Abstract
(225)Ac-targeted α-radiotherapy is a promising approach to treating malignancies, including prostate cancer. However, α-emitting isotopes are difficult to image because of low administered activities and a low fraction of suitable γ-emissions. The in vivo generator (134)Ce/(134)La has been proposed as a potential PET imaging surrogate for the therapeutic nuclides (225)Ac and (227)Th. In this report, we detail efficient radiolabeling methods using the (225)Ac-chelators DOTA and MACROPA. These methods were applied to radiolabeling of prostate cancer imaging agents, including PSMA-617 and MACROPA-PEG(4)-YS5, for evaluation of their in vivo pharmacokinetic characteristics and comparison to the corresponding (225)Ac analogs. Methods: Radiolabeling was performed by mixing DOTA/MACROPA chelates with (134)Ce/(134)La in NH(4)OAc, pH 8.0, at room temperature, and radiochemical yields were monitored by radio-thin-layer chromatography. In vivo biodistributions of (134)Ce-DOTA/MACROPA.NH(2) complexes were assayed through dynamic small-animal PET/CT imaging and ex vivo biodistribution studies over 1 h in healthy C57BL/6 mice, compared with free (134)CeCl(3) In vivo, preclinical imaging of (134)Ce-PSMA-617 and (134)Ce-MACROPA-PEG(4)-YS5 was performed on 22Rv1 tumor-bearing male nu/nu-mice. Ex vivo biodistribution was performed for (134)Ce/(225)Ac-MACROPA-PEG(4)-YS5 conjugates. Results: (134)Ce-MACROPA.NH(2) demonstrated near-quantitative labeling with 1:1 ligand-to-metal ratios at room temperature, whereas a 10:1 ligand-to-metal ratio and elevated temperatures were required for DOTA. Rapid urinary excretion and low liver and bone uptake were seen for (134)Ce/(225)Ac-DOTA/MACROPA. NH(2) conjugates in comparison to free (134)CeCl(3) confirmed high in vivo stability. An interesting observation during the radiolabeling of tumor-targeting vectors PSMA-617 and MACROPA-PEG(4)-YS5-that the daughter (134)La was expelled from the chelate after the decay of parent (134)Ce-was confirmed through radio-thin-layer chromatography and reverse-phase high-performance liquid chromatography. Both conjugates, (134)Ce-PSMA-617 and (134)Ce-MACROPA-PEG(4)-YS5, displayed tumor uptake in 22Rv1 tumor-bearing mice. The ex vivo biodistribution of (134)Ce-MACROPA.NH(2), (134)Ce-DOTA and (134)Ce-MACROPA-PEG(4)-YS5 corroborated well with the respective (225)Ac-conjugates. Conclusion: These results demonstrate the PET imaging potential for (134)Ce/(134)La-labeled small-molecule and antibody agents. The similar (225)Ac and (134)Ce/(134)La-chemical and pharmacokinetic characteristics suggest that the (134)Ce/(134)La pair may act as a PET imaging surrogate for (225)Ac-based radioligand therapies.