title: PET of insulinoma using ¹⁸F-FBEM-EM3106B, a new GLP-1 analogue.
abstract: Derived from endocrine pancreatic beta cells, insulinomas express glucagon-like peptide-1 (GLP-1) receptor with high density and incidence. In this study, we labeled a novel GLP-1 analogue, EM3106B, with (18)F and performed PET imaging to visualize insulinoma tumors in an animal model. A GLP-1 analogue that contains multiple lactam bridges, EM3106B, was labeled with (18)F through a maleimide-based prosthetic group, N-2-(4-(18)F-fluorobenzamido)ethylmaleimide ((18)F-FBEM). The newly developed radiotracer was characterized by cell based receptor-binding assay, cell uptake and efflux assay. The stability in serum was evaluated by radio-HPLC analysis. In vivo PET imaging was performed in nude mice bearing subcutaneous INS-1 insulinoma tumors and MDA-MB-435 tumors of melanoma origin. Ex vivo biodistribution study was performed to confirm the PET imaging data. EM3106B showed high binding affinity (IC(50) = 1.38 nM) and high cell uptake (5.25 ± 0.61% after 120 min incubation). (18)F-FBEM conjugation of EM3106B resulted in high labeling yield (24.9 ± 2.4%) and high specific activity (>75 GBq/μmol at the end of bombardment). EM3106B specifically bound and was internalized by GLP-1R positive INS-1 cells. After intravenous injection of 3.7 MBq (100 μCi) of (18)F-FBEM-EM3106B, the INS-1 tumors were clearly visible with high contrast in relation to the contralateral background on PET images, and tumor uptake of (18)F-FBEM-EM3106B was determined to be 28.5 ± 4.7 and 25.4 ± 4.1% ID/g at 60 and 120 min, respectively. (18)F-FBEM-EM3106B showed low uptake in MB-MDA-435 tumors with low level of GLP-1R expression. Direct tissue sampling biodistribution experiment confirmed high tracer uptake in INS-1 tumors and receptor specificity in both INS-1 tumor and pancreas. In conclusion, (18)F-FBEM-EM3106B exhibited GLP-1R-receptor-specific targeting properties in insulinomas. The favorable characteristics of (18)F-FBEM-EM3106B, such as high specific activity and high tumor uptake, and high tumor to nontarget uptake, demonstrate that it is a promising tracer for clinical insulinoma imaging.
authors.affiliation: Laboratory of Molecular Imaging and Nanomedicine, National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health, Bethesda, Maryland 20892, United States.
authors.forename: Haokao
authors.initials: H
authors.lastname: Gao
authors.forename: Gang
authors.initials: G
authors.lastname: Niu
authors.forename: Min
authors.initials: M
authors.lastname: Yang
authors.forename: Qimeng
authors.initials: Q
authors.lastname: Quan
authors.forename: Ying
authors.initials: Y
authors.lastname: Ma
authors.forename: Eunice N
authors.initials: EN
authors.lastname: Murage
authors.forename: Jung-Mo
authors.initials: JM
authors.lastname: Ahn
authors.forename: Dale O
authors.initials: DO
authors.lastname: Kiesewetter
authors.forename: Xiaoyuan
authors.initials: X
authors.lastname: Chen
mesh_terms: D000818:Animals; D001692:Biological Transport; D045744:Cell Line, Tumor; D003287:Contrast Media / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics; D004355:Drug Stability; D005260:Female; D052216:Glucagon-Like Peptide 1 / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics; D000067757:Glucagon-Like Peptide-1 Receptor; D006801:Humans; D007340:Insulinoma / Q000175:diagnosis* / Q000378:metabolism / Q000473:pathology; D007515:Islets of Langerhans / Q000378:metabolism / Q000473:pathology; D007769:Lactams / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics; D008301:Maleimides / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics; D051379:Mice; D008819:Mice, Nude; D057054:Molecular Imaging / Q000379:methods*; D009363:Neoplasm Proteins / Q000378:metabolism; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics; D010455:Peptides / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics; D049268:Positron-Emission Tomography; D018027:Receptors, Glucagon / Q000819:agonists / Q000378:metabolism; D014018:Tissue Distribution; D051598:Whole Body Imaging
chemical_list: D003287:Contrast Media; C000593833:GLP1R protein, human; C000593834:Glp1r protein, mouse; D000067757:Glucagon-Like Peptide-1 Receptor; D007769:Lactams; D008301:Maleimides; C512447:N-(2-(4-18F-fluorobenzamido)ethyl)maleimide; C570222:N-2-(4-fluorobenzamido)ethylmaleimide-EM 3106B; D009363:Neoplasm Proteins; D010446:Peptide Fragments; D010455:Peptides; D018027:Receptors, Glucagon; C061970:glucagon-like peptide 1 (7-36); D052216:Glucagon-Like Peptide 1