Synthesis and Characterization of a Promising Novel FFAR1/GPR40 Targeting Fluorescent Probe for β-Cell Imaging.
Diabetes affects an increasing number of patients worldwide and is responsible for a significant rise in healthcare expenses. Imaging of β-cells bears the potential to contribute to an improved understanding, diagnosis, and development of new treatment options for diabetes. Here, we describe the first small molecule fluorescent probe targeting the free fatty acid receptor 1 (FFAR1/GPR40). This receptor is highly expressed on β-cells, and was up to now unexplored for imaging purposes. We designed a novel probe by facile modification of the selective and potent FFAR1 agonist TAK-875. Effective and specific binding of the probe was demonstrated using FFAR1 overexpressing cells. We also successfully labeled FFAR1 on MIN6 and INS1E cells, two widely used β-cell models, by applying an effective amplification protocol. Finally, we showed that the probe is capable of inducing insulin secretion in a glucose-dependent manner, thus demonstrating that functional activity of the probe was maintained. These results suggest that our probe represents a first important step to successful β-cell imaging by targeting FFAR1. The developed probe may prove to be particularly useful for in vitro and ex vivo studies of diabetic cellular and animal models to gain new insights into disease pathogenesis.
Diabetes Division, Research & Translational Medicine, Sanofi GmbH , Frankfurt am Main 65926, Germany.|Department of Nuclear Medicine, Radboud UMC , Nijmegen 6525, The Netherlands.
Romain
R
Bertrand
Diabetes Division, Research & Translational Medicine, Sanofi GmbH , Frankfurt am Main 65926, Germany.
Andrea
A
Wolf
Diabetes Division, Research & Translational Medicine, Sanofi GmbH , Frankfurt am Main 65926, Germany.
Yuri
Y
Ivashchenko
Diabetes Division, Research & Translational Medicine, Sanofi GmbH , Frankfurt am Main 65926, Germany.
Matthias
M
Löhn
Diabetes Division, Research & Translational Medicine, Sanofi GmbH , Frankfurt am Main 65926, Germany.
Matthias
M
Schäfer
DSAR/Drug Disposition, Sanofi GmbH , Frankfurt am Main 65926, Germany.|Helmholtz Centre for Infection Research, Braunschweig 38124, Germany.
Mark
M
Brönstrup
Department of Nuclear Medicine, Radboud UMC , Nijmegen 6525, The Netherlands.
Martin
M
Gotthardt
DSAR/Drug Disposition, Sanofi GmbH , Frankfurt am Main 65926, Germany.
Volker
V
Derdau
Diabetes Division, Research & Translational Medicine, Sanofi GmbH , Frankfurt am Main 65926, Germany.|Institute of Medicinal Chemistry, Helmholtz Zentrum München , Ingolstaedter Landstr. 1, Neuherberg 85764, Germany.|Leibniz University Hannover, Schneiderberg 1 B, Hannover 30167, Germany.
Oliver
O
Plettenburg
D000818:Animals; D001572:Benzofurans / Q000737:chemistry / Q000494:pharmacology; D003920:Diabetes Mellitus / Q000000981:diagnostic imaging; D005456:Fluorescent Dyes / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D057809:HEK293 Cells; D006801:Humans; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism; D051379:Mice; D057054:Molecular Imaging; D051381:Rats; D043562:Receptors, G-Protein-Coupled / Q000819:agonists / Q000737:chemistry / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013450:Sulfones / Q000737:chemistry / Q000494:pharmacology
D001572:Benzofurans; C473034:FFAR1 protein, human; D005456:Fluorescent Dyes; D007328:Insulin; D043562:Receptors, G-Protein-Coupled; D013450:Sulfones; C557331:TAK-875