Synthesis and evaluation of 18F-labeled mitiglinide derivatives as positron emission tomography tracers for β-cell imaging
| Autor: | Kenji Arimitsu, Nobuya Inagaki, Eri Mukai, Hiroyuki Kimura, Yu Ogawa, Mikako Takagi, Masahiro Ono, Hiroshi Nakamura, Hiroyuki Fujimoto, Kentaro Toyoda, Hirokazu Matsuda, Hideo Saji |
|---|---|
| Rok vydání: | 2014 |
| Předmět: |
Fluorine Radioisotopes
Biodistribution Mitiglinide Clinical Biochemistry Analytical chemistry Pharmaceutical Science Sulfonylurea receptor 1 Mice Inbred Strains Isoindoles Biochemistry Mice Structure-Activity Relationship In vivo Insulin-Secreting Cells Glyburide Drug Discovery medicine Animals Tissue Distribution (18)F Molecular Biology Dose-Response Relationship Drug Molecular Structure Chemistry Pancreatic islets Organic Chemistry Radiochemistry medicine.anatomical_structure Positron-Emission Tomography Positron emission tomography tracers Molecular Medicine Sulfonylurea receptor Pancreas Ex vivo Preclinical imaging medicine.drug |
| Zdroj: | Bioorganic & Medicinal Chemistry. 22:3270-3278 |
| ISSN: | 0968-0896 |
| DOI: | 10.1016/j.bmc.2014.04.059 |
| Popis: | Measuring changes in β-cell mass in vivo during progression of diabetes mellitus is important for understanding the pathogenesis, facilitating early diagnosis, and developing novel therapeutics for this disease. However, a non-invasive method has not been developed. A novel series of mitiglinide derivatives (o-FMIT, m-FMIT and p-FMIT; FMITs) were synthesized and their binding affinity for the sulfonylurea receptor 1 (SUR1) of pancreatic islets were evaluated by inhibition studies. (+)-(S)-o-FMIT had the highest affinity of our synthesized FMITs (IC50=1.8μM). (+)-(S)-o-[(18)F]FMIT was obtained with radiochemical yield of 18% by radiofluorination of racemic precursor 7, hydrolysis, and optical resolution with chiral HPLC; its radiochemical purity was >99%. In biodistribution experiments using normal mice, (+)-(S)-o-[(18)F]FMIT showed 1.94±0.42% ID/g of pancreatic uptake at 5min p.i., and decreases in radioactivity in the liver (located close to the pancreas) was relatively rapid. Ex vivo autoradiography experiments using pancreatic sections confirmed accumulation of (+)-(S)-o-[(18)F]FMIT in pancreatic β-cells. These results suggest that (+)-(S)-o-[(18)F]FMIT meets the basic requirements for an radiotracer, and could be a candidate positron emission tomography tracer for in vivo imaging of pancreatic β-cells. |
| Databáze: | OpenAIRE |
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