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- Title
Toward molecular imaging of the free fatty acid receptor 1.
- Authors
Hellström-Lindahl, Ewa; Åberg, Ola; Ericsson, Cecilia; O'mahony, Gavin; Johnström, Peter; Skrtic, Stanko; Eriksson, Olof
- Abstract
Aims: 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. Methods: 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]AZ1, [H]AZ2 and [H]TAK-875) for their off-target binding, receptor density and affinity in human pancreatic tissue (islets and exocrine) and rodent insulinoma. Results: [H]AZ1 showed improved specificity to FFAR1, with decreased off-target binding compared to [H]AZ2 and [H]TAK-875, while retaining high affinity in the nanomolar range. FFAR1 density in human islets was approximately 50% higher than in exocrine tissue. Conclusions: 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.
- Subjects
FREE fatty acids; DRUG development; DRUG lipophilicity; PANCREATIC physiology; IMAGING systems in biology
- Publication
Acta Diabetologica, 2017, Vol 54, Issue 7, p663
- ISSN
0940-5429
- Publication type
Article
- DOI
10.1007/s00592-017-0989-7