In recent years, copper-64 and copper-67 have been considered as a useful theranostic pair in nuclear medicine, due to their favourable and complementary decay properties. As ⁶⁷Cu and ⁶⁴Cu are chemically identical, development of both existing and new bifunctional chelators for ⁶⁴Cu imaging agents can be readily adapted for the ⁶⁷Cu-radionuclide. In this study, we explored the use of photoactivatable copper chelators based on the asymmetric bis(thiosemicarbazone) scaffold, H₂ATSM/en, for the photoradiolabelling of protein. Photoactivatable ⁶⁴CuATSM-derivatives were prepared by both direct synthesis and transmetallation from the corresponding ^natZn complex. Then, irradiation with UV light in the presence of a protein of interest in a pH buffered aqueous solution afforded the ⁶⁴Cu-labelled protein conjugates in decay-corrected radiochemical yield of 86.9 ± 1.0% via the transmetallation method and 35.3 ± 1.7% from the direct radiolabelling method. This study successfully demonstrates the viability of photochemically induced conjugation methods for the development of copper-based radiotracers for potential applications in diagnostic positron emission tomography (PET) imaging and targeted radionuclide therapy.

⁸⁹Zr-radiolabelled proteins functionalised with desferrioxamine B are a cornerstone of diagnostic positron emission tomography. In the clinical setting, ⁸⁹Zr-labelled proteins are produced manually. Here, we explore the potential of using a microfluidic photochemical flow reactor to prepare ⁸⁹Zr-radiolabelled proteins. The light-induced functionalisation and ⁸⁹Zr-radiolabelling of human serum albumin ([⁸⁹Zr]ZrDFO-PEG₃-Et-azepin-HSA) was achieved by flow photochemistry with a decay-corrected radiochemical yield (RCY) of 31.2 ± 1.3% (n = 3) and radiochemical purity >90%. In comparison, a manual batch photoreactor synthesis produced the same radiotracer in a decay-corrected RCY of 59.6 ± 3.6% (n = 3) with an equivalent RCP > 90%. The results indicate that photoradiolabelling in flow is a feasible platform for the automated production of protein-based ⁸⁹Zr-radiotracers, but further refinement of the apparatus and optimisation of the method are required before the flow process is competitive with manual reactions.

The photochemical activation and radiolabelling of proteins using new water soluble, photoactive chelates are depicted in the cover image. The wave in the background represents the water, ideal conditions for this chemistry. The beam of light refers to the photochemical aspects and the centrepiece shows the key chemical group (an azepine) produced by the photochemical process that links the metal complex to the protein of interest. More information can be found in the Communication by J. P. Holland et al. (DOI: 10.1002/chem.202001755).