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Targeting of the glucose-dependent insulinotropic polypeptide receptor (GIPR) is an emerging strategy in antidiabetic drug development. The aim of this study was to develop a positron emission tomography (PET) radioligand for the GIPR to enable the assessment of target distribution and drug target engagement in vivo. The GIPR-selective peptide S02-GIP was radiolabeled with 68Ga. The resulting PET tracer [68Ga]S02-GIP-T4 was evaluated for affinity and specificity to human GIPR (huGIPR). The in vivo GIPR binding of [68Ga]S02-GIP-T4 as well as the occupancy of a drug candidate with GIPR activity were assessed in nonhuman primates (NHPs) by PET. [68Ga]S02-GIP-T4 bound with nanomolar affinity and high selectivity to huGIPR in overexpressing cells. In vivo, pancreatic binding in NHPs could be dose-dependently inhibited by coinjection of unlabeled S02-GIP-T4. Finally, subcutaneous pretreatment with a high dose of a drug candidate with GIPR activity led to a decreased pancreatic binding of [68Ga]S02-GIP-T4, corresponding to a GIPR drug occupancy of almost 90%. [68Ga]S02-GIP-T4 demonstrated a safe dosimetric profile, allowing for repeated studies in humans. In conclusion, [68Ga]S02-GIP-T4 is a novel PET biomarker for safe, noninvasive, and quantitative assessment of GIPR target distribution and drug occupancy. [ABSTRACT FROM AUTHOR]

Activating brown adipose tissue (BAT) could provide a potential approach for the treatment of obesity and metabolic disease in humans. Obesity is associated with upregulation of the endocannabinoid system, and blocking the cannabinoid type 1 receptor (CB1R) has been shown to cause weight loss and to decrease cardiometabolic risk factors. These effects may be mediated partly via increased BAT metabolism, since there is evidence that CB1R antagonism activates BAT in rodents. To investigate the significance of CB1R in BAT function, we quantified the density of CB1R in human and rodent BAT using the positron emission tomography radioligand [18F]FMPEP-d2 and measured BAT activation in parallel with the glucose analog [18F]fluorodeoxyglucose. Activation by cold exposure markedly increased CB1R density and glucose uptake in the BAT of lean men. Similarly, β3-receptor agonism increased CB1R density in the BAT of rats. In contrast, overweight men with reduced BAT activity exhibited decreased CB1R in BAT, reflecting impaired endocannabinoid regulation. Image-guided biopsies confirmed CB1R mRNA expression in human BAT. Furthermore, CB1R blockade increased glucose uptake and lipolysis of brown adipocytes. Our results highlight that CB1Rs are significant for human BAT activity, and the CB1Rs provide a novel therapeutic target for BAT activation in humans. [ABSTRACT FROM AUTHOR]

GPR44 expression has recently been described as highly β-cell selective in the human pancreas and constitutes a tentative surrogate imaging biomarker in diabetes. A radiolabeled small-molecule GPR44 antagonist, [11C]AZ12204657, was evaluated for visualization of β-cells in pigs and nonhuman primates by positron emission tomography as well as in immunodeficient mice transplanted with human islets under the kidney capsule. In vitro autoradiography of human and animal pancreatic sections from subjects without and with diabetes, in combination with insulin staining, was performed to assess β-cell selectivity of the radiotracer. Proof of principle of in vivo targeting of human islets by [11C]AZ12204657 was shown in the immunodeficient mouse transplantation model. Furthermore, [11C]AZ12204657 bound by a GPR44-mediated mechanism in pancreatic sections from humans and pigs without diabetes, but not those with diabetes. In vivo [11C]AZ12204657 bound specifically to GPR44 in pancreas and spleen and could be competed away dose-dependently in nondiabetic pigs and nonhuman primates. [11C]AZ12204657 is a first-in-class surrogate imaging biomarker for pancreatic β-cells by targeting the protein GPR44. [ABSTRACT FROM AUTHOR]

