Imidazole fused phenanthroline (PIP) ligands for the preparation of multimodal Re(i) and 99mTc(i) probes

Abstract

A small library of [2 + 1] ^99mTc(I) complexes based on phenyl-imidazole-fused phenanthroline (PIP) ligands were synthesized and evaluated as multimodal molecular imaging probes. Using either a two-step or a one-pot synthesis method, ^99mTc-PIP complexes containing N-methylimidazole as the monodentate ligand were prepared and isolated in good (54 to 89%) radiochemical yield, with the exception of one derivative bearing a strongly electron-withdrawing substituent. The stability of the [2 + 1] complexes was assessed in saline and in cysteine and histidine challenge studies, showing 6 hours stability, making them suitable for in vivo studies. In parallel, the Re(I) analogues were prepared as reference standards to verify the structure of the ^99mTc complexes. The optical properties were consistent with other previously reported [2 + 1] type Re(I) complexes that have been used as cellular dyes and sensors. To facilitate the development of targeted derivatives, a tetrazine-PIP ligand was also synthesized. The ^99mTc complex of the tetrazine PIP ligand effectively coupled to compounds containing a trans-cyclooctene (TCO) group including a TCO-albumin derivative, which was prepared as a model targeting molecule. An added benefit of the Re-PIP-Tz construct is that the emission from the metal complex was quenched by the presence of the tetrazine. Following the addition of TCO, there was a 70-fold increase in fluorescence emission, which can in future be leveraged during in vitro studies to reduce background signal.