Development and Evaluation of <sup>18</sup>F-TTCO-Cys<sup>40</sup>-Exendin-4: A PET Probe for Imaging Transplanted Islets

Wu, Zhanhong; Liu, Shuanglong; Hassink, Matthew; Nair, Indu; Park, Ryan; Li, Lin; Todorov, Ivan; Fox, Joseph M.; Li, Zibo; Shively, John E.; Conti, Peter S.; Kandeel, Fouad

doi:10.2967/jnumed.112.109694

Cited by 97 publications

(94 citation statements)

References 31 publications

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“…For the GLP-1R antagonist exendin-(9-39) labelled with 18 F, however, no correlation between uptake and pancreatic BCM could be demonstrated in a rat model [16]. This is probably due to the fact that the antagonist exendin- is not suitable for in vivo targeting of the GLP-1R [31], indicating that agonistic activity is required for successful visualisation of beta cells in vivo.…”

Section: Discussionmentioning

confidence: 67%

“…Previous preclinical studies with exendin labelled with 18 F or 64 Cu have demonstrated their ability to visualise transplanted islets and subcutaneous tumours in rodents [18,19]. For the GLP-1R antagonist exendin-(9-39) labelled with 18 F, however, no correlation between uptake and pancreatic BCM could be demonstrated in a rat model [16].…”

Section: Discussionmentioning

confidence: 82%

“…A potential target for measurement of the BCM is the glucagon-like peptide 1 receptor (GLP-1R) as it is abundantly expressed in rat, mouse and human pancreatic beta cells but not in α, δ and pp cells [13,14]. Exendin is a stable agonist of the GLP-1R and it has been used for in vivo targeting of the GLP-1R after labelling with various radionuclides [15][16][17][18][19]. Exendin labelled with indium-111 could be used to determine the BCM in vivo by SPECT.…”

Section: Introductionmentioning

confidence: 99%

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Non-invasive quantification of the beta cell mass by SPECT with 111In-labelled exendin

et al. 2014

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Aims/hypothesis A reliable method for in vivo quantification of pancreatic beta cell mass (BCM) could lead to further insight into the pathophysiology of diabetes. The glucagonlike peptide 1 receptor, abundantly expressed on beta cells, may be a suitable target for imaging. We investigated the potential of radiotracer imaging with the GLP-1 analogue exendin labelled with indium-111 for determination of BCM in vivo in a rodent model of beta cell loss and in patients with type 1 diabetes and healthy individuals. MethodsThe targeting of 111 In-labelled exendin was examined in a rat model of alloxan-induced beta cell loss. Rats were injected with 15 MBq 111 In-labelled exendin and single photon emission computed tomography (SPECT) acquisition was performed 1 h post injection, followed by dissection, biodistribution and ex vivo autoradiography studies of pancreatic sections. BCM was determined by morphometric analysis after staining with an anti-insulin antibody. For clinical evaluation SPECT was acquired 4, 24 and 48 h after injection of 150 MBq 111 In-labelled exendin in five patients with type 1 Maarten Brom and Wietske Woliner-van der Weg contributed equally to this study. Diabetologia (2014) 57:950-959 DOI 10.1007 diabetes and five healthy individuals. The tracer uptake was determined by quantitative analysis of the SPECT images. Results In rats, 111 In-labelled exendin specifically targets the beta cells and pancreatic uptake is highly correlated with BCM. In humans, the pancreas was visible in SPECT images and the pancreatic uptake showed high interindividual variation with a substantially lower uptake in patients with type 1 diabetes. Conclusions/interpretation These studies indicate that 111 Inlabelled exendin may be suitable for non-invasive quantification of BCM.

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Section: Discussionmentioning

confidence: 67%

Section: Discussionmentioning

confidence: 82%

Section: Introductionmentioning

confidence: 99%

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Non-invasive quantification of the beta cell mass by SPECT with 111In-labelled exendin

et al. 2014

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“…This strategy was applied by Wu et al, who used PET after injection of exendin-4 labeled with 64 Cu or 18 F to visualize islets transplanted into the liver (9,20). In these studies, nonspecific uptake of the tracer in the liver caused relatively high background signal (20), which might hamper accurate quantification of GLP-1R-mediated accumulation of the tracer.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2016

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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...

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“…Moreover, Wu's group used 18 F-tetrazine trans-cycloctene (TTCO) ligation for the development of an 18 F-labeled exendin-4 targeting the glucagonlike peptide-1 receptor (GLP-1R) ( Table 2, entry 5). The resulting 18 F-TTCO-Cys 40 -exendin-4 shows specific binding to GLP-1R and provides a method to noninvasively image transplanted islets through small animal PET studies [45]. With the aim to increase the in vivo stability of the 18 F-TCO moiety, Knight et al used an 18 F-labeled norbornene derivative, which was synthesized by acylation reaction of the amine-functionalized norbornene precursor with the known 18 C-labeled tetrazine for the TTCO ligation ( Table 2, entry 7).…”

Section: Diels-alder Cycloadditionmentioning

confidence: 99%

Click Reaction: An Applicable Radiolabeling Method for Molecular Imaging

Choi

Lee

2015

Nucl Med Mol Imaging

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Development and Evaluation of ¹⁸F-TTCO-Cys⁴⁰-Exendin-4: A PET Probe for Imaging Transplanted Islets

Cited by 97 publications

References 31 publications

Non-invasive quantification of the beta cell mass by SPECT with 111In-labelled exendin

Non-invasive quantification of the beta cell mass by SPECT with 111In-labelled exendin

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

Click Reaction: An Applicable Radiolabeling Method for Molecular Imaging

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Development and Evaluation of 18F-TTCO-Cys40-Exendin-4: A PET Probe for Imaging Transplanted Islets

Cited by 97 publications

References 31 publications

Non-invasive quantification of the beta cell mass by SPECT with 111In-labelled exendin

Non-invasive quantification of the beta cell mass by SPECT with 111In-labelled exendin

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

Click Reaction: An Applicable Radiolabeling Method for Molecular Imaging

Contact Info

Product

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Development and Evaluation of ¹⁸F-TTCO-Cys⁴⁰-Exendin-4: A PET Probe for Imaging Transplanted Islets

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