Synthesis and evaluation of 18F-labeled mitiglinide derivatives as positron emission tomography tracers for β-cell imaging.
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.
Department of Patho-Functional Bioanalysis, Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Yoshida Shimoadachi-cho, Sakyo-ku, Kyoto 606-8501, Japan.
Hiroyuki
H
Kimura
Department of Patho-Functional Bioanalysis, Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Yoshida Shimoadachi-cho, Sakyo-ku, Kyoto 606-8501, Japan; Research & Development Division, Arkray, Inc., Yousuien-nai, 59 Gansuin-cho, Kamigyo-ku, Kyoto 602-0008, Japan.
Hirokazu
H
Matsuda
Department of Diabetes, Endocrinology and Nutrition, Graduate School of Medicine, Kyoto University, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan.
Hiroyuki
H
Fujimoto
Department of Patho-Functional Bioanalysis, Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Yoshida Shimoadachi-cho, Sakyo-ku, Kyoto 606-8501, Japan.
Kenji
K
Arimitsu
Institute for Advancement of Clinical and Translational Science, Kyoto University Hospital, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan.
Kentaro
K
Toyoda
Department of Medical Physiology, Graduate School of Medicine, Chiba University, 1-8-1 lnohana, Chuo-ku, Chiba, Chiba 260-8677, Japan.
Eri
E
Mukai
Research & Development Division, Arkray, Inc., Yousuien-nai, 59 Gansuin-cho, Kamigyo-ku, Kyoto 602-0008, Japan.
Hiroshi
H
Nakamura
Department of Patho-Functional Bioanalysis, Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Yoshida Shimoadachi-cho, Sakyo-ku, Kyoto 606-8501, Japan.
Yu
Y
Ogawa
Research & Development Division, Arkray, Inc., Yousuien-nai, 59 Gansuin-cho, Kamigyo-ku, Kyoto 602-0008, Japan.
Mikako
M
Takagi
Department of Patho-Functional Bioanalysis, Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Yoshida Shimoadachi-cho, Sakyo-ku, Kyoto 606-8501, Japan.
Masahiro
M
Ono
Department of Diabetes, Endocrinology and Nutrition, Graduate School of Medicine, Kyoto University, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan.
Nobuya
N
Inagaki
Department of Patho-Functional Bioanalysis, Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Yoshida Shimoadachi-cho, Sakyo-ku, Kyoto 606-8501, Japan. Electronic address: hsaji@pharm.kyoto-u.ac.jp.
Hideo
H
Saji
D000818:Animals; D004305:Dose-Response Relationship, Drug; D005462:Fluorine Radioisotopes / Q000737:chemistry / Q000494:pharmacology*; D005905:Glyburide / Q000037:antagonists & inhibitors*; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000187:drug effects*; D054833:Isoindoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051379:Mice; D008815:Mice, Inbred Strains; D015394:Molecular Structure; D049268:Positron-Emission Tomography; D013329:Structure-Activity Relationship; D014018:Tissue Distribution
D005462:Fluorine Radioisotopes; D054833:Isoindoles; C087255:mitiglinide; D005905:Glyburide
(18)F; Mitiglinide; Positron emission tomography tracers; Sulfonylurea receptor 1