During the first half of this PhotoPHARMA project we have made strong progress on the experimental goals. Specifically, after establishing our new team, we focused efforts on the synthesis and characterisation of different photoactivatable radiotracers. This work explored three main avenues: 1) development of new photoactive chelates for complexation of a range of different radionuclides; 2) exploration of the chemistry and mechanisms of photochemically activated conjugation handles to proteins; and 3) development of automated radiosynthesis tools to facilitate future clinical translation.
We have now reported experimental data on over a dozen photoactivatable compounds which facilitate complexation chemistry with a wide range of radionuclides ions including: 68Ga, 64Cu, 89Zr and 18F for positron emission tomography (PET) imaging, 111In for Auger therapy, 99mTc for single-photon emission computed tomography (SPECT) / -ray imaging, and the beta-emitting radiotherapeutic nuclides 177Lu, 188Re and 161Tb. Notably, the chemistry of these radionuclides is vastly different and required us to develop several new synthetic methods. For example, many of the photoactivatable groups that we have tested (see below) are unstable under the strongly reducing conditions which are an essential part of most 99mTc and 188Re-based radiolabelled methods. Here, we designed new chelates for stable complexation of Tc / Re ions in the 5+ oxidation state combined with photoreactive handles that are stable toward SnCl2 reduction (Jonas Genz; 2 manuscripts in preparation). Similarly, metal complexes of lanthanoid ions like 177Lu3+ and 161Tb3+ require different coordination environments. For this we turned to the chemistry of bispidine chelates which increase the overall complex stability and radiolabelling efficiency (177Lu: Cieslik et al. Chem. Eur. J., 2024; 161Tb Cieslik et al. manuscript in preparation; Klingler et al. manuscript in preparation; Nisli et al. manuscript in preparation). Other examples of new photoactive chelate development include (Guillou et al. Inorg. Chem. Frontiers, 2022; and Earley et al. Dalton Trans., 2022, which was selected by the editor as a ‘Hot Paper’).
We have also performed extensive fundamental photochemical and radiochemical studies exploring the light-induced reactivity of over 14 different functional groups. Experimental data from these studies have appeared in several publications (e.g. Fay et al. Chem. Eur. J., 2021; Guillou et al. Bioconjugate Chem., 2021; and detailed mechanistic work was reported in the article Earley et al. Charting the chemical and mechanistic scope of light-triggered protein ligation; JACS Au, 2022).
To facilitate a broader scope of utility, we have also expanded the chemistry beyond radiolabelled compounds of combining our photolabelling technology with fluorophores (see Guillou et al. J. Med. Chem., 2022).
In parallel to the fundamental chemistry, we have produced two new automated radiolabelling devices which use both batch-type photochemical reactors (Klingler et al. Automated light-induced synthesis of 89Zr-radiolabeled antibodies for immuno-positron emission tomography; Sci. Reports, 2022) and microfluidic technology (Earley et al. Molecules, 2021) for hands-free radiolabelling of proteins and antibodies. So far, it appears that batch-based reactors are more practical for implementing our new radiochemistry, but we will continue to explore flow-based options in the second half of PhotoPHARMA.
Other notable achievements which utilise the PhotoPHARMA chemistry, but which were not directly related to the initial objectives of the project include our recent development of supramolecular radiotracers (please see d’Orchymont et al., Chem. Sci., 2022, Commun. Chem., 2023; J. Am. Chem. Soc., 2023).
