Synthesis of [18F]-labeled (2-(2-fluoroethoxy)ethyl)tris(4-methoxyphenyl) phosphonium cation as a potential agent for positron emission tomography myocardial imaging

Introduction: Established radiotracers for positron emission tomography (PET) myocardial perfusion study are commonly labeled with short-lived radio-isotopes that limit their widespread clinical use. Thus, we synthesized (2-(2[F-18]fluoroethoxy)ethyl)tris(4-methoxyphenyl)phosphonium salt ([F-18]FETMP) as a novel myocardial perfusion agent that penetrates the hydrophobic barriers of the plasma and mitochondrial membranes and accumulate in mitochondria of cardiomyocytes in response to the negative inner-transmembrane potentials. Methods: The [F-18]FETMP was synthesized via two-step nucleophilic substitution reactions of no-carrier-added [F-18]fluoride with the precursor 2,2'-oxybis(ethane-2,1-diyl)bis(4-methylbenzenesulfonate) in the presence of Kryptofix 2.2.2 and K2CO3. The [F-18]FETMP accumulation was measured in cell culture with rat embryonic cardiomyoblast (H9c2) and mouse normal fibroblast (NIH/3T3) cell lines. The mitochondrial membrane potential-dependent cellular uptake of [F-18]FETMP was further assessed using the H9c2 cells treated with carbonyl cyanide m-chlorophenylhydrazone (CCCP) which is a protonophore that selectively abolishes the mitochondrial membrane potential. Biodistribution and micro-PET studies were performed in normal BALB/c mice to test and optimize the kinetics for radiolabeled phosphonium cation. Results: The radiolabeled compound was synthesized with 10%-20% yield. The radiochemical purity was >98% by analytical HPLC, and the specific activity was >5.92 TBq/urnol. The cellular uptake assay showed preferential uptake of [F-18]FETMP in cardiomyocytes. The results of biodistribution and micro-PET imaging studies of [F-18]FETMP in mice and rats showed preferential accumulation in the myocardium. Conclusions: The results suggest that [F-18]FETMP would be a promising candidate for myocardial imaging and might be useful for clinical cardiac PET/CT applications. (c) 2012 Elsevier Inc. All rights reserved.