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

Abstract

Two 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 [99mTcN] 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. The 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 99mTc-nitrido intermediate was prepared from 99mTcO(-)4 using commercially available nitrido kits. The complexation was carried out by mixing the freshly prepared 99mTc-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. The ligands were synthesized in near quantitative yields. They were radiolabelled in > 95% yields using the 99mTc-nitrido core, at low ligand concentrations of 0.01 mg . ml(-1) (5.8 x 10(-5) M) for TBDTC and 1 mg . ml(-1) (4.8 x 10(-3) 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 99mTcN(TBDTC)2 complex showed a better heart/blood and heart/lung ratio when compared to 99mTcN(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 99mTc-D,L-HMPAO at all time points studied. 99mTcN(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. 99mTcN(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. Both the complexes under study showed myocardial as well as brain uptake. The results obtained with 99mTcN(TBDTC)2 shows promise towards its development as a potential brain imaging agent.