UNLABELLED: 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-[(18)F]fluroethoxy)ethoxy]benzyloxy]-4-chloro-2H-pyridazin-3-one ([(18)F]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-[(19)F]fluroethoxy)ethoxy]benzyloxy]-4-chloro-2H-pyridazin-3-one ([(19)F]FP2OP) were synthesized and characterized by IR, (1)H NMR, (13)C NMR and MS analysis. By substituting tosyl of precursor OTs-P2OP with (18)F, the radiolabeled complex [(18)F]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 [(18)F]F(-) Kryptofix 2.2.2./K(2)CO(3) solution, the total reaction time for [(18)F]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 [(18)F]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 [(18)F]FP2OP in blood and urine at 30 min. Ex vivo autoradiography demonstrates that [(18)F]FP2OP may have high affinity with MC-I and that can be blocked by [(19)F]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: [(18)F]FP2OP was synthesized with high radiochemical yield. The promising biological properties of [(18)F]FP2OP suggest high potential as MPI agent for positron emission tomography in the future. Copyright (c) 2009 Elsevier Ltd. All rights reserved.
UNLABELLED: 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-[(18)F]fluroethoxy)ethoxy]benzyloxy]-4-chloro-2H-pyridazin-3-one ([(18)F]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-[(19)F]fluroethoxy)ethoxy]benzyloxy]-4-chloro-2H-pyridazin-3-one ([(19)F]FP2OP) were synthesized and characterized by IR, (1)H NMR, (13)C NMR and MS analysis. By substituting tosyl of precursor OTs-P2OP with (18)F, the radiolabeled complex [(18)F]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 [(18)F]F(-) Kryptofix 2.2.2./K(2)CO(3) solution, the total reaction time for [(18)F]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 [(18)F]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 [(18)F]FP2OP in blood and urine at 30 min. Ex vivo autoradiography demonstrates that [(18)F]FP2OP may have high affinity with MC-I and that can be blocked by [(19)F]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: [(18)F]FP2OP was synthesized with high radiochemical yield. The promising biological properties of [(18)F]FP2OP suggest high potential as MPI agent for positron emission tomography in the future. Copyright (c) 2009 Elsevier Ltd. All rights reserved.
Authors: Mark D Bartholomä; Shaohui Zhang; Vamsidhar Akurathi; Christina A Pacak; Patricia Dunning; Frederic H Fahey; Douglas B Cowan; S Ted Treves; Alan B Packard Journal: Nucl Med Biol Date: 2015-06-18 Impact factor: 2.408
Authors: Mark D Bartholomä; Vijay Gottumukkala; Shaohui Zhang; Amanda Baker; Patricia Dunning; Frederic H Fahey; S Ted Treves; Alan B Packard Journal: J Med Chem Date: 2012-12-14 Impact factor: 7.446