TY - JOUR

T1 - Synthesis and Characterization of a Promising Novel FFAR1/GPR40 Targeting Fluorescent Probe for β-Cell Imaging

AU - Bertrand, Romain

AU - Wolf, Andrea

AU - Ivashchenko, Yuri

AU - Löhn, Matthias

AU - Schäfer, Matthias

AU - Brönstrup, Mark

AU - Gotthardt, Martin

AU - Derdau, Volker

AU - Plettenburg, Oliver

N1 - Funding Information: The research leading to these results has received funding from the People Program (Marie Curie Actions) of the European Union's Seventh Framework Program FP7/2007-2013/under REA Grant Agreement No. 289932. Publisher Copyright: © 2016 American Chemical Society.

PY - 2016/6/17

Y1 - 2016/6/17

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84975462015&partnerID=8YFLogxK

U2 - 10.1021/acschembio.5b00791

DO - 10.1021/acschembio.5b00791

M3 - Article

C2 - 27115176

AN - SCOPUS:84975462015

VL - 11

SP - 1745

EP - 1754

JO - ACS chemical biology

JF - ACS chemical biology

SN - 1554-8929

IS - 6

ER -