2. Academic Validation
  3. Fluorinated aldosterone synthase (CYP11B2)-inhibitors for differential diagnosis between bilateral and unilateral conditions of primary aldosteronism

Fluorinated aldosterone synthase (CYP11B2)-inhibitors for differential diagnosis between bilateral and unilateral conditions of primary aldosteronism

  • Bioorg Med Chem Lett. 2023 Nov 15:96:129501. doi: 10.1016/j.bmcl.2023.129501.
Philipp Maier 1,  Britta Heinze 2,  Sabine Gabor 2,  Samario Reese 2,  Stefanie Hahner 2,  Andreas Schirbel 3
Affiliations

Affiliations

  • 1 Department of Nuclear Medicine, University Hospital of Würzburg, University of Würzburg, 97080 Würzburg, Germany; University Clinic for Radiology and Nuclear Medicine, Otto von Guericke University (OvGU), 39120 Magdeburg, Germany; Division of Endocrinology & Diabetes, Department of Medicine I, University Hospital of Würzburg, University of Würzburg, 97080 Würzburg, Germany.
  • 2 Division of Endocrinology & Diabetes, Department of Medicine I, University Hospital of Würzburg, University of Würzburg, 97080 Würzburg, Germany.
  • 3 Department of Nuclear Medicine, University Hospital of Würzburg, University of Würzburg, 97080 Würzburg, Germany. Electronic address: [email protected].
PMID: 37804995 DOI: 10.1016/j.bmcl.2023.129501
Abstract

The Enzyme aldosterone synthase (CYP11B2) is specifically expressed in aldosterone-producing tissue of the adrenal cortex and is overexpressed in aldosterone-producing adenomas (APA). It therefore represents an ideal target for molecular imaging, particularly for the differential diagnosis between bilateral hyperplasia and unilateral APA in primary aldosteronism. However, the presence of the cortisol-producing Enzyme 11β-hydroxylase (CYP11B1) in the adrenal cortex remains very challenging owing to its high homology to CYP11B2. Within this study, we efficiently synthesized a variety of disubstituted fluorinated pyridines and pyrazines by Suzuki coupling reactions. These compounds were evaluated for their ability to inhibit CYP11B1 and CYP11B2 in transfected Y1 cells and in NCI-h295 cells. Several compounds were found to exhibit excellent affinity (IC50 < 10 nM) to CYP11B2 as well as strong selectivity (up to 125-fold) over CYP11B1. These findings support the further development of an analogous 18F-labelled PET tracer.

Keywords

Disubstituted pyridines and pyrazines; Fluorinated CYP11B2 inhibitors; Molecular imaging; NCI-h295 cells; Primary aldosteronism.

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