Entwicklung eines Radiopharmakons zur Darstellung von Insulinomen im Tiermodell auf Basis des Inkretinhormons GLP-1(7-36)amid und seiner Analoga

The non-invasive detection of insulinomas remains a diagnostic problem that is not jet solved completely. In this MD thesis, radiopharmaceuticals for the scintigraphic detection of insulinomas were examined. These radiopharmaceuticals were used to visualize tumours in an animal model. The following experiments were performed: 1. Radioiodination of GLP-1, its analogue exendin3, and a modified peptide [Y39]-exendin4 followed by purification with HPLC and a Sephadex column. 2. An insulinoma model was established in rats. 3. Biodistribution studies of the radiopeptides in healthy animals. Investigation of the blood clearance and the influence of different stabilizing agents by the use of scintigraphy. 4. Visualisation of tumours induced in the animal model with the radiotracers developed in the experiments performed for this thesis. GLP-1 was labelled successfully with radioiodine. Radiolabelling of exendin3 resulted in a very low specific activity, whereas radiolabelled [Y39]-exendin4 showed an intermediate specific activity. An insulinoma model could be established using a rat insulinoma cell line. RINm5F cells were cultivated and injected subcutanously in NEDH rats. Further tumour transfer was carried out by the transplantation of tumour tissue. Biodistribution studies showed rapid blood clearance and rapid renal elimination. The time-activity curves of the heart showed two-phase kinetics, as would be expected for oligopeptides. The blood half life was within minutes for GLP-1 and [Y39]-exendin4, with evidence for a longer circulation of [Y39]-exendin4. In both peptides, deiodination occurred, resulting in accumulation of activity in the thyroid gland and the stomach. No significant influence of a DP IV inhibitor on the blood half life of both peptides was found. In contrast to GLP-1 and [Y39]-exendin4, exendin3 proved to be more stable. No free iodine was found in the thyroid gland using this compound. Insulinomas in rats could be visualized by I-123-GLP-1, I-123-[Y39]-exendin4 and I-123-exendin3. There was rapid accumulation of activity in the tumours. By using I-123-exendin3, a superior tumour to background ratio was achieved. In this thesis, a new scintigraphic method based on the visualization of GLP-1-receptors has been developed. In conclusion this thesis showed that GLP-1 receptor scintigraphy has potential for the non-invasive pre operative localisation of insulinomas. Stable radiolabelling of GLP-1 and its analogues with radionuclides other than iodine, preferably radiometals, may better suit the purpose of tumour scintigraphy in man.