Structure, Stability, and Biodistribution of Cationic [M(CO)3]+ (M = Re, 99Tc, 99mTc) Complexes with Tridentate Amine Ligands

Abstract

Bifunctional chelating molecules linking the fac‐[99mTc(CO)3]+ core with targeting biomolecules are required for the development of specific diagnostic radiopharmaceuticals. Diethylenetriamine (1) and N‐(pyridin‐2‐ylmethyl)ethane‐1,2‐diamine (2) both react readily with [99mTc(H2O)3(CO)3]+ in 0.9% saline at micromolar concentrations to form the cationic complexes [99mTc(1)(CO)3]+ (5) and [99mTc(2)(CO)3]+ (6) in quantitative yields. The crystal structures of the corresponding Re or 99Tc complexes were determined and exhibit in particular the small size of 5. Challenging both 99mTc complexes 5 and 6 with a 104 excess of histidine or cysteine showed no decomposition or ligand exchange after 24 hours and both compounds were also stable against reoxidation to [99mTcO4]−. In normal mice, complex 5 revealed a good and fast clearance from the blood, and most organs. Only limited accumulation in the large intestine was visible after 4 hours. Complex 6 was also excreted relatively quickly from the blood but retention was observed in some tissues after 4 h. In order to illustrate the potential of both ligands to be further functionalized, two derivatives containing potentially DNA binding functionalities, N‐(2‐Amino‐ethyl)‐N′‐pyren‐1‐ylmethyl‐ethane‐1,2‐diamine (3) and N‐(quinolin‐2‐ylmethyl)ethane‐1,2‐diamine (4) were synthesized. The respective Re or 99Tc complexes were fully characterized. Based on these results, it appears that functionalization of biomolecules with acyclic triamine ligands is biologically relevant. Complex 5 in particular could be used to mimic a terminal amino group in, e.g., a peptide due to its small size and positive charge. We thank Mallinckrodt Med. BV, Petten, NL for financial support.