Albumin-Binding and Conventional PSMA Ligands in Combination with 161 Tb: Biodistribution, Dosimetry, and Preclinical Therapy.

The favorable decay characteristics of ¹⁶¹ Tb attracted the interest of clinicians in using this novel radionuclide for radioligand therapy (RLT). ¹⁶¹ Tb decays with a similar half-life to ¹⁷⁷ Lu, but beyond the emission of β ^- -particles and γ-rays, ¹⁶¹ Tb also emits conversion and Auger electrons, which may be particularly effective to eliminate micrometastases. The aim of this study was to compare the dosimetry and therapeutic efficacy of ¹⁶¹ Tb and ¹⁷⁷ Lu in tumor-bearing mice using SibuDAB and PSMA-I&T, which differ in their blood residence time and tumor uptake. Methods: [ ¹⁶¹ Tb]Tb-SibuDAB and [ ¹⁶¹ Tb]Tb-PSMA-I&T were evaluated in vitro and investigated in biodistribution, imaging, and therapy studies using PC-3 PIP tumor-bearing mice. The ¹⁷⁷ Lu-labeled counterparts served for dose calculations and comparison of therapeutic efficacy. The tolerability of RLT in mice was monitored on the basis of body mass, blood plasma parameters, blood cell counts, and the histology of relevant organs and tissues. Results: The prostate-specific membrane antigen (PSMA)-targeting radioligands, irrespective of whether labeled with ¹⁶¹ Tb or ¹⁷⁷ Lu, showed similar in vitro data and comparable tissue distribution profiles. As a result of the albumin-binding properties, [ ¹⁶¹ Tb]Tb/[ ¹⁷⁷ Lu]Lu-SibuDAB had an enhanced blood residence time and higher tumor uptake (62%-69% injected activity per gram at 24 h after injection) than [ ¹⁶¹ Tb]Tb/[ ¹⁷⁷ Lu]Lu-PSMA-I&T (30%-35% injected activity per gram at 24 h after injection). [ ¹⁶¹ Tb]Tb-SibuDAB inhibited tumor growth more effectively than [ ¹⁶¹ Tb]Tb-PSMA-I&T, as can be ascribed to its 4-fold increased absorbed tumor dose. At any of the applied activities, the ¹⁶¹ Tb-based radioligands were therapeutically more effective than their ¹⁷⁷ Lu-labeled counterparts, as agreed with the approximately 40% increased tumor dose of ¹⁶¹ Tb compared with that of ¹⁷⁷ Lu. Under the given experimental conditions, no obvious adverse events were observed. Conclusion: The data of this study indicate the promising potential of ¹⁶¹ Tb in combination with SibuDAB for RLT of prostate cancer. Future clinical studies using ¹⁶¹ Tb-based RLT will shed light on a potential clinical benefit of ¹⁶¹ Tb over ¹⁷⁷ Lu.
(© 2023 by the Society of Nuclear Medicine and Molecular Imaging.)