Endocrine Abstracts

Objective: The major diagnostic problem in primary aldosteronism is the differentiation between bilateral hyperplasia and aldosterone producing adenoma which is essential for further treatment. Adrenal vein sampling is regarded as the current gold standard, however it is an invasive, highly examiner-dependent method. Molecular imaging targeting the aldosterone synthase (CYP11B2) which is expressed specifically in aldosterone producing adrenal tissue may be an useful alternative. CYP11B2 is highly homologous to 11β-hydroxylase (CYP11B1) (93%). We, therefore, aimed to develop a PET tracer which binds to CYP11B2 with both high affinity and high selectivity.

Methods: We have synthesized more than 90 new compounds so far mostly containing a fluorine atom which enables radiolabelling with 18F for PET imaging. Compounds were tested for inhibition of aldosterone/cortisol (corticosterone) in NCI-H295 cells, murine Y1 cells expressing human CYP11B1/CYP11B2 and in V79 chinese hamster fibroblasts expressing rat CYP11B1/CYP11B2.

Results: After structural optimization, 7 fluorinated CYP11B2 inhibitors could be identified (IC50 values for inhibition of aldosterone synthesis up to 5.5 nM, selectivity factors for inhibition of aldosterone vs cortisol synthesis in murine Y1 cells mostly >100).

Conclusion: We developed several fluorinated inhibitors of CYP11B2 exhibiting high affinity and selectivity binding to the target enzyme. These compounds may be suitable for specific molecular imaging in primary hyperaldosteronism. Establishment of radiosynthesis and in vivo evaluation is subject of ongoing studies.

Declaration of interest: The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research project.

Funding: This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.