PET of insulinoma using 18F-FBEM-EM3106B, a new GLP-1 analogue

Haokao Gao, Gang Niu, Min Yang, Qimeng Quan, Ying Ma, Eunice N. Murage, Jung Mo Ahn, Dale O. Kiesewetter, Xiaoyuan Chen

Research output: Contribution to journalArticle

55 Scopus citations

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 18F 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 18F through a maleimide-based prosthetic group, N-2-(4- 18F-fluorobenzamido)ethylmaleimide (18F-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 (IC50 = 1.38 nM) and high cell uptake (5.25 ± 0.61% after 120 min incubation). 18F-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 18F-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 18F-FBEM- EM3106B was determined to be 28.5 ± 4.7 and 25.4 ± 4.1% ID/g at 60 and 120 min, respectively. 18F-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, 18F-FBEM-EM3106B exhibited GLP-1R-receptor-specific targeting properties in insulinomas. The favorable characteristics of 18F-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.

Original languageEnglish (US)
Pages (from-to)1775-1782
Number of pages8
JournalMolecular Pharmaceutics
Volume8
Issue number5
DOIs
StatePublished - Oct 3 2011

Keywords

  • F-FBEM
  • PET
  • bicyclic GLP-1 analogue
  • glucagon-like peptide-1 receptor
  • insulinoma

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmaceutical Science
  • Drug Discovery

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  • Cite this

    Gao, H., Niu, G., Yang, M., Quan, Q., Ma, Y., Murage, E. N., Ahn, J. M., Kiesewetter, D. O., & Chen, X. (2011). PET of insulinoma using 18F-FBEM-EM3106B, a new GLP-1 analogue. Molecular Pharmaceutics, 8(5), 1775-1782. https://doi.org/10.1021/mp200141x