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Evaluation of PET Brain Radioligands for Imaging Pancreatic ?-Cell Mass: Potential Utility of 11C-(+)-PHNO.

ABSTRACT: Type 1 diabetes mellitus (T1DM) is characterized by a loss of ?-cells in the islets of Langerhans of the pancreas and subsequent deficient insulin secretion in response to hyperglycemia. Development of an in vivo test to measure ?-cell mass (BCM) would greatly enhance the ability to track diabetes therapies. ?-cells and neurologic tissues have common cellular receptors and transporters, therefore, we screened brain radioligands for their ability to identify ?-cells. Methods: We examined a ?-cell gene atlas for endocrine pancreas receptor targets and cross-referenced these targets with brain radioligands that were available at our institution. Twelve healthy control subjects and 2 T1DM subjects underwent dynamic PET/CT scans with 6 tracers. Results: The D2/D3 receptor agonist radioligand 11C-(+)-4-propyl-9-hydroxynaphthoxazine (PHNO) was the only radioligand to demonstrate sustained uptake in the pancreas with high contrast versus abdominal organs such as the kidneys, liver, and spleen, based on the first 30 min of data. Mean SUV from 20 to 30 min demonstrated high uptake of 11C-(+)-PHNO in healthy controls (SUV, 13.8) with a 71% reduction in a T1DM subject with undetectable levels of C-peptide (SUV, 4.0) and a 20% reduction in a T1DM subject with fasting C-peptide level of 0.38 ng/mL (SUV, 11.0). SUV in abdominal organs outside the pancreas did not show measurable differences between the control and T1DM subjects, suggesting that the changes in SUV of 11C-(+)-PHNO may be specific to changes in the pancreas between healthy controls and T1DM subjects. When D3 and D2 antagonists were used in nonhuman primates, specific pancreatic binding (SUVR-1) of 11C-PHNO was reduced by 57% and 38%, respectively. Conclusion:11C-(+)-PHNO is a potential marker of BCM, with 2:1 binding of D3 receptors over D2 receptors. Further in vitro and in vivo studies to establish D2/D3 receptor specificity to ?-cells is warranted to characterize 11C-(+)-PHNO as a candidate for clinical measurement of BCM in healthy control and diabetic subjects.

SUBMITTER: Bini J

PROVIDER: S-EPMC6071501 | biostudies-other | 2018 Aug

REPOSITORIES: biostudies-other

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Evaluation of PET Brain Radioligands for Imaging Pancreatic β-Cell Mass: Potential Utility of <sup>11</sup>C-(+)-PHNO.

Bini Jason J Naganawa Mika M Nabulsi Nabeel N Huang Yiyun Y Ropchan Jim J Lim Keunpoong K Najafzadeh Soheila S Herold Kevan C KC Cline Gary W GW Carson Richard E RE

Journal of nuclear medicine : official publication, Society of Nuclear Medicine 20180125 8

Type 1 diabetes mellitus (T1DM) is characterized by a loss of β-cells in the islets of Langerhans of the pancreas and subsequent deficient insulin secretion in response to hyperglycemia. Development of an in vivo test to measure β-cell mass (BCM) would greatly enhance the ability to track diabetes therapies. β-cells and neurologic tissues have common cellular receptors and transporters, therefore, we screened brain radioligands for their ability to identify β-cells. <b>Methods:</b> We examined a ...[more]

PMID: 29371405

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Project description:Neuroreceptor imaging in the nonhuman primate (NHP) is valuable for translational research approaches in humans. However, most NHP studies are conducted under anesthesia, which affects the interpretability of receptor binding measures. The aims of this study were to develop awake NHP imaging with minimal head restraint and to compare in vivo binding of the ?-aminobutyric acid type A (GABAA)-benzodiazepine radiotracer (11)C-flumazenil under anesthetized and awake conditions. We hypothesized that (11)C-flumazenil binding potential (BPND) would be higher in isoflurane-anesthetized monkeys.The small animal PET scanner was fitted to a mechanical device that raised and tilted the scanner 45° while the awake NHP was tilted back 35° in a custom chair for optimal brain positioning, which required acclimation of the animals to the chair, touch-screen tasks, intravenous catheter insertion, and tilting. For PET studies, the bolus-plus-constant infusion method was used for (11)C-flumazenil administration. Two rhesus monkeys were scanned under the awake (n = 6 scans) and isoflurane-anesthetized (n = 4 scans) conditions. An infrared camera was used to track head motion during PET scans. Under the awake condition, emission and head motion-tracking data were acquired for 40-75 min after injection. Anesthetized monkeys were scanned for 90 min. Cortisol measurements were acquired during awake and anesthetized scans. Equilibrium analysis was used for both the anesthetized (n = 4) and the awake (n = 5) datasets to compute mean BPND images in NHP template space, using the pons as a reference region. The percentage change per minute in radioactivity concentration was calculated in high- and low-binding regions to assess the quality of equilibrium.The monkeys acclimated to procedures in the NHP chair necessary to perform awake PET imaging. Image quality was comparable between awake and anesthetized conditions. The relationship between awake and anesthetized values was BPND (awake) = 0.94 BPND (anesthetized) + 0.36 (r(2) = 0.95). Cortisol levels were significantly higher under the awake condition (P < 0.05).We successfully performed awake NHP imaging with minimal head restraint. There was close agreement in (11)C-flumazenil BPND values between awake and anesthetized conditions.

Dataset Information

Evaluation of PET Brain Radioligands for Imaging Pancreatic ?-Cell Mass: Potential Utility of 11C-(+)-PHNO.

Publications

Evaluation of PET Brain Radioligands for Imaging Pancreatic β-Cell Mass: Potential Utility of <sup>11</sup>C-(+)-PHNO.

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