Preparation and biodistribution of [18F]FP2OP as myocardial perfusion imaging agent for positron emission tomography

Myocardial extractions of pyridaben, a mitochondrial complex I (MC-I) inhibitor, is well correlated with blood flow. Based on the synthesis and characterization of pyridaben analogue 2-tert-butyl-5-[2-(2-[F-18]fluroethoxy)ethoxy]benzyloxy]-4-chloro-2H-pyridazin-3-one ([F-18]FP2OP), this study assessed its potential to be developed as myocardial perfusion imaging (MPI) agent. Methods: The tosylate labeling precursor 2-(2-(4-(tert-butyl-5-chloro-6-oxo-1,6-dihydro-pyridazin-4-yloxymethyl)benzyloxy)ethoxy) ethyl ester (OTs-P2OP) and the nonradioactive 2-tert-butyl-5-[2-(2-[F-19]fluroethoxy)ethoxy]benzyloxy]-4-chloro-2H-pyridazin-3-one ([F-19]FP2OP) were synthesized and characterized by IR, H-1 NMR, C-13 NMR and MS analysis. By substituting tosyl of precursor OTs-P2OP with F-18, the radiolabeled complex [F-18]FP2OP was prepared and further evaluated for its in vitro physicochemical properties, in vivo biodistribution, the metabolic stability in mice, ex vivo autoradiography and cardiac PET/CT imaging. Results: Starting with [F-18]F Kryptofix 2.2.2./K2CO3 solution, the total reaction time for [F-18]FP2OP was about 100 min, with final high-performance liquid chromatography purification included. Typical decay-corrected radiochemical yield stayed at 41 +/- 5.3%, the radiochemical purity, 98% or more. Biodistribution in mice showed that the heart uptake of [F-18]FP2OP was 41.90 +/- 4.52% ID/g at 2 min post-injection time, when the ratio of heart/liver, heart/lung and heart/blood reached 6.83, 9.49 and 35.74, respectively. Lipophilic molecule was further produced by metabolized [F-18]FP2OP in blood and urine at 30 min. Ex vivo autoradiography demonstrates that [F-18]FP2OP may have high affinity with MC-I and that can be blocked by [F-19] FP2OP or rotenone (a known MC-I inhibitor). Cardiac PET images were obtained in a Chinese mini-swine at 5, 15, 30 and 60 min post-injection time with high quality. Conclusion: [F-18]FP2OP was synthesized with high radiochemical yield. The promising biological properties of [F-18]FP2OP suggest high potential as MPI agent for positron emission tomography in the future. (C) 2009 Elsevier Ltd. All rights reserved.