Evaluation of [68Ga]DO3A-VS-Cys40-Exendin-4 as a PET Probe for Imaging Human Transplanted Islets in the Liver

Abstract

[ 68 Ga]DO3A-VS-Cys 40 -Exendin-4, a glucagon-like peptide 1 receptor agonist, was evaluated as a potential PET tracer for the quantitation of human islets transplanted to the liver. The short-lived PET radionuclide 68 Ga, available on a regular basis from a 68 Ge/ 68 Ga generator, is an attractive choice. Human C-peptide was measured to evaluate human islet function post-transplantation and prior to microPET imaging. [ 68 Ga]DO3A-VS-Cys 40 -Exendin-4 was radiosynthesized and evaluated for PET imaging of transplanted human islets in the liver of healthy NOD/SCID mice. The biodistribution of the tracer was evaluated to determine the uptake into various organs, and qPCR of liver samples was conducted to confirm engrafted islet numbers after PET imaging. Measurement of human C-peptide indicated that higher engrafted islet mass resulted in higher human C-peptide levels in post-transplantation. The microPET imaging yielded high resolution images of liver-engrafted islets and also showed significant retention in mouse livers at 8 weeks post-transplantation. Biodistribution studies in mice revealed that liver uptake of [ 68 Ga]DO3A-VS-Cys 40 -Exendin-4 was approximately 6-fold higher in mice that received 1000 islet equivalent (IEQ) than in non-transplanted mice. qPCR analysis of insulin expression suggested that islet engraftment numbers were close to 1000 IEQ transplanted. In conclusion, human islets transplanted into the livers of mice exhibited significant uptake of [ 68 Ga]DO3A-VS-Cys 40 -Exendin-4 compared to the livers of untreated mice; and imaging of the mice using PET showed the human islets clearly with high contrast against liver tissue, enabling accurate quantitation of islet mass. Further validation of [ 68 Ga]DO3A-VS-Cys 40 -Exendin-4 as an islet imaging probe for future clinical application is ongoing.

Non-invasive Beta-cell Imaging: Visualization, Quantification, and Beyond

“…Although exendin-3 probe uptake in islet grafts might be affected by the glycemic state via GLP-1R expression (presumably due to the small number of islets in a graft), the linear correlation between probe uptake and islet graft volume was maintained (110). In mice that underwent intraportal islet transplantation, 68 Ga-DO3A-VS-Cys 40 -exendin-4 PET visualized human transplanted islets in the liver (112). As a clinical report of a patient with the autologous transplanted islets in the left brachioradialis muscle, [Lys 40 (Ahx-DTPA- 111 In)NH2]exendin-4 SPECT demonstrated focal accumulation in the left forearm at the site of islet transplantation (113).…”

Optimal Time to Ship Human Islets Post Tissue Culture to Maximize Islet Recovery

“…There continues to be an overwhelming need for high-quality human islets for a myriad of research studies attempting to understand and treat diabetes. Human islets are a staple for diabetes investigators working on a wide range of experiments, from developing new diagnostic tools 31 , including new chip technology 32 , to prototypes for encapsulation studies 33 , 34 , alternate transplant sites 35 , 36 , selection of biomaterials for implants 37 , and basic science for the understanding of islet physiology 38 , 39 . As the need for human islets increases with the rise in the number of studies requiring them, islet distribution organizations need to be cognizant of variables that influence islet recovery and function.…”

In Vivo Imaging of Pancreatic Islet Grafts in Diabetes Treatment

“…Five hundred or one thousand human islets engrafted via the portal vein in the liver of immunodeficient NOD/SCID mice could be visualized with microPET at 90 min after systemic injection of ~4 MBq 68 Ga-DO3A-VS-Cys 40 -exendin-4, a radiolabeled glucagonlike peptide-1 receptor agonist ( 30 ). 18 F-fallypride bound to D2/D3 receptors of islets and enabled PET imaging of 6,000 syngeneic Sprague–Dawley rat islet implants in the spleen at 120–180 min after intravenous (i.v.)…”