Evaluation of¹³⁴Ce/¹³⁴La as a PET Imaging Theranostic Pair for²²⁵Ac α-Radiotherapeutics

Journal Article · 18 May 2023 · Journal of Nuclear Medicine

DOI: https://doi.org/10.2967/jnumed.122.265355 · OSTI ID:1992912

Bobba, Kondapa Naidu ^[1]; Bidkar, Anil P. ^[1]; Meher, Niranjan ^[1]; Fong, Cyril ^[1]; Wadhwa, Anju ^[1]; Dhrona, Suchi ^[1]; Sorlin, Alex ^[1]; Bidlingmaier, Scott ^[1]; Shuere, Becka ^[1]; He, Jiang ^[2]; Wilson, David M. ^[1]; Liu, Bin ^[1]; Seo, Youngho ^[1]; VanBrocklin, Henry F. ^[1]; Flavell, Robert R. ^[1]

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1. Univ. of California, San Francisco, CA (United States)
2. Univ. of Virginia, Charlottesville, VA (United States)

²²⁵Ac-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 ¹³⁴Ce/¹³⁴La has been proposed as a potential PET imaging surrogate for the therapeutic nuclides ²²⁵Ac and ²²⁷Th. In this report, we detail efficient radiolabeling methods using the ²²⁵Ac-chelators DOTA and MACROPA. These methods were applied to radiolabeling of prostate cancer imaging agents, including PSMA-617 and MACROPA-PEG₄-YS5, for evaluation of their in vivo pharmacokinetic characteristics and comparison to the corresponding ²²⁵Ac analogs. Methods: Radiolabeling was performed by mixing DOTA/MACROPA chelates with ¹³⁴Ce/¹³⁴La in NH₄OAc, pH 8.0, at room temperature, and radiochemical yields were monitored by radio–thin-layer chromatography. In vivo biodistributions of ¹³⁴Ce-DOTA/MACROPA.NH₂ 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 ¹³⁴CeCl₃. In vivo, preclinical imaging of ¹³⁴Ce-PSMA-617 and ¹³⁴Ce-MACROPA-PEG₄-YS5 was performed on 22Rv1 tumor–bearing male nu/nu-mice. Ex vivo biodistribution was performed for ¹³⁴Ce/²²⁵Ac-MACROPA-PEG₄-YS5 conjugates. Results: ¹³⁴Ce-MACROPA.NH₂ 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 ¹³⁴Ce/²²⁵Ac-DOTA/MACROPA. NH₂ conjugates in comparison to free ¹³⁴CeCl₃ confirmed high in vivo stability. An interesting observation during the radiolabeling of tumor-targeting vectors PSMA-617 and MACROPA-PEG₄-YS5—that the daughter ¹³⁴La was expelled from the chelate after the decay of parent ¹³⁴Ce—was confirmed through radio–thin-layer chromatography and reverse-phase high-performance liquid chromatography. Both conjugates, ¹³⁴Ce-PSMA-617 and ¹³⁴Ce-MACROPA-PEG₄-YS5, displayed tumor uptake in 22Rv1 tumor–bearing mice. The ex vivo biodistribution of ¹³⁴Ce-MACROPA.NH₂, ¹³⁴Ce-DOTA and ¹³⁴Ce-MACROPA-PEG₄-YS5 corroborated well with the respective ²²⁵Ac-conjugates. Conclusion: These results demonstrate the PET imaging potential for ¹³⁴Ce/¹³⁴La-labeled small-molecule and antibody agents. The similar ²²⁵Ac and ¹³⁴Ce/¹³⁴La-chemical and pharmacokinetic characteristics suggest that the ¹³⁴Ce/¹³⁴La pair may act as a PET imaging surrogate for ²²⁵Ac-based radioligand therapies.

• Research Organization: Univ. of California, San Francisco, CA (United States)
• Sponsoring Organization: USDOE
• Grant/Contract Number: SC0023467
• OSTI ID: 1992912
• Journal Information: Journal of Nuclear Medicine, Vol. 64, Issue 7; ISSN 0161-5505
• Publisher: Society of Nuclear Medicine and Molecular ImagingCopyright Statement
• Country of Publication: United States
• Language: English