Diabetes mellitus is a major metabolic disease with increasing significance. There are at least 20 million diabetic patients in the United States. Beta islet cells, which are the cells responsible for secreting insulin, play an important role in diabetes. Preserving or reversing the decline of beta cell mass (BCM) is one of the major goals for the treatment of diabetes. Measuring BCM in the pancreas by in vivo imaging will provide urgently needed information to understand the pathophysiology of diabetes and assist the development of new drug treatments. The objective of this proposal is to develop 18F labeled (+)-dihydrotetrabenazine ([18F](+)-DTBZ) derivatives to study vesicular monoamine transporter 2 (VMAT2) binding sites on the beta cells by positron emission tomography (PET) imaging. Recent reports suggested that [11C]DTBZ, a VMAT2 selective agent used in the diagnosis of Parkinson's disease, also showed promise for mapping the BCM of human pancreas by in vivo PET imaging. However, the short half-life (20 min) of 11C limits its widespread application;therefore, we propose to develop its 18F derivatives with a longer half-life (110 min) and an improved pancreas targeting ability suitable for a widespread clinical application. Additional novel DTBZ derivatives containing an in vivo metabolizing group (epoxide) for faster liver and kidney excretion will be synthesized and radiolabeled. In vivo biodistribution will demonstrate the binding of VMAT2 in normal and streptozotocin-treated rats (model for diabetes). One of the 18F labeled DTBZ derivatives recently developed in our laboratory showed superior pancreas targeting and low background noise. The uptake in the pancreas of normal rats was >5 %dose/g at 30 min after an iv injection and the uptake was blocked (>80%) by a pretreatment of a challenging dose of VMAT2 ligand, suggesting a competitive binding to the same VMAT2 binding sites. PET imaging studies of normal rats showed excellent images of the pancreas with outstanding contrast to the surrounding tissues or organs. On the basis of the exciting preliminary results, the proposed 18F labeled DTBZ derivatives may provide an excellent platform to search for optimal imaging agents for beta cell mass (BCM). The proposed beta cell targeting PET imaging agents for measuring BCM in the pancreas are scientifically important and they may be useful for diagnosis and management of diabetic patients.

Public Health Relevance

Diabetes mellitus is a major metabolic disease with increasing significance in the United States. Beta islet cells, which are the cells responsible for secreting insulin, play an important role in diabetes. Measuring beta cell mass (BCM) in the pancreas by in vivo imaging will provide critically useful information for diagnosis and management of diabetic patients.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK081342-04
Application #
8462596
Study Section
Special Emphasis Panel (ZRG1-MEDI-A (09))
Program Officer
Laughlin, Maren R
Project Start
2010-04-01
Project End
2014-03-31
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
4
Fiscal Year
2013
Total Cost
$306,178
Indirect Cost
$88,154
Name
University of Pennsylvania
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Wu, Zehui; Zha, Zhihao; Li, Genxun et al. (2014) [(18)F](2S,4S)-4-(3-Fluoropropyl)glutamine as a tumor imaging agent. Mol Pharm 11:3852-66
Graham, Thomas J A; Lambert, R Frederick; Ploessl, Karl et al. (2014) Enantioselective radiosynthesis of positron emission tomography (PET) tracers containing [ยน?F]fluorohydrins. J Am Chem Soc 136:5291-4
Zhu, Lin; Ploessl, Karl; Kung, Hank F (2014) PET/SPECT imaging agents for neurodegenerative diseases. Chem Soc Rev 43:6683-91
Zhu, Lin; Li, Genxun; Choi, Seok Rye et al. (2013) An improved preparation of [18F]FPBM: a potential serotonin transporter (SERT) imaging agent. Nucl Med Biol 40:974-9
Wang, Limin; Zha, Zhihao; Qu, Wenchao et al. (2012) Synthesis and evaluation of 18F labeled alanine derivatives as potential tumor imaging agents. Nucl Med Biol 39:933-43
Liu, Jingying; Zhu, Lin; Plossl, Karl et al. (2011) Synthesis and evaluation of novel N-fluoropyridyl derivatives of tropane as potential PET imaging agents for the dopamine transporter. Bioorg Med Chem Lett 21:2962-5
Zheng, Pinguan; Lieberman, Brian P; Choi, Seok Rye et al. (2011) Synthesis and biological evaluation of 3-alkyl-dihydrotetrabenazine derivatives as vesicular monoamine transporter-2 (VMAT2) ligands. Bioorg Med Chem Lett 21:3435-8