Good practices for Zr radiopharmaceutical production and quality control.

Background: During the previous two decades, PET imaging of biopharmaceuticals radiolabeled with zirconium-89 has become a consistent tool in preclinical and clinical drug development and patient selection, primarily due to its advantageous physical properties that allow straightforward radiolabeling of antibodies (Zr-immuno-PET). The extended half-life of 78.4 h permits flexibility with respect to the logistics of tracer production, transportation, and imaging and allows imaging at later points in time. Additionally, its relatively low positron energy contributes to high-sensitivity, high-resolution PET imaging. Considering the growing interest in radiolabeling antibodies, antibody derivatives, and other compound classes with Zr in both clinical and pre-clinical settings, there is an urgent need to acquire valuable recommendations and guidelines towards standardization of labeling procedures.

Main Body: This review provides an overview of the key aspects of Zr-radiochemistry and radiopharmaceuticals. Production of Zr, conjugation with the mostly used chelators and radiolabeling strategies, and quality control of the radiolabeled products are described in detail, together with discussions about alternative options and critical steps, as well as recommendations for troubleshooting. Moreover, some historical background on Zr-immuno-PET, coordination chemistry of Zr, and future perspectives are provided. This review aims to serve as a quick-start guide for scientists new to the field of Zr-immuno-PET and to suggest approaches for harmonization and standardization of current procedures.

Conclusion: The favorable PET imaging characteristics of Zr, its excellent availability due to relatively simple production and purification processes, and the development of suitable bifunctional chelators have led to the widespread use of Zr. The combination of antibodies and Zr, known as Zr-immuno-PET, has become a cornerstone in drug development and patient selection in recent years. Despite the advanced state of Zr-immuno-PET, new developments in chelator conjugation and radiolabeling procedures, application in novel compound classes, and improved PET scanner technology and quantification methods continue to reshape its landscape towards improving clinical outcomes.