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In Vivo Visualization of beta-Cells by Targeting of GPR44
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Theranostics.
Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
Karolinska Institutet and Stockholm County Council, Stockholm, Sweden.
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2018 (English)In: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 67, no 2, p. 182-192Article in journal (Refereed) Published
Abstract [en]

GPR44 expression has recently been described as highly beta-cell selective in the human pancreas and constitutes a tentative surrogate imaging biomarker in diabetes. A radiolabeled small-molecule GPR44 antagonist, [C-11]AZ12204657, was evaluated for visualization of beta-cells in pigs and non-human primates by positron emission tomography as well as in immunodeficient mice transplanted with human islets under the kidney capsule. In vitro autoradiography of human and animal pancreatic sections from subjects without and with diabetes, in combination with insulin staining, was performed to assess beta-cell selectivity of the radiotracer. Proof of principle of in vivo targeting of human islets by [C-11]AZ12204657 was shown in the immunodeficient mouse transplantation model. Furthermore, [C-11]AZ12204657 bound by a GPR44-mediated mechanism in pancreatic sections from humans and pigs without diabetes, but not those with diabetes. In vivo [C-11]AZ12204657 bound specifically to GPR44 in pancreas and spleen and could be competed away dose-dependently in nondiabetic pigs and nonhuman primates. [C-11]AZ12204657 is a first-in-class surrogate imaging biomarker for pancreatic beta-cells by targeting the protein GPR44.

Place, publisher, year, edition, pages
2018. Vol. 67, no 2, p. 182-192
National Category
Endocrinology and Diabetes
Identifiers
URN: urn:nbn:se:uu:diva-342900DOI: 10.2337/db17-0764ISI: 000426034500003PubMedID: 29208633OAI: oai:DiVA.org:uu-342900DiVA, id: diva2:1185330
Funder
Swedish Research Council, K2015-54X-12219-19-4, K2013-64X-08268-26-3, K2013-55X-15043, 921-2014-7054Ernfors FoundationGöran Gustafsson Foundation for Research in Natural Sciences and MedicineSwedish Child Diabetes FoundationSwedish Diabetes AssociationEXODIAB - Excellence of Diabetes Research in SwedenAvailable from: 2018-02-23 Created: 2018-02-23 Last updated: 2018-05-09Bibliographically approved

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Eriksson, OlofSelvaraju, Ram kumarKorsgren, Olle

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