Noninvasive Imaging of Islet Transplants with ¹¹¹In-Exendin-3 SPECT/CT

Abstract

Islet transplantation is a promising treatment for type 1 diabetic patients. However, there is acute as well as chronic loss of islets after transplantation. A noninvasive imaging method that could monitor islet mass might help to improve transplantation outcomes. In this study, islets were visualized after transplantation in a rat model with a dedicated small-animal SPECT scanner by targeting the glucagonlike peptide-1 receptor (GLP-1R), specifically expressed on β-cells, with 111 In-labeled exendin-3. Methods: Targeting of 111 Inexendin-3 to GLP-1R was tested in vitro on isolated islets of WAG/Rij rats. For in vivo evaluation, 400 or 800 islets were transplanted into the calf muscle of WAG/Rij rats (6-8 wk old). Four weeks after transplantation, SPECT/CT images were acquired 1 h after injection of 111 In-labeled exendin-3. After SPECT acquisition, the muscles containing the transplant were analyzed immunohistochemically and autoradiographically. Results: The binding assay, performed on isolated islets, showed a linear correlation between the number of islets and 111 In-exendin-3 accumulation (Pearson r 5 0.98). In vivo, a 1.70 ± 0.44-fold difference in tracer uptake between 400 and 800 transplanted islets was observed. Ex vivo analysis of the islet transplant showed colocalization of tracer accumulation on autoradiography, with insulin-positive cells and GLP-1R expression on immunohistochemistry. Conclusion: 111 In-exendin-3 accumulates specifically in the β-cells after islet transplantation and is a promising tracer for noninvasive monitoring of the islet mass. For type 1 diabetic patients with poor glycemic control, pancreatic islet transplantation is a promising but still experimental treatment. The standard transplantation procedure is infusion of pancreatic islets in the portal vein, where islets are trapped in the sinusoidal capillaries of the liver. Most patients become insulinindependent for more than 1 y after transplantation. However, insulin independency drops to approximately 10% 5 y after transplantation (1). Even though these insulin-dependent patients still profit from this treatment because instability of blood glucose levels and risk of hypoglycemia are reduced, further improvement of transplant survival and islet function is warranted, especially in view of the side effects of the immunosuppressive treatment that is required to prevent rejection of the transplanted islets (1-3).Current methods of monitoring islets after transplantation, such as measurement of hemoglobin A 1C , C-peptide, and insulin levels, provide only functional information and cannot accurately predict the number of surviving islets. Medical imaging methods may offer the possibility of monitoring the number of surviving islets after transplantation, potentially providing information (complementary to functional capacity) about the effect of interventions on transplantation outcome. This information might help to further improve this new therapeutic approach in order to achieve longerlasting insulin independency.Numerous st...

Association of glucagon‐like peptide‐1 receptor‐targeted imaging probe with in vivo glucagon‐like peptide‐1 receptor agonist glucose‐lowering effects

“…For the purpose of visualization and quantification of b-cells, GLP-1R-targeted imaging methods, such as single-photon emission computed tomography (SPECT) and positron emission tomography have recently emerged [8][9][10][11] . These methods were developed for the detection of insulinoma and transplanted islets, and the evaluation of b-cell mass [12][13][14] , and they have not been used for clinical prediction of drug efficacy in diabetes treatment. Using these methods in the present study, we investigated factors that might be related to the determination of in vivo GLP-1RA efficacy.…”

Improved Quantification of the Beta Cell Mass after Pancreas Visualization with 99mTc-demobesin-4 and Beta Cell Imaging with 111In-exendin-3 in Rodents

“…The reaction mixture was purified by solid-phase extraction using an HLB reversed-phase sorbent cartridge (30 mg, Water Oasis, Milford, MA, U.S.A.), as previously described. 10 After purification the radiochemical purity was >99%, with an average radiochemical yield of ∼60% 99m Tc-demobesin-4. Demobesin-4 was provided by the Molecular Radiopharmacy, NCSR Demokritos (Athens, Greece) and dissolved in 0.1% acetic acid in water and ethanol (8:2, v/v) at a final concentration of 1.8 mg/mL; aliquots thereof were stored at −20 °C.…”

“…The labeling efficiency was determined on silica gel instant thin layer chromatography (ITLC) using 0.1 M EDTA in 0.1 M NH 4 Ac pH 5.5 ( R f = 0, 111 In-exendin-3; R f = 1, 111 In-EDTA). The reaction mixture was purified by solid-phase extraction using an HLB reversed-phase sorbent cartridge (30 mg, Water Oasis, Milford, MA, U.S.A.), as previously described . After purification the radiochemical purity was >99%, with an average radiochemical yield of ∼60%…”

Squalene-PEG-Exendin as High-Affinity Constructs for Pancreatic Beta-Cells

“…1 H NMR (300 MHz, CDCl 3 ) δ 6.71 (br s, 1H, NH), 5.13−5.06 (m, 5H, CH), 3.72 (t, J = 5.8 Hz, 2H, CH 2 ), 3.67−3.61 (m, 26H, CH 2 ), 3.58−3.51 (m, 4H, 2×CH 2 −PEG), 3.37 (s, 3H, CH 3 O), 3.20 (q, J = 6.7 Hz, 2H, CH 2 NH), 2.49 (t, J = 5.7 Hz, 2H, CH 2 CO), 2.12−1.93 (m, 18H, CH 2 −SQ), 1.67 (s, 3H, CH 3 −SQ), 1.59 (br s, 15H, CH 3 −SQ). 13 C NMR (75 MHz, CDCl 3 ) δ 171.81, 135. 33, 135.24, 135.11, 134.24, 131.46, 125.14, 124.60, 124.53, 124.46, 72.14, 70.81, 70.78, 70.74, 70.73, 70.56, 70.45, 67.57, 59.25, 39.96, 39.93, 39.41, 37.15, 37.13, 28.49, 27.98, 26.97, 26.92, 26.87, 25.92, 17.91, 16.27, 16.22, 16.09.…”