Evaluation of Ce/La as a PET Imaging Theranostic Pair for Ac α-Radiotherapeutics.

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 Ce/La has been proposed as a potential PET imaging surrogate for the therapeutic nuclides Ac and Th. In this report, we detail efficient radiolabeling methods using the Ac-chelators DOTA and MACROPA. These methods were applied to radiolabeling of prostate cancer imaging agents, including PSMA-617 and MACROPA-PEG-YS5, for evaluation of their in vivo pharmacokinetic characteristics and comparison to the corresponding Ac analogs. Radiolabeling was performed by mixing DOTA/MACROPA chelates with Ce/La in NHOAc, pH 8.0, at room temperature, and radiochemical yields were monitored by radio-thin-layer chromatography. In vivo biodistributions of Ce-DOTA/MACROPA.NH 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 CeCl In vivo, preclinical imaging of Ce-PSMA-617 and Ce-MACROPA-PEG-YS5 was performed on 22Rv1 tumor-bearing male nu/nu-mice. Ex vivo biodistribution was performed for Ce/Ac-MACROPA-PEG-YS5 conjugates. Ce-MACROPA.NH 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 Ce/Ac-DOTA/MACROPA. NH conjugates in comparison to free CeCl confirmed high in vivo stability. An interesting observation during the radiolabeling of tumor-targeting vectors PSMA-617 and MACROPA-PEG-YS5-that the daughter La was expelled from the chelate after the decay of parent Ce-was confirmed through radio-thin-layer chromatography and reverse-phase high-performance liquid chromatography. Both conjugates, Ce-PSMA-617 and Ce-MACROPA-PEG-YS5, displayed tumor uptake in 22Rv1 tumor-bearing mice. The ex vivo biodistribution of Ce-MACROPA.NH, Ce-DOTA and Ce-MACROPA-PEG-YS5 corroborated well with the respective Ac-conjugates. These results demonstrate the PET imaging potential for Ce/La-labeled small-molecule and antibody agents. The similar Ac and Ce/La-chemical and pharmacokinetic characteristics suggest that the Ce/La pair may act as a PET imaging surrogate for Ac-based radioligand therapies.