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Objective To investigate the biodistribution of 4-chloro-2-tert-butyl-5-[2-[[1-[2-[2-18 F-fluroethoxy] ethoxymethyl]-1H-1,2,3-triazol-4-yl] methyl] phenylmethoxy]-3(2H)-pyridazinone (18F-MyoZone) and evaluate its clinical potential as a PET myocardial perfusion imaging (MPI) tracer in miniswine.Methods 18F-MyoZone was prepared.Twelve Bama mini-swine were intravenously injected with approximately 111 MBq of 18F-MyoZone to evaluate PET imaging characteristics.Whole-body PET scans were performed at the timing of 5,20,40,60 and 120 min postinjection to measure time-dependent mean stand-ardized uptake value (SUVmean) in multiple organs of health animals (n =6).SUVmean ratios of myocardium/liver and myocardium/lung over time were then calculated.Mini-swine with induced acute myocardial infarction (n =3) and chronic myocardial ischemia (n =3) accompanying with health mini-swine (n =3) were utilized to evaluate the diagnostic capability of 18F-MyoZone PET MPI.Results The typical decay-corrected radiochemical yield of 18 F-MyoZone reached (52.0±4.3)％ (n =3) with a high radiochemical purity (＞98％).In the biodistribution study,high initial myocardial uptake (SUVmean =10.40±2.40 at 5 min postinjection) and remarkable myocardial retention (SUVmean =9.30±2.00 at 120 min postinjection) were observed.The adjacent organs (like the liver and lungs) indicated low tracer uptake and rapid clearance.The heart/liver and heart/lung SUVmean ratios were 4.77±0.91 and 17.14±5.84 respectively at 5 min postinjection,with an increase to 11.16± 1.38 and 21.69±7.09 at 120 min postinjection.In the MPI study of miniswine,normal myocardium demonstrated uniform tracer distribution with clearly visualizable myocardial boundary,infarct myocardium and severe ischemia myocardium performed intense resting perfusion defect,and ischemia myocardium revealed reversible perfusion defect by stress/rest MPI.The myocardial image quality remained stable within 120 min postinjection.Conclusions MPI with 18F-MyoZone exhibits high initial myocardial uptake and low extracardiac activities in adjacent organs.Advantages in early imaging and wide diagnostic time window make it a promising PET MPI tracer.
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Objective To investigate the mechanism of uptake and retention of a novel PET myocardial perfusion imaging agent 18F-MyoZone in cardiomyocytes. Methods 1) Mechanism of inhibition of mitochondrial respiratory chain enzyme activity: With mitochondrial respiratory chain enzyme complex I (MC-I) activity assay kit, a sequence of 19F-MyoZone solution (start at 15 μmol/L, 3 times dilution, 12 points) was interacted with MC-I to detect the half inhibition rate (IC50) of 19F-MyoZone inhibiting mitochondrial respiratory chain activity. 2) Autoradiography experiment of 18F-MyoZone combining with MC-I: Myocardial tissue sections of neonatal rat were hatched with normal saline and 4 known MC-I inhibitors [rotenone (4 μmol/L), 19F-Flurpiridaz (4 μmol/L), 19F-MyoZone (4 μmol/L) and pyridaben (4 μmol/L)], and then 18F-MyoZone was added to autoradiography for detecting whether 18F-MyoZone can specifically bind the cardiomyocytes MC-I; and then the myocardial tissue sections of rat were hatched for 30 min with different concentrations of rotenone or 19F-MyoZone solution (0, 20 μmol/L, 2 μmol/L and 200 nmol/L, 20 nmol/L), then the 18F-MyoZone was added and hatched for 30 min again, developing for 10 min with phosphor storage screen after cleaning the slice, and analyzing and calculating the inhibition rate of each inhibitor concentration. 3) Experiment of rotenone inhibitting the uptake of 18F-MyoZone by cardiomyocytes: Neonate rats' primary cardiomyocytes were cultured for 15 min with different concentrations of 19F-MyoZone or equivalent rotenone (start at 10 μmol/L, 3 times dilution, 12 points), then 50 μl of 18F-MyoZone (about 17 kBq) was added and culturing for 30 min. The lysate was then collected, the radioactivity was counted and the IC50 of rotenone was calculated. 4) Outflow experiment of 18F-MyoZone from cardiomyocytes: Cultured neonate rats' primary cardiomyocytes were interacted with 500 μl of 18F-MyoZone (about 37 kBq) for 30 min, then the cell supernatant and lysate were separated to do photon counts at the time points of 0, 10, 20, 30, 60, 90, 120 and 150 min. The ratio of cardiomyocyte outflow rate was then calculated. Results Enzyme activity studies showed that 19F-MyoZone may effectively inhibit the activity of MC-I(IC50=229.9 nmol/L) in a dose dependent manner. MyoZone could specifically bind to MC-I with binding sites in accordance with the inhibitors rotenone, pyridaben and 19F-Flurpiridaz. Experiment of rotenone inhibitting the uptake of 18F-MyoZone by cardiomyocytes showed that 18F-MyoZone could be absorbed by rat's cardiomyocytes, and with the increase of rotenone concentration, the radio uptake of cardiomyocytes decreased gradually with inhibitor IC50 as 7 nmol/L. Outflow experiment showed that rat's cardiomyocytes could uptake 18F-MyoZone and stably detain over time. The outflow rate increased gradually within 0-30 min, and then maintained constantly from 60 min to 150 min. The amount of retention was about 20% of the entire uptake. Conclusions 18F-MyoZone may specifically bind MC-I and detain for a long time in rat's cardiomyocytes. 18F-MyoZone is a valuable myocardial perfusion imaging agent with great research value.
