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| 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 |
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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