Design, Synthesis, and Characterization of a Fluoroprobe for Live Human Islet Cell Imaging of Serotonin 5-HT1A Receptor

Garvey, Robert W.; Lacivita, Enza; Niso, Mauro; Duszyńska, Beata; Harris, Paul Emerson; Leopoldo, Marcello

Mounting evidence suggests that the serotonin system serves in signal transmission to regulate insulin secretion in pancreatic islets of Langerhans. Among the 5-HT receptor subtype found in pancreatic islets, serotonin receptor 1 A (5-HT1A) demonstrates a unique ability to inhibit β-cell insulin secretion. We report the design, synthesis, and characterization of two novel fluorescent probes for the 5-HT1A receptor. The compounds were prepared by conjugating the scaffold of the 5-HT1A receptor agonist 8-OH-DPAT with two fluorophores suitable for live-cell imaging. Compound 5a {5-(dimethylamino)-N-[5-[(8-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)(propyl)amino]pentyl]naphtalen-1-sulfonammide} showed high affinity for the 5-HT1A receptor (Ki=1.8 nM). Fluoroprobe 5a was able to label the 5-HT1A receptor in pancreatic islet cell cultures in a selective manner, as the fluorescence emission was significantly attenuated by co-administration of the 5-HT1A receptor antagonist WAY-100635. Thus, fluoroprobe 5a showed useful properties to further characterize this unique receptor‘s role.


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April 4, 2022


Work supported by the NYSTEM: Stem Cell Research Experience for Pre-College Teachers, Contract #C30163GG, and the Columbia University Summer Research Program (R.W.G.) and the NIDDK (1R01DK104740), the Nancy H. Biddle Family Foundation (P.E.H.).