title: 68Ga-labelled exendin-3, a new agent for the detection of insulinomas with PET.
abstract: OBJECTIVE
  Insulinomas are neuroendocrine tumours derived from pancreatic beta-cells. The glucagon-like peptide 1 receptor (GLP-1R) is expressed with a high incidence (>90%) and high density in insulinomas. Glucagon-like peptide 1 (GLP-1), the natural ligand of GLP-1R, is rapidly degraded in vivo. A more stable agonist of GLP-1R is exendin-3. We investigated imaging of insulinomas with DOTA-conjugated exendin-3 labelled with (68)Ga.
  
  
  METHODS
  Targeting of insulinomas with [Lys(40)(DOTA)]exendin-3 labelled with either (111)In or (68)Ga was investigated in vitro using insulinoma tumour cells (INS-1). [Lys(40)((111)In-DTPA)]Exendin-3 was used as a reference in this study. In vivo targeting was investigated in BALB/c nude mice with subcutaneous INS-1 tumours. PET imaging was performed using a preclinical PET/CT scanner.
  
  
  RESULTS
  In vitro exendin-3 specifically bound and was internalized by GLP-1R-positive cells. In BALB/c nude mice with subcutaneous INS-1 tumours a high uptake of [Lys(40)((111)In-DTPA)]exendin-3 in the tumour was observed (33.5 +/- 11.6%ID/g at 4 h after injection). Uptake was specific, as determined by coinjection of an excess of unlabelled [Lys(40)]exendin-3 (1.8 +/- 0.1%ID/g). The pancreas also exhibited high and specific uptake (11.3 +/- 1.0%ID/g). High uptake was also found in the kidneys (144 +/- 24%ID/g) and this uptake was not receptor-mediated. In this murine tumour model optimal targeting of the GLP-1R expressing tumour was obtained at exendin doses < or =0.1 microg. Remarkably, tumour uptake of (68)Ga-labelled [Lys(40)(DOTA)]exendin-3 was lower (8.9 +/- 3.1%ID/g) than tumour uptake of (111)In-labelled [Lys(40)(DTPA)]exendin-3 (25.4 +/- 7.2%ID/g). The subcutaneous tumours were clearly visualized by small-animal PET imaging after injection of 3 MBq of [Lys(40)((68)Ga-DOTA)]exendin-3.
  
  
  CONCLUSIONS
  [Lys(40)((68)Ga-DOTA)]Exendin-3 specifically accumulates in insulinomas, although the uptake is lower than that of [Lys(40)((111)In-DTPA)]exendin-3. Therefore, [Lys(40)((68)Ga-DOTA)]exendin-3 is a promising tracer to visualize insulinomas with PET.
authors.affiliation: Department of Nuclear Medicine, Radboud University Nijmegen Medical Centre, PO Box 9101, 6500 HB, Nijmegen, The Netherlands. m.brom@nucmed.umcn.nl
authors.forename: Maarten
authors.initials: M
authors.lastname: Brom
authors.forename: Wim J G
authors.initials: WJ
authors.lastname: Oyen
authors.forename: Lieke
authors.initials: L
authors.lastname: Joosten
authors.forename: Martin
authors.initials: M
authors.lastname: Gotthardt
authors.forename: Otto C
authors.initials: OC
authors.lastname: Boerman
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001692:Biological Transport; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D005260:Female; D005710:Gallium Radioisotopes; D006573:Heterocyclic Compounds, 1-Ring / Q000737:chemistry; D020128:Inhibitory Concentration 50; D007267:Injections; D007340:Insulinoma / Q000000981:diagnostic imaging* / Q000378:metabolism; D007700:Kinetics; D008239:Lysine / Q000737:chemistry; D051379:Mice; D008969:Molecular Sequence Data; D004369:Pentetic Acid / Q000737:chemistry; D010455:Peptides / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics; D049268:Positron-Emission Tomography / Q000379:methods*; D051381:Rats
chemical_list: D005710:Gallium Radioisotopes; D006573:Heterocyclic Compounds, 1-Ring; D010455:Peptides; C066448:exendin 3; C071349:1,4,7,10-tetraazacyclododecane- 1,4,7,10-tetraacetic acid; D004369:Pentetic Acid; D008239:Lysine