Pancreatic islet transplantation can be a more permanent treatment for type 1 diabetes compared to daily insulin administration. Quantitative and longitudinal noninvasive imaging of viable transplanted islets might help to further improve this novel therapy. Since islets express dopamine 2 (D2) receptors, they could be visualized by targeting this receptor. Therefore, the D2 receptor antagonist based tracer [(125/123)I][IBZM] was selected to visualize transplanted islets in a rat model. BZM was radioiodinated, and the labeling was optimized for position 3 of the aromatic ring. [(125)I]-3-IBZM was characterized in vitro using INS-1 cells and isolated islets. Subsequently, 1,000 islets were transplanted in the calf muscle of WAG/Rij rats and SPECT/CT images were acquired 6 weeks after transplantation. Finally, the graft containing muscle was dissected and analyzed immunohistochemically. Oxidative radioiodination resulted in 3 IBZM isomers with different receptor affinities. The use of 0.6 mg/mL chloramine-T hydrate resulted in high yield formation of predominantly [(125)I]-3-IBZM, the isomer harboring the highest receptor affinity. The tracer showed D2 receptor mediated binding to isolated islets in vitro. The transplant could be visualized by SPECT 6 weeks after transplantation. The transplants could be localized in the calf muscle and showed insulin and glucagon expression, indicating targeting of viable and functional islets in the transplant. Radioiodination was optimized to produce high yields of [(125)I]-3-IBZM, the isomer showing optimal D2R binding. Furthermore, [(123)I]IBZM specifically targets the D2 receptors on transplanted islets. In conclusion, this tracer shows potential for noninvasive in vivo detection of islets grafted in the muscle by D2 receptor targeting.

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Phosphorous-31 magnetic resonance spectroscopy (31P-MRS) provides a unique noninvasive window into myocardial energy homeostasis. Mouse models of cardiac disease are widely used in preclinical studies, but application of 31P-MRS in the in vivo mouse heart has been limited. The small-sized, fast-beating mouse heart imposes challenges regarding localized signal acquisition devoid of contamination with signal originating from surrounding tissues. Here, we report the implementation and validation of 3D Image Selected In vivo Spectroscopy (ISIS) for localized 31P-MRS of the in vivo mouse heart at 9.4 T. Cardiac 31P MR spectra were acquired in vivo in healthy mice (n = 9) and in transverse aortic constricted (TAC) mice (n = 8) using respiratory-gated, cardiac-triggered 3D ISIS. Localization and potential signal contamination were assessed with 31P-MRS experiments in the anterior myocardial wall, liver, skeletal muscle and blood. For healthy hearts, results were validated against ex vivo biochemical assays. Effects of isoflurane anesthesia were assessed by measuring in vivo hemodynamics and blood gasses. The myocardial energy status, assessed via the phosphocreatine (PCr) to ATP ratio, was ~25% lower in TAC mice compared to controls (0.76 ± 0.13 vs. 1.00 ± 0.15; P < 0.01). Localization with 1D ISIS resulted in two-fold higher PCr/ATP ratios than measured with 3D ISIS, due to high PCr levels of chest skeletal muscle that contaminate the 1D ISIS measurements. Ex vivo determinations of the myocardial PCr/ATP ratio (0.94 ± 0.24; n = 8) confirmed in vivo observations in control mice. Heart rate (497 ± 76 beats/min), mean arterial pressure (90 ± 3.3 mmHg), and blood oxygen saturation (96.2 ± 0.6 %) during the experimental conditions of in vivo 31P-MRS were within the normal physiological range. Our results show that respiratory-gated, cardiac-triggered 3D ISIS allows for noninvasive assessments of in vivo mouse myocardial energy homeostasis with 31P-MRS under physiological conditions.

Pancreatic islet transplantation is a promising therapy for patients with type 1 diabetes. However, the duration of long-term graft survival is limited due to inflammatory as well as non-inflammatory processes and routine clinical tests are not suitable to monitor islet survival. 111In-exendin-SPECT (single photon emission computed tomography) is a promising method to non-invasively image islets after transplantation and has the potential to help improve the clinical outcome. Whether 111In-exendin-SPECT allows detecting small differences in beta-cell mass (BCM) and measuring the actual volume of islets that were successfully engrafted has yet to be demonstrated. Here, we evaluated the performance of 111In-exendin-SPECT using an intramuscular islet transplantation model in C3H mice. In vivo imaging of animals transplanted with 50, 100, 200, 400 and 800 islets revealed an excellent linear correlation between SPECT quantification of 111In-exendin uptake and insulin-positive area of islet transplants, demonstrating that 111In-exendin-SPECT specifically and accurately measures BCM. The high sensitivity of the method allowed measuring small differences in graft volumes, including grafts that contained less than 50 islets. The presented method is reliable, convenient and holds great potential for non-invasive monitoring of BCM after islet transplantation in humans.

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...

Radiolabeled exendin is used for non-invasive quantification of beta cells in the islets of Langerhans in vivo. High accumulation of radiolabeled exendin in the islets raised concerns about possible radiation-induced damage to these islets in man. In this work, islet absorbed doses resulting from exendin-imaging were calculated by combining whole organ dosimetry with small scale dosimetry for the islets. Our model contains the tissues with high accumulation of radiolabeled exendin: kidneys, pancreas and islets. As input for the model, data from a clinical study (radiolabeled exendin distribution in the human body) and from a preclinical study with Biobreeding Diabetes Prone (BBDP) rats (islet-to-exocrine uptake ratio, beta cell mass) were used. We simulated 111In-exendin and 68Ga-exendin absorbed doses in patients with differences in gender, islet size, beta cell mass and radiopharmaceutical uptake in the kidneys. In all simulated cases the islet absorbed dose was small, maximum 1.38 mGy for 68Ga and 66.0 mGy for 111In. The two sources mainly contributing to the islet absorbed dose are the kidneys (33–61%) and the islet self-dose (7.5–57%). In conclusion, all islet absorbed doses are low (<70 mGy), so even repeated imaging will hardly increase the risk on diabetes.

Tc-demobesin-4 shows high accumulation in the pancreas of rats. It is a suitable tracer for accurate delineation of the pancreas and can be conveniently used for simultaneous acquisition with In labeled exendin-3. This method provides a straightforward, reliable, and objective method for preclinical beta cell mass (BCM) quantification withIn-exendin-3.