Pyridyl-Substituted Naphthalenes and 3,4-dihydro-1H-quinolin-2-ones as Fluorinated Aldosterone Synthase (CYP11B2) Inhibitors for the Differential Diagnosis of Primary Aldosteronism

Author(s): Philipp Maier, Andreas Schirbel, Magdalena Schneider, Sabine Gabor, Samario Reese, Stefanie Hahner, Britta Heinze

Aldosterone synthase (CYP11B2) is specifically expressed in aldosterone-producing tissue of the adrenal cortex. It cata-lyzes the final steps in aldosterone synthesis and is pathophysiologically relevant in primary aldosteronism. Therefore, it presents an excellent PET imaging target for the localization of aldosterone excess. To expand compound library for the development of an appropriate F-18 labelled radiotracer, we synthesized fluorinated derivatives of pyridyl-substituted naphthalenes 1 and 3,4-dihydro-1H-quinolin-2-ones 2. Despite the high homology of CYP11B2 with the cortisol-producing enzyme 11β-hydroxylase (CYP11B1) both classes of compounds are well known as selective CYP11B2 inhib-itors. Some of the 30 substances prepared proved to be highly potent CYP11B2 inhibitors (IC50 < 10 nM) in in vitro evaluation using transfected Y1 cells and NCI-H295 cells. Moreover, several compounds exhibited outstanding selec-tivity over CYP11B1 and thus deserve further biological investigations of their F-18 labelled analogues.