Document Detail

Evaluation of a Mitochondrial Voltage Sensor, (18F-Fluoropentyl)Triphenylphosphonium Cation, in a Rat Myocardial Infarction Model.
MedLine Citation:
PMID:  23038748     Owner:  NLM     Status:  Publisher    
Radiolabeled lipophilic cationic compounds, such as (18)F-labeled phosphonium salt, accumulate in the mitochondria through a negative inner transmembrane potential. The purpose of this study was to develop and evaluate ((18)F-fluoropentyl)triphenylphosphonium salt ((18)F-FPTP) as a myocardial PET agent. METHODS: A reference compound of (18)F-FPTP was synthesized via 3-step nucleophilic substitution reactions and was radiolabeled via 2-step nucleophilic substitution reactions of no-carrier-added (18)F-fluoride. Accumulations of (18)F-FPTP, (3)H-tetraphenylphosphonium, and (99m)Tc-sestamibi were compared in a cultured embryonic cardiomyoblast cell line (H9c2). The biodistribution of (18)F-FPTP was assessed using BALB/c mice. The (18)F-FPTP small-animal PET study was performed in Sprague-Dawley rats with or without left coronary artery (LCA) ligation. RESULTS: (18)F-FPTP was synthesized with a radiochemical yield of 15%-20% and radiochemical purity of greater than 98%. Specific activity was greater than 6.3 TBq/μmol. Cell uptake of (18)F-FPTP was more than 15-fold higher in H9c2 than in normal fibroblasts (human normal foreskin fibroblasts). Selective collapse of mitochondrial membrane potential substantially decreased cellular uptake for (18)F-FPTP and (3)H-tetraphenylphosphonium, compared with that for (99m)Tc-sestamibi. The biodistribution data in mice (n = 24) showed rapid blood clearance and high accumulation in the heart. Heart-to-blood ratios at 10 and 30 min were 54 and 133, respectively. Heart-to-lung and heart-to-liver ratios at 10, 30, and 60 min were 4, 4, and 7 and 4, 5, and 7, respectively. Dynamic small-animal PET for 60 min after injection of (18)F-FPTP showed an initial spike of radioactivity, followed by retention in the myocardium and rapid clearance from the background. (18)F-FPTP small-animal PET images in LCA-occluded rats demonstrated sharply defined myocardial defects in the corresponding area of the myocardium. The myocardial defect size measured by (18)F-FPTP small-animal PET correlated closely with the hypoperfused area measured by quantitative 2,3,5-triphenyltetrazolium chloride staining (r(2) = 0.92, P < 0.001). CONCLUSION: The excellent pharmacokinetics of (18)F-FPTP and its correlation with 2,3,5-triphenyltetrazolium chloride staining in normal and LCA-occluded rats suggest that this molecular probe may have a high potential as a mitochondrial voltage sensor for PET. This probe may also allow high throughput, with multiple daily studies and a wide distribution of PET myocardial imaging in the clinic.
Dong-Yeon Kim; Hyeon-Sik Kim; Uyenchi Nguyen Le; Sheng Nan Jiang; Hee-Jung Kim; Kyo-Chul Lee; Sang-Keun Woo; Jihwa Chong; Hyung-Seok Kim; Hee-Seung Bom; Kook-Hyun Yu; Jung-Joon Min
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2012-10-4
Journal Detail:
Title:  Journal of nuclear medicine : official publication, Society of Nuclear Medicine     Volume:  -     ISSN:  1535-5667     ISO Abbreviation:  J. Nucl. Med.     Publication Date:  2012 Oct 
Date Detail:
Created Date:  2012-10-5     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  0217410     Medline TA:  J Nucl Med     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Department of Nuclear Medicine, Chonnam National University Medical School, Gwangju, Republic of Korea.
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