[Tc-99m][Tc(N)(DASD)(PNPn)](+) (DASD=1,4-Dioxa-8-azaspiro[4,5]decandithiocarbamate, PNPn = Bisphosphinoamine) for Myocardial Imaging: Synthesis, Pharmacological and Pharmacokinetic Studies

摘要

[Tc-99m][TcN-DBODC(5) is the lead candidate of a class of cationic complexes proposed as myocardial imaging agents (MPIAs). Phase I clinical studies showed that its clinical properties were comparable to those of the commercially available agents. Thus, modification of [Tc-99m]TcN-DBODC(5), directed to obtain an ideal myocardial imaging without interference from the adjacent organ activities, is desirable. This work describes the pharmacological and pharmacokinetic development of four new complexes of general formula [Tc-99m][Tc(N)(DASD)(PNPn)](+), [Tc-99m]TcN-DASD(n) (DASD = 1,4-dioxa-8-azaspiro[4,5]decandithiocarbamate; PNPn = bisphosphinoamine), proposed as improved MPIAs. Among the tested compounds, [Tc-99m]TcN-DASD(5) and [Tc-99m]TcN-DASD(7) showed enhanced heart uptake compared with the gold standards, with a rapid liver washout and superior heart-to-liver ratio. These features might shorten the duration of imaging procedures below 30 min, consenting the early acquisition of high-quality images. In addition, mechanistic studies were performed in cellulo by using human drug-sensitive and drug-resistant cancer cell lines, obtaining results which might be conveniently applied to tumor imaging.