Preparation and biological evaluation of 99mTcN-4-(cyclohexylpiperazin-1-yl)-dithioformate as a potential sigma receptor imaging agent

The goal of this study is to develop a novel Tc-99m-labeled sigma receptor imaging agent. Potassium 4-(cyclohexylpiperazin-1-yl)-dithioformate, 2, and the corresponding rhenium complex, ReN-2, were synthesized and characterized. ReN-2 possessed moderate affinity toward sigma(1) (K-i = 1.94 +/- 0.60 mu mol/L) and sigma(2) (K-i = 2.83 +/- 1.39 mu mol/L) receptors. The radiolabeled complex (TcN)-Tc-99m-2 was prepared in high yield (> 95%) through the [(TcN)-Tc-99m](int)(2+) precursor and characterized by HPLC. (TcN)-Tc-99m-2 was found to be a lipophilic and neutral complex with good stability. The biodistribution in tumor-bearing mice showed that (TcN)-Tc-99m-2 had good tumor uptake (2.12 +/- 0.01 %ID/g at 2 h p.i.) and moderate brain uptake (0.27 +/- 0.05 %ID/g at 2 h p.i.). After blocking with haloperidol, the uptakes by tumor and brain were lower than control. The results indicated that the complex has specific binding to the sigma receptors in vivo. Further structural modifications of this complex are needed to obtain Tc-99m-based a receptor imaging agents with high affinity and subtype selectivity. Copyright (C) 2007 John Wiley & Sons, Ltd.