68Ga-labelled exendin-3, a new agent for the detection of insulinomas with PET

M. Brom, W. Oyen, L. Joosten, M. Gotthardt and O. Boerman

Department of Nuclear Medicine, Radboud University Nijmegen Medical Centre, PO Box 9101, 6500 HB, Nijmegen, The Netherlands. m.brom@nucmed.umcn.nl
Jul, 2010



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.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.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.[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.