title: Islet-selectivity of G-protein coupled receptor ligands evaluated for PET imaging of pancreatic β-cell mass.
abstract: A critical unmet need exists for methods to quantitatively measure endogenous pancreatic β-cell mass (BCM) for the clinical evaluation of therapies to prevent or reverse loss of BCM and diabetes progression. Our objective was to identify G-protein coupled receptors (GPCRs) that are expressed with a high degree of specificity to islet β-cells for receptor-targeted imaging of BCM. GPCRs enriched in pancreatic islets relative to pancreas acinar and hepatic tissue were identified using a database screen. Islet-specific expression was confirmed by human pancreas immunohistochemistry (IHC). In vitro selectivity assessment was determined from the binding and uptake of radiolabeled ligands to the rat insulinoma INS-1 832/13 cell line and isolated rat islets relative to the exocrine pancreas cell-type, PANC-1. Tail-vein injections of radioligands into rats were used to determine favorable image criteria of in vivo biodistribution to the pancreas relative to other internal organs (i.e., liver, spleen, stomach, and lungs). Database and IHC screening identified four candidate receptors for further in vitro and in vivo evaluation for PET imaging of BCM: prokineticin-1 receptor (PK-1R), metabotropic glutamate receptor type-5 (mGluR5), neuropeptide Y-2 receptor (NPY-2R), and glucagon-like peptide 1 receptor (GLP-1R). In vitro specificity ratios gave the following receptor rank order: PK-1R>GLP-1R>NPY-2R>mGluR5. The biodistribution rank order of selectivity to the pancreas was found to be PK-1R>VMAT2∼GLP-1R>mGluR5. Favorable islet selectivity and biodistribution characteristics suggest several GPCRs as potential targets for PET imaging of pancreatic BCM.
authors.affiliation: Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520-8020, USA. gary.cline@yale.edu
authors.forename: Gary W
authors.initials: GW
authors.lastname: Cline
authors.forename: Xiaojian
authors.initials: X
authors.lastname: Zhao
authors.forename: Amy B
authors.initials: AB
authors.lastname: Jakowski
authors.forename: Walter C
authors.initials: WC
authors.lastname: Soeller
authors.forename: Judith L
authors.initials: JL
authors.lastname: Treadway
mesh_terms: D000818:Animals; D002460:Cell Line; D000067757:Glucagon-Like Peptide-1 Receptor; D006801:Humans; D050417:Insulin-Secreting Cells / Q000737:chemistry / Q000166:cytology / Q000378:metabolism*; D008024:Ligands; D008297:Male; D049268:Positron-Emission Tomography / Q000379:methods*; D051381:Rats; D017207:Rats, Sprague-Dawley; D064529:Receptor, Metabotropic Glutamate 5; D043562:Receptors, G-Protein-Coupled / Q000032:analysis / Q000378:metabolism*; D018027:Receptors, Glucagon / Q000032:analysis / Q000378:metabolism; D018094:Receptors, Metabotropic Glutamate / Q000032:analysis / Q000378:metabolism; D017476:Receptors, Neuropeptide Y / Q000032:analysis / Q000378:metabolism; D014018:Tissue Distribution
chemical_list: C000593833:GLP1R protein, human; C578935:GRM5 protein, human; C000593835:Glp1r protein, rat; D000067757:Glucagon-Like Peptide-1 Receptor; C578937:Grm5 protein, rat; D008024:Ligands; C470837:PROKR1 protein, human; D064529:Receptor, Metabotropic Glutamate 5; D043562:Receptors, G-Protein-Coupled; D018027:Receptors, Glucagon; D018094:Receptors, Metabotropic Glutamate; D017476:Receptors, Neuropeptide Y; C095889:neuropeptide Y2 receptor