Examination of the PET in vivo generator 134Ce as a theranostic match for 225Ac.

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 of ¹³⁴Ce offer perspectives for developing innovative in vivo investigations that are not possible with ²²⁵Ac. In this work, ²²⁵Ac- and ¹³⁴Ce-labelled 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 with ²²⁵Ac or ¹³⁴Ce 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. The ²²⁵Ac and ¹³⁴Ce-labelled 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 both ²²⁵Ac and ¹³⁴Ce-labelled tracers led to comparable results, confirming the matching pharmacokinetics of this theranostic pair. However, PET imaging of the ¹³⁴Ce-labelled precursors indicated that quantification is highly dependent on tracer internalization due to the redistribution of ¹³⁴Ce's PET-compatible daughter ¹³⁴La. Consequently, radiotracers based on internalizing vectors like PSMA-617 are suited for this theranostic pair, while slow-internalizing ²²⁵Ac-labelled tracers are not quantitatively represented by ¹³⁴Ce PET imaging. Conclusion: When employing slow-internalizing vectors, ¹³⁴Ce might not be an ideal match for ²²⁵Ac due to the underestimation of tumour uptake caused by the in vivo redistribution of ¹³⁴La. However, this same characteristic makes it possible to estimate the redistribution of ²²⁵Ac'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. [ABSTRACT FROM AUTHOR]