Imidazole fused phenanthroline (PIP) ligands for the preparation of multimodal Re() and Tc() probes

A small library of [2 + 1] 99m Tc( 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, 99m Tc-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 99m Tc 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 99m Tc 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. A small library of [2 + 1] 99m Tc( i ) complexes based on phenyl-imidazole-fused phenanthroline (PIP) ligands were synthesized and evaluated as multimodal molecular imaging probes.