A thiourea‐bridged ^99mTc(CO)₃‐dipicolylamine‐2‐nitroimidazole complex for targeting tumor hypoxia: Utilizing metabolizable thiourea‐bridge to improve pharmacokinetics

Abstract

The 2‐nitroimidazole based 99mTc‐radiopharmaceuticals are widely explored for imaging tumor hypoxia. Radiopharmaceuticals for targeting hypoxia are often lipophilic and therefore, show significant uptake in liver and other vital organs. In this context, lipophilic radiopharmaceuticals with design features enabling faster clearance from liver may be more desirable. A dipicolylamine‐NCS bifunctional chelator that could generate a thiourea‐bridge up on conjugation to primary amine bearing molecule was used to synthesize a 2‐nitroimidazole‐dipicolyl amine ligand for radiolabeling with 99mTc(CO)3 core. Corresponding Re(CO)3‐analogue was prepared to establish the structure of 2‐nitroimidazole‐99mTc(CO)3 complex prepared in trace level. The 2‐nitroimidazole‐99mTc(CO)3 complex showed a hypoxic to normoxic ratio of ~2.5 in CHO cells at 3 h. In vivo, the complex showed accumulation and retention in tumor with high tumor to blood and tumor to muscle ratio. The study demonstrated the utility of metabolizable thiourea‐bridge in 2‐nitroimidazole‐99mTc(CO)3 complex in inducing faster clearance of the radiotracer from liver. The dipicolylamine‐NCS bifunctional chelator reported herein can also be used for radiolabeling other class of target specific molecules with 99mTc(CO)3 core.