Development of 68Ga- and 89Zr-Labeled Exendin-4 as Potential Radiotracers for the Imaging of Insulinomas by PET.

Unlabelled: Clinical studies have demonstrated the potential of radiometallated exendin-4 derivatives for the imaging of glucagonlike peptide-1 receptor-overexpressing insulinomas. Recently investigated exendin-4 derivatives were radiolabeled with the SPECT isotopes 99mTc or 111In. Despite promising results, the low spatial resolution associated with SPECT and the occasional need to perform imaging several days after injection for the demarcation of insulinomas from the kidneys represent current limitations. The aim of this work was the development of exendin-4 derivatives for the imaging of insulinomas by high-resolution PET at early or late time points after injection of the radiotracer.

Methods: An exendin-4 derivative conjugated to desferrioxamine (DFO) was used for radiolabeling with the PET isotopes 68Ga and 89Zr. Both radiotracers were evaluated in vitro with RIN-m5F cells for their cell internalization properties as well as affinities and specificities toward the glucagonlike peptide-1 receptor. Serum stabilities of the radiopeptides were assessed in blood serum, and their distribution coefficient was determined by the shake-flask method. Biodistribution experiments were performed with nude mice bearing RIN-m5F xenografts. For all experiments, clinically evaluated [Lys40-(AHX-DTPA-111In)NH2]exendin-4 was used as a reference compound.

Results: [Lys40-(AHX-DFO)NH2]exendin-4 was labeled with 89Zr and 68Ga in high radiochemical yield and purity. In vitro experiments showed favorable cell uptake and receptor affinity for [Lys40-(AHX-DFO-68Ga)NH2]exendin-4, and [Lys40-(AHX-DFO-89Zr)NH2]exendin-4 and [Lys40-(AHX-DTPA-111In)NH2]exendin-4 performed similarly well. In biodistribution experiments, [Lys40-(AHX-DFO-68Ga)NH2]exendin-4 exhibited a significantly enhanced tumor uptake 1 h after injection in comparison to the other 2 radiotracers. Tumor uptake of [Lys40-(AHX-DFO-89Zr)NH2]exendin-4 was comparable to that of [Lys40-(AHX-DTPA-111In)NH2]exendin-4 at 1-48 h after injection. All compounds showed a fast blood clearance and low accumulation in receptor-negative organs and tissue with the exception of the kidneys, a known characteristic for exendin-4-based radiotracers.

Conclusion: 68Ga- and 89Zr-radiolabeled [Lys40-(AHX-DFO)NH2]exendin-4 exhibit characteristics comparable or superior to the clinically tested reference compound [Lys40-(AHX-DTPA-111In)NH2]exendin-4 and, thus, represent potential new tracers for the imaging of insulinomas by PET.