserved.