Monooxorhenium(V) complexes with 222-N 2 S 2 MAMA ligands for bifunctional chelator agents: Syntheses and preliminary in vivo evaluation

Targeted radiotherapy using the bifunctional chelate approach with Re(V) is challenging because of the susceptibility of monooxorhenium(V)-based complexes to oxidize in vivo at high dilution. A monoamine-monoamide dithiol (MAMA)-based bifunctional chelating agent was evaluated with both rhenium and technetium to determine its utility for in vivo applications. A 222-MAMA chelator, 222-MAMA(N-6-Ahx-OEt) bifunctional chelator, and 222-MAMA(N-6-Ahx-BBN(7-14)NH ) were synthesized, complexed with rhenium, radiolabeled with Tc and Re (carrier added and no carrier added), and evaluated in initial biological distribution studies. An IC value of 2.0±0.7nM for ReO-222-MAMA(N-6-Ahx-BBN(7-14)NH ) compared to [ I]-Tyr -BBN(NH ) was determined through competitive cell binding assays with PC-3 tumor cells. In vivo evaluation of the no-carrier added Tc-222-N S (N-6-Ahx-BBN(7-14)NH ) complex showed little gastric uptake and blockable pancreatic uptake in normal mice. The ReO-222-N S (N-6-Ahx-BBN(7-14)NH ) complex showed stability in biological media, which indicates that the 222-N S chelator is appropriate for chelating Re in radiopharmaceuticals involving peptides. Additionally, the in vitro cell studies showed that the ReO-222-N S (N-6-Ahx-BBN(7-14)NH ) complex (macroscopically) bound to PC3-tumor cell surface receptors with high affinity. The Tc analog was stable in vivo and exhibited pancreatic uptake in mice that was blockable, indicating BB2r targeting.