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Toward molecular imaging of the free fatty acid receptor 1
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Molecular Imaging.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Molecular Imaging.
AstraZeneca R&D, SE-43150 Molndal, Sweden..
AstraZeneca R&D, SE-43150 Molndal, Sweden..
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2017 (English)In: Acta Diabetologica, ISSN 0940-5429, E-ISSN 1432-5233, Vol. 54, no 7, p. 663-668Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
SPRINGER-VERLAG ITALIA SRL , 2017. Vol. 54, no 7, p. 663-668
Keywords [en]
FFAR1, GPR40, Beta cell imaging, Islet imaging, Drug development
National Category
Endocrinology and Diabetes
Identifiers
URN: urn:nbn:se:uu:diva-329002DOI: 10.1007/s00592-017-0989-7ISI: 000403508100006PubMedID: 28409274OAI: oai:DiVA.org:uu-329002DiVA, id: diva2:1138625
Funder
Swedish Child Diabetes FoundationSwedish Diabetes AssociationGöran Gustafsson Foundation for Research in Natural Sciences and MedicineAvailable from: 2017-09-06 Created: 2017-09-06 Last updated: 2017-09-06Bibliographically approved

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