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

Abstract

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. 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 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 β-cells is warranted to characterize ¹¹C-(+)-PHNO as a candidate for clinical measurement of BCM in healthy control and diabetic subjects.