Bioorganic and Medicinal Chemistry p. 1312 - 1320 (2010)
Update date:2022-08-02
Topics:
Mou, Tiantian
Jing, Huihui
Yang, Wenjiang
Fang, Wei
Peng, Cheng
Guo, Feng
Zhang, Xianzhong
Pang, Yan
Ma, Yunchuan
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-[18F]fluroethoxy)ethoxy]benzyloxy]-4-chloro-2H-pyridazin-3-one ([18F]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-[19F]fluroethoxy)ethoxy]benzyloxy]-4-chloro-2H-pyridazin-3-one ([19F]FP2OP) were synthesized and characterized by IR, 1H NMR, 13C NMR and MS analysis. By substituting tosyl of precursor OTs-P2OP with 18F, the radiolabeled complex [18F]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 [18F]F- Kryptofix 2.2.2./K2CO3 solution, the total reaction time for [18F]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 [18F]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 [18F]FP2OP in blood and urine at 30 min. Ex vivo autoradiography demonstrates that [18F]FP2OP may have high affinity with MC-I and that can be blocked by [19F]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: [18F]FP2OP was synthesized with high radiochemical yield. The promising biological properties of [18F]FP2OP suggest high potential as MPI agent for positron emission tomography in the future.
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