Exploring the PET in vivo generator¹³⁴Ce as a theranostic match for²²⁵Ac

Abstract

Purpose: The radionuclide pair cerium-134/lanthanum-134 (134Ce/134La) was recently proposed as a suitable diagnostic counterpart for the therapeutic alpha-emitter actinium-225 (225Ac). The unique properties of134Ce offer perspectives for developing innovative in vivo investigations not possible with225Ac. In this work,225Ac- and134Ce-labeled tracers were directly compared using internalizing and slow-internalizing cancer models to evaluate their in vivo comparability, progeny meandering, and potential as a matched theranostic pair for clinical translation. Despite being an excellent chemical match,134Ce/134La has limitations to the setting of quantitative positron emission tomography imaging.Methods: The precursor PSMA-617 and a macropa-based tetrazine-conjugate (mcp-PEG8-Tz) were radiolabelled with225Ac or134Ce and compared in vitro and in vivo using standard (radio)chemical methods. Employing biodistribution studies and positron emission tomography (PET) imaging in athymic nude mice, the radiolabelled PSMA-617 tracers were evaluated in a PC3/PIP (PC3 engineered to express a high level of prostate-specific membrane antigen) prostate cancer mouse model. The134Ac and134Ce-labeled mcp-PEG8-Tz were investigated in a BxPC-3 pancreatic tumour model harnessing the pretargeting strategy based on a trans-cyclooctene-modified 5B1 monoclonal antibody.Results: In vitro and in vivo studies with both225Ac and134Ce-labelled tracers led to comparable results, confirming the matching pharmacokinetics of this theranostic pair. However, PET imaging of the134Ce-labelled precursors indicated that quantification is highly dependent on tracer internalization due to the redistribution of134Ce's PET-compatible daughter134La. Consequently, radiotracers based on internalizing vectors like PSMA-617 are suited for this theranostic pair, while slow-internalizing225Ac-labelled tracers are not quantitatively represented by134Ce PET imaging.Conclusion: When employing slow-internalizing vectors,134Ce might not be an ideal match for225Ac due to the underestimation of tumour uptake caused by the in vivo redistribution of134La. However, this same characteristic makes it possible to estimate the redistribution of225Ac's progeny noninvasively. In future studies, this unique PET in vivo generator will further be harnessed to study tracer internalization, trafficking of receptors, and the progression of the tumour microenvironment.