Abstract
AimsMolecular 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.MethodsIn 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 ([3H]AZ1, [3H]AZ2 and [3H]TAK-875) for their off-target binding, receptor density and affinity in human pancreatic tissue (islets and exocrine) and rodent insulinoma.Results[3H]AZ1 showed improved specificity to FFAR1, with decreased off-target binding compared to [3H]AZ2 and [3H]TAK-875, while retaining high affinity in the nanomolar range. FFAR1 density in human islets was approximately 50% higher than in exocrine tissue.ConclusionsAZ1 is a suitable lead compound for PET labeling for molecular imaging of FFAR1 in humans, due to high affinity and reduced off-target binding.
Highlights
Free fatty acid receptor 1 (FFAR1), known as GPR40, is emerging as an important therapeutic target
free fatty acid receptor 1 (FFAR1) is highly expressed in the brain where it has been linked to neuronal function and pain as well as in taste bud cells acting as a dietary fat sensor
We examined radiolabeled small molecule FFAR1 binding probes for their off-target binding in human pancreatic tissue, in order to identify a lead compound for future Positron Emission Tomography (PET) labeling for quantitative imaging of FFAR1 in human
Summary
Free fatty acid receptor 1 (FFAR1), known as GPR40, is emerging as an important therapeutic target. It is a G-coupled transmembrane protein, which acts as a nutrient sensor by interacting with medium to long chain fatty acids, in particular eicosatrienoic acid (20:3) and docosahexaenoic acid (22:6) in the blood stream. It has been intricately linked with energy homeostasis, as receptor activation contributes to downstream increase in insulin secretion in the pancreatic beta cells. It could contribute to directly assess its regulation during different metabolic states in human
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