Abstract
Type 1 diabetes mellitus (T1DM) is characterized by a loss of beta 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 neurological tissues have common cellular receptors and transporters, therefore, we screened brain radioligands for their ability to identify β-cells. Methods: We examined a β-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 (HC) subjects and two T1DM subjects underwent dynamic positron emission tomography/computed tomography (PET/CT) scans with six 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 standardized uptake value (SUV) from 20-30 minutes demonstrated high uptake of 11C-(+)-PHNO in HCs (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 measureable 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 HCs and T1DM subjects. Using D3- and D2-antagonists, in non-human primates (NHP), 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 β-cells is warranted to characterize 11C-(+)-PHNO as a candidate for clinical measurement of BCM in HC and diabetic subjects.
- Copyright © 2018 by the Society of Nuclear Medicine and Molecular Imaging, Inc.