Synthesis and evaluation of picolinic acid based bifunctional chelating agent for application in molecular imaging

The existing bifunctional acyclic chelators are based on DOTA and DTPA derivatives. However, elevated chelation temperature or low in vivo stability limits the use of these chelators in diagnostic imaging. In this direction, a new family of chelators based on picolinic acid 'pa' family are being explored which exhibit mild labelling conditions and stable complexation with radiometals. The focus of this study was on the development of the "pa" scaffold chelate, 6,60- (2-aminoethylazanediyl) bis (methylene) dipicolinic acid, H₂pentapa-en-NH₂ which will be further utilized for metal complexation and targeted imaging. The chelator contains two pyridine moieties derivatized with carboxylate groups. For the synthesis of the chelator, pyridine-2,6-dicarbonyl chloride was used as a precursor and conjugated to the amine group of ethylene diamine, providing the basic skeleton of the chelate. Finally, in the last step, deprotection in 2 M NaOH gave H₂pentapa-en-NH₂. The developed agent was complexed with ^99mTc in high radiochemical purity and yield after optimising the various parameters of radiolabeling. Further, The in vitro stability of ^99mTc-pentapa-en-NH₂ in PBS buffer was assessed. The "pa" scaffold based chelator, H₂pentapa-en-NH₂ was successfully synthesized in high purity and >95% yield. The chelator was characterized using NMR and Mass spectroscopy. The radiochemical yield of H₂pentapa-en-NH₂ with ^99mTc was found to be 97.2% by ITLCSG, and the specific activity was 135-140 MBq mmol^-1. In vitro competition experiments with human serum and PBS buffer show that the ^99mTc remained predominantly chelate bound with only 7% transchelated to serum proteins after 24 h. Picolinic acid based H₂pentapa-en-NH₂ chelate was synthesised using a simple and versatile synthetic approach. The developed chelate was labelled with ^99mTc with a facile radiolabeling procedure for the applications in SPECT imaging. High yield of radiocomplexation and in vitro stability in PBS established enhanced biocompatibility and the suitability of chelator for complexation with other radiometals. (author)