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

• Published in: Bioorganic & medicinal chemistry 2010-02, Vol.18 (3), p.1312-1320
• Main Authors: Mou, Tiantian, Jing, Huihui, Yang, Wenjiang, Fang, Wei, Peng, Cheng, Guo, Feng, Zhang, Xianzhong, Pang, Yan, Ma, Yunchuan
• Format: Article
• Language: English
• Subjects: [ 18F]FP2OP; Animals; Fluorine - chemistry; Mice; Mitochondria complex I; Myocardial perfusion imaging; Myocardium - metabolism; Perfusion Imaging - methods; Positron emission tomography; Positron-Emission Tomography - methods; Pyridazines - chemical synthesis; Pyridazines - chemistry; Radiopharmaceuticals - chemical synthesis; Radiopharmaceuticals - chemistry; Rats; Rats, Sprague-Dawley; Swine
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2009.12.022

A pyridaben analogue as mitochondria complex I inhibitor was synthesized and radiolabeled with 18F ([ 18F]FP2OP) by one-step synthesis, then it was evaluated as a potential PET myocardial perfusion imaging agent. 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-2 H-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-2 H-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./K 2CO 3 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.