Synthesis and preclinical evaluation of a bismuth pyclen chelate with superior water solubility, high stability, and low osmolarity for multisystem CT imaging in vivo

Bismuth chelates represent promising alternatives to clinical iodinated contrast agents for computed tomography (CT) imaging, given their higher X-ray attenuation and favorable safety profiles. However, achieving an optimal balance among imaging performance, physicochemical properties, biosafety, and scalable production remains a major challenge for their potential clinical translation. Herein, we report a scalable synthesis of a bismuth pyclen chelate with superior water solubility, high stability, and low osmolarity for preclinical in vivo CT imaging. Bi-PCTA can be achieved starting from 2,6-pyridinedimethanol through a six-step procedure on a 16-g scale, exhibiting low osmolarity and high stability. Notably, Bi-PCTA featured superior water solubility compared to the developed non-ionic bismuth chelates, which is beneficial for biocompatibility, renal clearance efficiency, and contrast enhancement. In vivo gastrointestinal and renal CT imaging studies in rat models proved its diagnostic capabilities for related diseases. The high K-edge of Bi (91 keV) enabled Bi-PCTA for metal artifact-reducing CT angiography (CTA) in rabbits. Especially, the high water solubility of Bi-PCTA allowed for the successful acquisition of high-quality CTA images in a porcine model, highlighting its strong potential for clinical translation.