Synthesis and evaluation of 18F-labeled mitiglinide derivatives as positron emission tomography tracers for β-cell imaging.
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Abstract
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.
Journal
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- Bioorganic & medicinal chemistry
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Bioorganic & medicinal chemistry 22 (13), 3270-3278, 2014-07-01
Elsevier BV
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Details 詳細情報について
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- CRID
- 1050001335794247680
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- NII Article ID
- 120005456028
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- NII Book ID
- AA10938083
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- ISSN
- 09680896
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- HANDLE
- 2433/188927
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- Text Lang
- en
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- Article Type
- journal article
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- Data Source
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- IRDB
- CiNii Articles
- KAKEN