ECEESPE2025 Rapid Communications Rapid Communications 9: Endocrine Related Cancer (5 abstracts)
Preclinical development and first clinical use of a radioiodinated CYP17 inhibitor for adrenal theranostics
Andreas Schirbel 1 , Philipp Maier 1,2,3 , Wiebke Schlötelburg 1 , Carmina Teresa Fuss 2 , Philipp Hartrampf 1 , Britta Heinze 2 & Stefanie Hahner 2
1Department of Nuclear Medicine, University Hospital Würzburg, Würzburg, Germany; 2Division of Endocrinology and Diabetes, Dept of Medicine I, University Hospital Würzburg, Würzburg, Germany; 3Clinic for Radiology and Nuclear Medicine, Otto von Guericke University, Magdeburg, Germany
JOINT2913
Background: The CYP11B1/2-selective tracers iodometomidate and IMAZA have been used for theranostics in adrenocortical carcinoma (ACC), but only ~40% of ACC patients show sufficient uptake, limiting their diagnostic and therapeutic utility. Since CYP17 is more frequently and highly expressed in ACC than CYP11B1/2, we designed several radiolabeled CYP17 inhibitors.
Methods: We designed and synthesised fluorinated and iodinated derivatives of known CYP17 inhibitors and evaluated their adrenostatic potential on CYP17-related enzymatic steps in NCI-H295 cells. Steroid concentrations of 17-OH-progesterone, DHEA and androstenedione were measured by LC-MS in supernatant after coincubation with the respective compounds and IC50 values were calculated. After successful establishment of the radiochemistry, the tracers were investigated in cell uptake experiments, cryosection binding studies and biodistribution analyses in hsCYP17-humanised mice.
Results: Ten derivatives of the known CYP17-inhibitor CFG920 showed single-digit nanomolar inhibition of at least one target steroid. Tracers showed up to 40% intracellular uptake, accumulating mainly in the endoplasmic reticulum fraction. Cryo-binding studies identified several tracers with high and specific tissue binding, with the radioiodinated compound IPIMA standing out. In animal studies, IPIMA exhibited high, sustained accumulation in CYP17-expressing tissues. Initial clinical studies in IMAZA-negative ACC patients showed that IPIMA effectively visualized tumor lesions undetected by IMAZA.
Conclusion: The CYP17-targeting radioiodinated compound IPIMA is a promising theranostic agent for adrenocortical tumors.
Volume 110
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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