‘4+1’ Mixed Ligand Strategy for the Preparation of ^99m Tc-Radiopharmaceuticals for Hypoxia Detecting Applications

Abstract

The ‘4+1’ mixed ligand strategy enables radiolabeling of biomolecules with 99mTc at low ligand concentration without affecting it's in vivo biological activity. The ‘4+1’ mixed‐ligand complexes consist of central Tc(III) metal atom coordinated to a tetradentate tripodal chelator 2,2′,2′′‐nitrilotriethanethiol (NS3) and a monodentate isocyanide group tethered to a biomolecule. The present work describes the use of ‘4+1’ mixed ligand strategy to design radiopharmaceuticals for the detection of tissue hypoxia in vivo. Isocyanide derivatives of two nitroimidazoles, viz. 2‐nitroimidazole (2NimNC) and metronidazole (MetNC), were synthesized and radiolabeled with 99mTc using ‘4+1’ mixed ligand approach. The complexes [99mTc(NS3)(2NimNC)] and [99mTc(NS3)(MetNC)] could be prepared in excellent yield (>90%). The structure of 99mTc‐complexes prepared at the no‐carrier‐added (nca) level was corroborated by spectroscopic analysis of corresponding rhenium analogues at the macroscopic level. Preliminary biological evaluation of the two nitroimidazole‐‘4+1’ mixed ligand complexes in Swiss mice bearing fibrosarcoma tumor showed uptake and retention of the complexes in tumor.

99mTc Labelling Strategies for the Development of Potential Nitroimidazolic Hypoxia Imaging Agents

“…Vats et al [49] applied the same labelling strategy using isocyanide bearing 2-and 5-nitroimidazoles. Both complexes showed moderate uptake and retention in tumour (fibrosarcoma) and favourable tumour/muscle ratios with very similar absolute values for 2-and 5-nitroimidazoles.…”

“…Molecular structure of isonitrile ligands used for labelling with technetium through the formation of 4+1 Tc(III) complexes[48,49].…”

Synthesis of 99mTc-labeled 2-Mercaptobenzimidazole as a novel radiotracer to diagnose tumor hypoxia

“…It has been observed that 99m Tc-2-MBI has high uptake in S180 tumor bearing mice as well as tumor/muscle and tumor/blood ratio were also found to be more challenging than other 99m Tc-labeled imidazole based radiotracers reported in the literature [ 20 , 21 ]. As per concern for the uptake of radiotracer in non-targeted tissues and organs such as lungs, liver and intestine, our proposed radiotracer seems to be much superior than others at 4 h post-injection [ 45 , 46 ]. To the best of our knowledge and outcomes obtained from biological evaluation, this radiotracer can be significantly use as a potential radiotracer for detection of tumor hypoxia.…”

Preparation and Bioevaluation of Novel 99mTc-Labeled Complexes with a 2-Nitroimidazole HYNIC Derivative for Imaging Tumor Hypoxia

“…Several SPECT and PET radiotracers with nitroimidazole have been reported to date and have attracted attention [ 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 ]. [ 18 F]FMISO is one of the most widely used PET radiotracers for imaging hypoxia [ 22 ].…”

“…Technetium-99m has been the most widely used SPECT isotope because it possesses ideal nuclide properties ( t 1/2 = 6 h, Eg = 140 keV) and rich coordination chemistry with various oxidation states and donor atom sets [ 25 ]. In addition, its in-house availability and reasonable cost have resulted in wide clinical use, especially in many developing countries and less-developed regions [ 13 , 14 , 15 , 16 ].…”