99mTcN complexes of tert-butyl dithiocarbamate and methoxyisobutyl dithiocarbamate as myocardial and brain imaging agents

OBJECTIVETwo ligands viz. tert-butyl dithiocarbamate (TBDTC) and methoxyisobutyl dithiocarbamate (MIBDTC), which are analogous to the tert-butyl isonitrile (TBI) and sestamibi (MIBI) ligands, were synthesized and labelled with the [TcN] core to evaluate their potential as myocardial agents. As these complexes have low molecular weights, and are neutral and lipophilic in nature, they have a tendency to cross the blood–brain barrier and thus deserve evaluation as potential brain perfusion imaging agents. METHODSThe dithiocarbamate ligands were synthesized from their respective amines, i.e., tert-butylamine and methoxyisobutylamine, by reacting with carbon disulfide in dry ether in the presence of crushed sodium hydroxide. The ligands were characterized by elemental analyses. The Tc-nitrido intermediate was prepared from TcO4 using commercially available nitrido kits. The complexation was carried out by mixing the freshly prepared Tc-nitrido intermediate and the ligand followed by incubation at room temperature for 10 min. These complexes were characterized by high-performance liquid chromatography (HPLC) using a C-18 reversed phase column with acetonitrile:water as the mobile phase, and by paper electrophoresis. Biodistribution studies were carried out in normal Swiss mice. RESULTSThe ligands were synthesized in near quantitative yields. They were radiolabelled in > 95% yields using the Tc-nitrido core, at low ligand concentrations of 0.01 mg · ml (5.8×10 M) for TBDTC and 1 mg · ml (4.8×10 M) for MIBDTC, respectively. Both the complexes were found to be neutral and eluted out as single species in HPLC. Both the complexes showed myocardial as well as brain uptake. The TcN(TBDTC)2 complex showed a better heart/blood and heart/lung ratio when compared to TcN(NOEt)2, an agent in phase III clinical trials proposed for myocardial imaging. This complex also showed brain uptake (3.74%ID/g) at 10 min post-injection (p.i.) with brain/blood ratios better than that of the standard agent Tc-D,L-HMPAO at all time points studied. TcN(MIBDTC)2 showed myocardial uptake of 6.41%ID/g at 5 min p.i., which decreased to 1.76%ID/g, 60 min p.i. TcN(MIBDTC)2 also showed good brain uptake (3.21%ID/g at 5 min p.i.) but relatively fast washout (1.33%ID/g at 60 min p.i.) from the target organ. CONCLUSIONBoth the complexes under study showed myocardial as well as brain uptake. The results obtained with TcN(TBDTC)2 shows promise towards its development as a potential brain imaging agent.