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Toward molecular imaging of the free fatty acid receptor 1

Journal article
Authors E. Hellstrom-Lindahl
O. Aberg
C. Ericsson
G. O'Mahony
P. Johnstrom
Stanko Skrtic
O. Eriksson
Published in Acta Diabetologica
Volume 54
Issue 7
Pages 663-668
ISSN 0940-5429
Publication year 2017
Published at Institute of Medicine
Pages 663-668
Language en
Links dx.doi.org/10.1007/s00592-017-0989-...
https://gup.ub.gu.se/file/207016
Keywords FFAR1, GPR40, Beta cell imaging, Islet imaging, Drug development, GLUCAGON-SECRETION, COUPLING REACTIONS, BETA-CELLS, GPR40, RADIOTRACERS, TAK-875, AGONIST, INSULIN, IODIDE
Subject categories Diabetology

Abstract

Molecular imaging of the free fatty acid receptor 1 (FFAR1) would be a valuable tool for drug development by enabling in vivo target engagement studies in human. It has also been suggested as a putative target for beta cell imaging, but the inherent lipophilicity of most FFAR1 binders produces high off-target binding, which has hampered progress in this area. The aim of this study was to generate a suitable lead compound for further PET labeling. In order to identify a lead compound for future PET labeling for quantitative imaging of FFAR1 in human, we evaluated tritiated small molecule FFAR1 binding probes ([H-3]AZ1, [H-3]AZ2 and [H-3]TAK-875) for their off-target binding, receptor density and affinity in human pancreatic tissue (islets and exocrine) and rodent insulinoma. [H-3]AZ1 showed improved specificity to FFAR1, with decreased off-target binding compared to [H-3]AZ2 and [H-3]TAK-875, while retaining high affinity in the nanomolar range. FFAR1 density in human islets was approximately 50% higher than in exocrine tissue. AZ1 is a suitable lead compound for PET labeling for molecular imaging of FFAR1 in humans, due to high affinity and reduced off-target binding.

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