Glucagonlike Peptide-1 Receptor Imaging in Individuals with Type 2 Diabetes

Abstract

The glucagonlike peptide-1 receptor (GLP1R) is a gut hormone receptor, intricately linked to regulation of blood glucose homeostasis via several mechanisms. It is an established and emergent drug target in metabolic disease. The PET radioligand 68Ga-DO3A-VS-exendin4 (68Ga-exendin4) has the potential to enable longitudinal studies of GLP1R in the human pancreas. Methods:68Ga-exendin4 PET/CT examinations were performed on overweight-to-obese individuals with type 2 diabetes (n = 13) as part of a larger target engagement study (NCT03350191). A scanning protocol was developed to optimize reproducibility (target amount of 0.5 MBq/kg [corresponding to peptide amount of <0.2 µg/kg], blood sampling, and tracer stability assessment). The pancreas and abdominal organs were segmented, and binding was correlated with clinical parameters. Results: Uptake of 68Ga-exendin4 in the pancreas, but not in other abdominal tissues, was high but variable between individuals. There was no evidence of self-blocking of GLP1R by the tracer in this protocol, despite the high potency of exendin4. The results showed that a full dynamic scan can be simplified to a short static scan, potentially increasing throughput and reducing patient discomfort. The 68Ga-exendin4 concentration in the pancreas (i.e., GLP1R density) correlated inversely with the age of the individual and tended to correlate positively with body mass index. However, the total GLP1R content in the pancreas did not. Conclusion: In summary, we present an optimized and simplified 68Ga-exendin4 scanning protocol to enable reproducible imaging of GLP1R in the pancreas. 68Ga-exendin4 PET may enable quantification of longitudinal changes in pancreatic GLP1R during the development of type 2 diabetes, as well as target engagement studies of novel glucagonlike peptide-1 agonists.

Keywords: GLP1R; PET; exendin; type 2 diabetes; β-cell mass.

© 2022 by the Society of Nuclear Medicine and Molecular Imaging.

Figures

Graphical abstract

FIGURE 1.

In vivo binding of 68Ga-exendin4 in NHP pancreas. (A) Dose escalation studies demonstrated strong binding in pancreas at mass doses below 0.2 µg/kg (black dotted line), which was progressively blocked by coinjection of increasing amounts of unlabeled DO3A-VS-exendin4 precursor peptide. A 50% blocking dose is indicated by gray dotted line. (B) There was strong correlation between Vt (obtained from dynamic 90-min scan and requiring blood plasma input signal) and SUV55 min, indicating that just static scan from 50 to 60 min can replace dynamic scan.

FIGURE 2.

Abdominal biodistribution of 68Ga-exendin4 in humans with T2D. (A and B) 68Ga-exendin4 was rapidly distributed, followed by washout from most tissues except pancreas and kidneys (average of 13 individuals). Representative maximum-intensity-projection PET images are shown. (C) There was strong variability in pancreas binding, which was not reflected in other tissues. (D) Representative transaxial PET/CT images demonstrate high, average, or low pancreas binding of 68Ga-exendin4. ****indicates P < 0.0001.

FIGURE 3.

In vivo binding of 68Ga-exendin4 in human T2D pancreas. (A) There was no obvious self-blocking mass effect at peptide doses below 0.2 μg/kg (i.e., no negative correlation). (B) In human pancreas, there was strong correlation between model parameter obtained from dynamic scan including blood (Patlak Ki) and SUV55 min, indicating that static scan is sufficient for accurate quantification.

FIGURE 4.

Correlation of 68Ga-exendin4 pancreas binding with biometric parameters. (A and B) Pancreatic GLP1R density (concentration of 68Ga-exendin4 binding) correlated negatively with age of examined individuals (A) and exhibited tendency to correlate with BMI (P = 0.064) (B). (C and D) However, total pancreas GLP1R content (i.e., 68Ga-exendin4 concentration multiplied by volume) did not correlate with age (C) or BMI (D) of participants. (E and F) Similarly, size of pancreas did not correlate with either age (E) or BMI (F) in this study.