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Synthesis and evaluation of [18F]exendin (9-39) as a potential biomarker to measure pancreatic ?-cell mass.

ABSTRACT: Glucagon-like peptide 1 (GLP-1) is released in response to food intake and plays an important role in maintaining blood glucose homeostasis. Exendin (9-39), a potent glucagon-like peptide 1 receptor antagonist, has been labeled with In-111 for SPECT imaging. We report here the first radiosynthesis of [(18)F]exendin (9-39) ([(18)F]Ex(9-39)) and an evaluation of its potential as a biomarker for in vivo positron emission tomography (PET) imaging of pancreatic ?-cell mass (BCM) in rats.F-18 label was introduced by conjugation of [(18)F]4-fluorobenzaldehyde with an Ex(9-39) derivative containing a 6-hydrazinonicotinyl group on the ?-amine of Lys27. Positron emission tomography imaging was carried out in Sprague-Dawley rats (five control and five streptozotocin-induced diabetic) and BioBreeding diabetes-prone rats (three at 7 weeks and three at 12 weeks) using the high-resolution research tomograph (HRRT) after 0.187 ± 0.084 mCi [(18)F]Ex(9-39) administration. Time-activity curves were obtained from pancreas, liver and kidney. Pancreases were assayed for insulin content after the imaging study.Site-specifically labeled [(18)F]Ex(9-39) was purified on a G15 open column with radiochemical and chemical purities >98%. Positron emission tomography imaging showed pancreatic standardized uptake value (SUV) peaked at 10 min and plateaued by 50 min to the end of scan (240 min). No correlations of pancreatic SUV with postmortem measures of insulin content were seen.[(18)F]Ex(9-39) was successfully prepared and used for PET imaging for the first time to measure pancreatic BCM. The results suggest that derivatization of the Lys27 residue might reduce binding affinity, as evidenced by the absence of specific binding. Exendin analogues radiolabeled at other sites may elucidate the active site required for binding.

SUBMITTER: Wang Y

PROVIDER: S-EPMC4484741 | biostudies-literature | 2012 Feb

REPOSITORIES: biostudies-literature

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Synthesis and evaluation of [18F]exendin (9-39) as a potential biomarker to measure pancreatic β-cell mass.

Wang Yi Y Lim Keunpoong K Normandin Marc M Zhao Xiaojian X Cline Gary W GW Ding Yu-Shin YS

Nuclear medicine and biology 20111026 2

<h4>Introduction</h4>Glucagon-like peptide 1 (GLP-1) is released in response to food intake and plays an important role in maintaining blood glucose homeostasis. Exendin (9-39), a potent glucagon-like peptide 1 receptor antagonist, has been labeled with In-111 for SPECT imaging. We report here the first radiosynthesis of [(18)F]exendin (9-39) ([(18)F]Ex(9-39)) and an evaluation of its potential as a biomarker for in vivo positron emission tomography (PET) imaging of pancreatic β-cell mass (BCM) ...[more]

PMID: 22033026

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Project description: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.

Dataset Information

Synthesis and evaluation of [18F]exendin (9-39) as a potential biomarker to measure pancreatic ?-cell mass.

Publications

Synthesis and evaluation of [18F]exendin (9-39) as a potential biomarker to measure pancreatic β-cell mass.

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