Large-scale synthesis of non-ionic bismuth chelate for computed tomography imaging in vivo

High atomic number elements-based X-ray computed tomography (CT) contrast agents offer a promising solution to address the inherent deficiencies of FDA-approved iodine contrast agents. However, they face substantial challenges in balancing imaging performance, safety, and large-scale production for clinical translation. Herein, inspired by the history of clinical gadolinium- and iodine-based contrast agents, we report a large-scale approach for synthesizing non-ionic bismuth (Bi) chelate for high-performance CT imaging in vivo. Bi-HPDO3A can be easily obtained from low-cost precursor within 4 steps at 6 g-scale. The non-ionic macrocyclic structure endows it with low osmolality, low viscosity, high stability, good renal clearable capability and biocompatibility. Additionally, Bi-HPDO3A realizes superior imaging performance across various in vivo applications, including gastrointestinal imaging, renal imaging, and computed tomography angiography (CTA). Especially, Bi-HPDO3A exhibits superior spectral imaging capability owing to the high K-edge of element Bi, achieving metal artifact-free CTA in vivo. The proposed Bi-HPDO3A that balances overall performance can serve as a high-performance CT contrast agent with potential for clinical translation.