Cyclopentadienyl Tricarbonyl 99mTc/Re Complexes Containing Spirocyclic Piperidine Moiety as Nonselective Sigma Receptor Ligands for Tumor Imaging and Therapy

We have designed and synthesized a series of cyclopentadienyl tricarbonyl 99mTc/Re complexes containing a spirocyclic piperidine moiety as sigma receptor ligands. Rhenium compound 3a (4-(3H-spiro(2-benzofuran-1,4’-piperidin)-1’-yl)butylcarbonylcyclopentadienyl tricarbonyl rhenium) showed high affinity for both sigma-1 (Ki = 13.8 ± 0.7 nM) and sigma-2 (Ki = 15.1 ± 3.5 nM) receptors. In the MTT assay, 3a displayed significant and comparable antiproliferative activity in DU145, MCF7 and MCF7/Adr tumor cells to siramesine, indicating 3a is an agonist of sigma-2 receptors and a potential antitumor agent. The corresponding radiolabeled compound [99mTc]3b was prepared via double-ligand-transfer reaction from the corresponding ferrocene precursor with a radiochemical yield of 48% and a radiochemical purity of more than 99%. Studies of the cellular accumulation of [99mTc]3b in C6 and DU145 tumor cells indicated that the total binding and the intracellular association is notably high. Incubation with haloperidol significantly reduced the radiotracer accumulation dose-dependently. The biodistribution of [99mTc]3b in nude mice bearing DU145 tumor xenografts showed high tumor uptake (4.27%ID/g) and high tumor-to-blood (12) and tumor-to-muscle (5) ratios at 2 h postinjection. Pretreatment with haloperidol resulted in a remarkable reduction of tumor accumulation, indicating the specific binding of [99mTc]3b to sigma receptors in the tumor. These findings highlight the further evaluation of cyclopentadienyl tricarbonyl 99mTc/Re complexes and prospectively the 188Re-labeled analogs containing a spirocyclic piperidine moiety as sigma ligands for tumor imaging and therapy.