Macrocyclic Bifunctional Chelators and Conjugation Strategies for Copper-64 Radiopharmaceuticals

Abstract The positron-emitting radionuclide copper-64 is of interest in the development of new molecular imaging agents for use with positron emission tomography. This account highlights the development and application of macrocyclic chelators that have been designed to form complexes of copper-64 that are exceptionally stable in vivo and can be readily conjugated to biologically active molecules and nanoparticles. “Click chemistry” is discussed as a conjugation technique that is bioorthogonal with both pre- and postlabeling capabilities. Enzyme-mediated site-specific strategies are introduced as new conjugation techniques with the potential to improve homogeneity, reproducibility, and the likelihood for retention of full biological function of targeted tracers for noninvasive diagnostic imaging.