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. Graphical abstract: (Figure presented.)