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Objective@#To investigate the biodistribution of 4-chloro-2-tert-butyl-5-[2-[[1-[2-[2-18F-fluroethoxy]ethoxymethyl]-1H-1, 2, 3-triazol-4-yl]methyl]phenylmethoxy]-3(2H)-pyridazinone (18F-MyoZone) and evaluate its clinical potential as a PET myocardial perfusion imaging (MPI) tracer in mini-swine.@*Methods@#18F-MyoZone was prepared. Twelve Bama mini-swine were intravenously injected with approximately 111 MBq of 18F-MyoZone to evaluate PET imaging characteristics. Whole-body PET scans were performed at the timing of 5, 20, 40, 60 and 120 min postinjection to measure time-dependent mean standardized uptake value (SUVmean) in multiple organs of health animals (n=6). SUVmean ratios of myocardium/liver and myocardium/lung over time were then calculated. Mini-swine with induced acute myocardial infarction (n=3) and chronic myocardial ischemia (n=3) accompanying with health mini-swine (n=3) were utilized to evaluate the diagnostic capability of 18F-MyoZone PET MPI.@*Results@#The typical decay-corrected radiochemical yield of 18F-MyoZone reached (52.0±4.3)%(n=3) with a high radiochemical purity (>98%). In the biodistribution study, high initial myocardial uptake (SUVmean=10.40±2.40 at 5 min postinjection) and remarkable myocardial retention (SUVmean=9.30±2.00 at 120 min postinjection) were observed. The adjacent organs (like the liver and lungs) indicated low tracer uptake and rapid clearance. The heart/liver and heart/lung SUVmean ratios were 4.77±0.91 and 17.14±5.84 respectively at 5 min postinjection, with an increase to 11.16±1.38 and 21.69±7.09 at 120 min postinjection. In the MPI study of mini-swine, normal myocardium demonstrated uniform tracer distribution with clearly visualizable myocardial boundary, infarct myocardium and severe ischemia myocardium performed intense resting perfusion defect, and ischemia myocardium revealed reversible perfusion defect by stress/rest MPI. The myocardial image quality remained stable within 120 min postinjection.@*Conclusions@#MPI with 18F-MyoZone exhibits high initial myocardial uptake and low extracardiac activities in adjacent organs. Advantages in early imaging and wide diagnostic time window make it a promising PET MPI tracer.
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Objective To study the factors affecting the synthesis of 18F-MyoZone,and to evaluate its potential as a myocardial perfusion imaging (MPI) agent in normal Chinese mini-swine.Methods 18F-MyoZone was prepared by substituting the leaving group toluenesulfonyloxy (OTs) from the precursor compound with 18F-fluoride (18F-F-).The conditions affecting the labeling yield were studied by varying the amount of K2CO3 and precursor compound,18F-fluorination reaction time and temperature.PET was performed at 5,30,60 and 120 min post-injection on normal Chinese mini-swine.Results The doses of K2CO3 and precursor,the reaction time and the reaction temperature could affect the labeling yield of 18F-MyoZone,especially K2CO3.The optimized synthetic condition was 1.0 mg K2CO3,2.0 mg mpp2-OTs,20 min reaction time at 90 ℃.The total radio-synthesis time in this condition was 60 min.The uncorrected radiochemical yield was (24.0±5.1) ％.The radiochemical purity was ＞98％.PET imaging showed that 18F-MyoZone had high initial uptake (SUV=8.17± 1.83 at 5 min post-injection) and good retention (SUV =5.78±0.99 at 120 min post-injection) in the heart.The clearance of 18F-MyoZone from liver was very fast.The heart/liver ratios were 3.32,5.31,6.09 and 5.76 at 5,30,60 and 120 min post-injection,respectively.From 5 to 120 min post-injection,the outline of heart was clear and intact.There was almost no interference from the adjacent organs.The quality of PET images was highly satisfactory.Conelusions 18 F-MyoZone has the potential to be a good myocardial perfusion agent.The amount of K2CO3 used could significantly affect the labeling yield of 18F-MyoZone.