No imaging methodology currently exists to monitor viable islet mass after clinical intraportal islet transplantation. We investigated the potential of the endocrine positron emission tomography (PET) marker [(11)C]5-hydroxytryptophan ([(11)C]5-HTP) for this purpose. In a preclinical proof-of-concept study, the ex vivo and in vivo [(11)C]5-HTP signal was compared with the number of islets transplanted in rats. In a clinical study, human subjects with an intraportal islet graft (n = 8) underwent two [(11)C]5-HTP PET and MRI examinations 8 months apart. The tracer concentration in the liver as a whole, or in defined hotspots, was correlated to measurements of islet graft function. In rat, hepatic uptake of [(11)C]5-HTP correlated with the number of transplanted islets. In human subjects, uptake in hepatic hotspots showed a correlation with metabolic assessments of islet function. Change in hotspot standardized uptake value (SUV) predicted loss of graft function in one subject, whereas hotspot SUV was unchanged in subjects with stable graft function. The endocrine marker [(11)C]5-HTP thus shows a correlation between hepatic uptake and transplanted islet function and promise as a tool for noninvasive detection of viable islets. The evaluation procedure described can be used as a benchmark for novel agents targeting intraportally transplanted islets. [ABSTRACT FROM AUTHOR]

In humans, a well-developed serotonin system is localized to the pancreatic islets while being absent in exocrine pancreas. Assessment of pancreatic serotonin biosynthesis could therefore be used to estimate the human endocrine pancreas. Proof of concept was tested in a prospective clinical trial by comparisons of type 1 diabetic (T1D) patients, with extensive reduction of β-cells, with healthy volunteers (HVs). C-peptide-negative (i.e., insulin-deficient) T1D subjects (n = 10) and HVs (n = 9) underwent dynamic positron emission tomography with the radiolabeled serotonin precursor [(11)C]5-hydroxy-tryptophan ([(11)C]5-HTP). A significant accumulation of [(11)C]5-HTP was obtained in the pancreas of the HVs, with large interindividual variation. A substantial and highly significant reduction (66%) in the pancreatic uptake of [(11)C]5-HTP in T1D subjects was observed, and this was most evident in the corpus and caudal regions of the pancreas where β-cells normally are the major constituent of the islets. [(11)C]5-HTP retention in the pancreas was reduced in T1D compared with nondiabetic subjects. Accumulation of [(11)C]5-HTP in the pancreas of both HVs and subjects with T1D was in agreement with previously reported morphological observations on the β-cell volume, implying that [(11)C]5-HTP retention is a useful noninvasive surrogate marker for the human endocrine pancreas. [ABSTRACT FROM AUTHOR]

In humans, a well-developed serotonin system is localized to the pancreatic islets while being absent in exocrine pancreas. Assessment of pancreatic serotonin biosynthesis could therefore be used to estimate the human endocrine pancreas. Proof of concept was tested in a prospective clinical trial by comparisons of type 1 diabetic (T1D) patients, with extensive reduction of β-cells, with healthy volunteers (HVs). C-peptide-negative (i.e., insulin-deficient) T1D subjects (n = 10) and HVs (n = 9) underwent dynamic positron emission tomography with the radiolabeled serotonin precursor [11C]5-hydroxy-tryptophan ([11C]5-HTP). A significant accumulation of [11C]5-HTP was obtained in the pancreas of the HVs, with large interindividual variation. A substantial and highly significant reduction (66%) in the pancreatic uptake of [11C]5-HTP in T1D subjects was observed, and this was most evident in the corpus and caudal regions of the pancreas where β-cells normally are the major constituent of the islets. [11C]5-HTP retention in the pancreas was reduced in T1D compared with nondiabetic subjects. Accumulation of [11C]5-HTP in the pancreas of both HVs and subjects with T1D was in agreement with previously reported morphological observations on the β-cell volume, implying that [11C]5-HTP retention is a useful noninvasive surrogate marker for the human endocrine pancreas. [ABSTRACT FROM AUTHOR]

