The use of radionuclides for targeted endoradiotherapy is a rapidly growing field in oncology. In particular, the focus on the biological effects of different radiation qualities is an important factor in understanding and implementing new therapies. Together with the combined approach of imaging and therapy, therapeutic nuclear medicine has recently made great progress. A particular area of research is the use of alpha-emitting radionuclides, which have unique physical properties associated with outstanding advantages, e.g., for single tumor cell targeting. Here, recent results and open questions regarding the production of alpha-emitting isotopes as well as their chemical combination with carrier molecules and clinical experience from compassionate use reports and clinical trials are discussed.

Eph receptor tyrosine kinases, particularly EphA2 and EphB4, represent promising candidates for molecular imaging due to their essential role in cancer progression and therapy resistance. Xanthine derivatives were identified to be potent Eph receptor inhibitors with IC₅₀ values in the low nanomolar range (1–40 nm). These compounds occupy the hydrophobic pocket of the ATP-binding site in the kinase domain. Based on lead compound 1, we designed two fluorine-18-labelled receptor tyrosine kinase inhibitors ([¹⁸F]2/3) as potential tracers for positron emission tomography (PET). Docking into the ATP-binding site allowed us to find the best position for radiolabelling. The replacement of the methyl group at the uracil residue ([¹⁸F]3) rather than the methyl group of the phenoxy moiety ([¹⁸F]2) by a fluoropropyl group was predicted to preserve the affinity of the lead compound 1. Herein, we point out a synthesis route to [¹⁸F]2 and [¹⁸F]3 and the respective tosylate precursors as well as a labelling procedure to insert fluorine-18. After radiolabelling, both radiotracers were obtained in approximately 5% radiochemical yield with high radiochemical purity (>98%) and a molar activity of >10 GBq μmol⁻¹. In line with the docking studies, first cell experiments revealed specific, time-dependent binding and uptake of [¹⁸F]3 to EphA2 and EphB4-overexpressing A375 human melanoma cells, whereas [¹⁸F]2 did not accumulate at these cells. Since both tracers [¹⁸F]3 and [¹⁸F]2 are stable in rat blood, the novel radiotracers might be suitable for in vivo molecular imaging of Eph receptors with PET.

The application of ²²⁵Ac (half-life T_1/2 = 9.92 d) dramatically reduces the activity used for peptide receptor radionuclide therapy by a factor of 1000 in comparison to ⁹⁰Y, ¹⁷⁷Lu or ¹⁸⁸Re while maintaining the therapeutic outcome. Additionally, the range of alpha particles of ²²⁵Ac and its daughter nuclides in tissue is much lower (47–85 μm for alpha energies E_α = 5.8–8.4 MeV), which results in a very precise dose deposition within the tumor. DOTA-conjugated commercially available peptides used for endoradiotherapy, which can readily be labeled with ¹⁷⁷Lu or ⁹⁰Y, can also accommodate ²²⁵Ac. The benefits are lower doses in normal tissue for the patient, dose reduction of the employees and environment and less shielding material. The low availability of ²²⁵Ac activity is preventing its application in clinical practice. Overcoming this barrier would open a broad field of ²²⁵Ac therapy. Independent which production pathway of ²²⁵Ac proves the most feasible, the use of automated synthesis and feasible and reproducible patient doses are needed. The Modular-Lab EAZY is one example of a GMP-compliant system, and the cassettes used for synthesis are small. Therefore, also the waste after the synthesis can be minimized. In this work, two different automated setups with different purification systems are presented. In its final configuration, three masterbatches were performed on the ML EAZY for DOTA-TATE and PSMA-I&T, respectively, fulfilling all quality criteria with final radiochemical yields of 80–90% for the ²²⁵Ac-labeled peptides.