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

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.

[1]  Xiaoyuan Chen,et al.  Automated radiochemical synthesis of [18F]FBEM: a thiol reactive synthon for radiofluorination of peptides and proteins. , 2011, Applied radiation and isotopes : including data, instrumentation and methods for use in agriculture, industry and medicine.

[2]  F. Pattou,et al.  GLP-1-receptor scanning for imaging of human beta cells transplanted in muscle. , 2010, The New England journal of medicine.

[3]  Jung-Mo Ahn,et al.  Development of potent glucagon-like peptide-1 agonists with high enzyme stability via introduction of multiple lactam bridges. , 2010, Journal of medicinal chemistry.

[4]  B. Keil,et al.  Exendin-4–Based Radiopharmaceuticals for Glucagonlike Peptide-1 Receptor PET/CT and SPECT/CT , 2010, Journal of Nuclear Medicine.

[5]  M. Culler,et al.  Taspoglutide, an analog of human glucagon-like Peptide-1 with enhanced stability and in vivo potency. , 2010, Endocrinology.

[6]  W. Oyen,et al.  68Ga-labelled exendin-3, a new agent for the detection of insulinomas with PET , 2010, European Journal of Nuclear Medicine and Molecular Imaging.

[7]  F. Forrer,et al.  Glucagon-like peptide-1 receptor imaging for localization of insulinomas. , 2009, The Journal of clinical endocrinology and metabolism.

[8]  B. Ahrén.  Islet G protein-coupled receptors as potential targets for treatment of type 2 diabetes , 2009, Nature Reviews Drug Discovery.

[9]  Emanuel Christ,et al.  Glucagon-like peptide 1-receptor scans to localize occult insulinomas. , 2008, The New England journal of medicine.

[10]  H. Maecke,et al.  68Ga-PET: a powerful generator-based alternative to cyclotron-based PET radiopharmaceuticals. , 2008, Contrast media & molecular imaging.

[11]  S. Kneifel,et al.  [Lys40(Ahx-DTPA-111In)NH2]-Exendin-4 Is a Highly Efficient Radiotherapeutic for Glucagon-Like Peptide-1 Receptor–Targeted Therapy for Insulinoma , 2007, Clinical Cancer Research.

[12]  J. Reubi,et al.  GLP-1 Receptor Expression in Human Tumors and Human Normal Tissues: Potential for In Vivo Targeting , 2007, Journal of Nuclear Medicine.

[13]  Martin Gotthardt,et al.  [Lys40(Ahx-DTPA-111In)NH2]exendin-4, a very promising ligand for glucagon-like peptide-1 (GLP-1) receptor targeting. , 2006, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[14]  K. Horton,et al.  Multi-detector row CT of pancreatic islet cell tumors. , 2006, Radiographics : a review publication of the Radiological Society of North America, Inc.

[15]  J. Jackson.  Angiography and arterial stimulation venous sampling in the localization of pancreatic neuroendocrine tumours. , 2005, Best practice & research. Clinical endocrinology & metabolism.

[16]  T. Pfammatter,et al.  Selective arterial calcium stimulation and hepatic venous sampling in the evaluation of hyperinsulinemic hypoglycemia: potential and limitations. , 2004, Journal of vascular and interventional radiology : JVIR.

[17]  J. Reubi,et al.  Concomitant expression of several peptide receptors in neuroendocrine tumours: molecular basis for in vivo multireceptor tumour targeting , 2003, European Journal of Nuclear Medicine and Molecular Imaging.

[18]  Martin Gotthardt,et al.  Use of the incretin hormone glucagon-like peptide-1 (GLP-1) for the detection of insulinomas: initial experimental results , 2002, European Journal of Nuclear Medicine and Molecular Imaging.

[19]  N. Kavatzas,et al.  Imaging and localization of pancreatic insulinomas. , 2001, Clinical imaging.

[20]  I. Modlin,et al.  Approaches to the diagnosis of gut neuroendocrine tumors: the last word (today). , 1997, Gastroenterology.

[21]  E. P. Krenning,et al.  Somatostatin receptor scintigraphy with [111In-DTPA-d-Phe1]- and [123I-Tyr3]-octreotide: the Rotterdam experience with more than 1000 patients , 1993, European Journal of Nuclear Medicine.