Synthesis and evaluation of new mixed "2 + 1" Re, 99mTc and 186Re tricarbonyl dithiocarbamate complexes with different monodentate ligands

Abstract

A series of "2 + 1" mixed ligand tricarbonyl complexes of the general formula fac-[Re/^99mTc/¹⁸⁶Re(CO)₃(DDTC)(L)] containing diethyldithiocarbamate (DDTC) as a monoanionic bidentate ligand and a series of monodentate ligands L was synthesized, characterized and evaluated. The impact of ligand L on the radiochemical yield (RCY) and biodistribution of the final compounds was also investigated. DDTC and the appropriate L ligand [cyclohexyl isocyanide (cisc), tert-butyl isocyanide (tbi), triphenylphosphine (PPh₃), methyldiphenylphosphine (PPh₂Me), triphenylarsine (AsPh₃), imidazole (im), and 4-aminopyridine (4AP)] readily reacted in equimolar amounts with the [Et₄N]₂[Re(CO)₃Br₃] precursor to afford fac-[Re(CO)₃(DDTC)(cisc)], Re1, fac-[Re(CO)₃(DDTC)(tbi)], Re2, fac-[Re(CO)₃(DDTC)(PPh₃)], Re3, fac-[Re(CO)₃(DDTC)(PPh₂Me)], Re4, fac-[Re(CO)₃(DDTC)(AsPh₃)], Re5, fac-[Re(CO)₃(DDTC)(im)], Re6 and fac-[Re(CO)₃(DDTC)(4AP)], Re7, complexes in high yields (>80%). All Re complexes were fully characterized by IR, NMR, and in addition Re4, Re5, and Re7 with X-ray crystallography. Analogous reactions as performed with Re were subsequently explored on the ^99mTc and ¹⁸⁶Re-tracer levels using the corresponding fac-[^99mTc/¹⁸⁶Re(CO)₃(H₂O)₃]⁺ precursor. Complexes ^99mTc1 - ^99mTc5, ¹⁸⁶Re1 and ¹⁸⁶Re3 were obtained in high radiochemical yield (>91%), while the complexes ^99mTc6, ^99mTc7 and ¹⁸⁶Re7 formed with radiochemical yields of 55%, 28%, and 75%, respectively. The ^99mTc and ¹⁸⁶Re-complexes were characterized by comparative HPLC analysis using the analogous Re complexes. During histidine and cysteine challenge experiments at 37 °C through 6 h, complexes ^99mTc1 - ^99mTc5 remained > 92% stable, while complexes ^99mTc6 and ^99mTc7 remained only 8% stable through 3 h. Similar studies for ¹⁸⁶Re-complexes showed that ¹⁸⁶Re1 and ¹⁸⁶Re3 remained > 95% stable for up to 48 h, while ¹⁸⁶Re7 had decreased to 7% after 3 h. LogD_7.4 data of ^99mTc1 - ^99mTc5, ¹⁸⁶Re1, and ¹⁸⁶Re3 complexes, which ranged from 2.59 to 3.39, suggested high lipophilicity. Biodistribution studies in healthy Swiss albino mice showed hepatobiliary excretion for ^99mTc1, ^99mTc2, and ^99mTc4, fast blood clearance for ^99mTc4, while high liver uptake and retention for ^99mTc3 and ^99mTc5 were measured. Moreover, ^99mTc2 showed high accumulation in the lungs with sustained retention (52.80% ID/g at 4 h p.i.) and significant brain uptake at 2 min p.i. (1.89% ID/g). The study showed the great influence of monodentate ligand in the synthesis and biodistribution of the mixed ligand complexes.

Keywords: Biodistribution; Dithiocarbamate; Microwave-assisted reactions; Rhenium; Rhenium-186; Technetium-99m; Tricarbonyl.