Toward molecular imaging of the free fatty acid receptor 1Show others and affiliations
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 Medicine2017-09-062017-09-062017-09-06Bibliographically approved