Intrahepatic transplantation of islets of Langerhans (ITx) is a treatment option for individuals with complicated type 1 diabetes and profoundly unstable glycemic control, but its therapeutic success is hampered by deterioration of graft function over time. To improve ITx strategies, technologies to noninvasively monitor the fate and survival of transplanted islets over time are of great potential value. We used [68Ga]Ga-NODAGA-exendin-4 (68Ga-exendin) positron emission tomography (PET)/computed tomography (CT) imaging to demonstrate the feasibility of quantifying β-cell mass in intrahepatic islet grafts in 13 individuals with type 1 diabetes, nine after ITx with functional islet grafts and four control patients not treated with ITx. β-Cell function was measured by mixed-meal tolerance test. With dynamic 68Ga-exendin PET/CT images, we determined tracer accumulation in hepatic hotspots, and intrahepatic fat was assessed using MRI and spectroscopy. Quantification of hepatic hotspots showed a significantly higher uptake of 68Ga-exendin in the ITx group compared with the control group (median 0.55 [interquartile range 0.51–0.63] vs. 0.43 [0.42–0.45]). GLP-1 receptor expression was found in transplanted islets by immunohistochemistry. Intrahepatic fat was not detected in a majority of the individuals. Our study provides the first clinical evidence that radiolabeled exendin imaging can be used to monitor viable transplanted islets after intraportal ITx. Article Highlights: This clinical study researched the potential of radiolabeled exendin to follow the fate and survival of intrahepatic islet grafts. Is it feasible to quantitatively detect intrahepatic islet transplants with [68Ga]Ga-NODAGA-exendin-4 (68Ga-exendin) positron emission tomography (PET) imaging? Our study findings indicate that the imaging technique 68Ga-exendin PET can be used to monitor viable islet mass after intrahepatic islet transplantation in humans. Alongside functional measures, 68Ga-exendin PET imaging could significantly aid in the evaluation of strategies designed to improve islet engraftment, survival, and function. [ABSTRACT FROM AUTHOR]

The longitudinal alterations of the pancreatic β-cell and islet mass in the progression of type 1 diabetes (T1D) are still poorly understood. The objective of this study was to repeatedly assess the endocrine volume and the morphology of the pancreas for up to 24 months after T1D diagnosis (n = 16), by 11C-5-hydroxytryptophan (11C-5-HTP) positron emission tomography (PET) and MRI. Study participants were examined four times by PET/MRI: at recruitment and then after 6, 12, and 24 months. Clinical examinations and assessment of β-cell function by a mixed-meal tolerance test and fasting blood samples were performed in connection with the imaging examination. Pancreas volume has a tendency to decrease from 50.2 ± 10.3 mL at T1D debut to 42.2 ± 14.6 mL after 24 months (P < 0.098). Pancreas uptake of 11C-5-HTP (e.g., the volume of the endocrine pancreas) did not decrease from T1D diagnosis (0.23 ± 0.10 % of injected dose) to 24-month follow-up, 0.21 ± 0.14% of injected dose, and exhibited low interindividual changes. Pancreas perfusion was unchanged from diagnosis to 24-month follow-up. The pancreas uptake of 11C-5-HTP correlated with the long-term metabolic control as estimated by HbA1c (P < 0.05). Our findings argue against a major destruction of β-cell or islet mass in the 2-year period after diagnosis of T1D. [ABSTRACT FROM AUTHOR]

[11C]5-hydroxy-tryptophan ([11C]5-HTP) positron emission tomography of the pancreas has been shown to be a surrogate imaging biomarker of pancreatic islet mass. The change in islet mass in different stages of type 2 diabetes (T2D) as measured by noninvasive imaging is currently unknown. Here, we describe a cross-sectional study where subjects at different stages of T2D development with expected stratification of pancreatic islet mass were examined in relation to individuals without diabetes. The primary outcome was the [11C]5-HTP uptake and retention in pancreas, as a surrogate marker for the endogenous islet mass. We found that metabolic testing indicated a progressive loss of β-cell function, but this was not mirrored by a decrease in [11C]5-HTP tracer accumulation in the pancreas. This provides evidence of retained islet mass despite decreased β-cell function. The results herein indicate that β-cell dedifferentiation, and not necessarily endocrine cell loss, constitutes a major cause of β-cell failure in T2D. [ABSTRACT FROM AUTHOR]