| Objectives:Several carbon-11 labeled PET imaging agents of cardiac sympathetic nerve were synthesized and their biological properties were characterized.The imaging agents were synthesized by introducing carbon-11 methyl group on the amino group of phenethylamine,core structure of of beta-adrenergic agonists.Hydroxyl group substituent(s)was introduced into the benzene ring of phenylethylamine molecule and number or positions of hydroxyl group were changed to alter biological properties of the imaging agents.Meanwhile attempt to introduce fluoro-18 fluoromethyl or fluoro-18 fluoroethyl group on the amino group of dopamine molecule to improve the clinical value of these imaging agents.Method:(1)Carbon-11 labeled N-methyl phenethylamine(11C-MPEA),carbon-11 labeled N-methyl m-tyramine(11C-m-MTyr),carbon-11 labeled N-methyl p-tyramine(11C-p-MTyr)and carbon-11 labeled N-methyl dopamine(11C-MDA)were synthesized through reaction of Triflate-CH3 with phenethylamine,m-tyramine,p-tyramine and dopamine,respectively.The target compounds were confirmed by high performance liquid chromatography(HPLC),and their specific activity,lipid partition coefficient and Kunming mice biodistribution were measured.The imaging effect of 11C-p-MTyr and 11C-MDA on New Zealand white rabbits was measured by PET/CT imaging.(2)PET/CT myocardial neuroimaging with 11C-MDA and PET/CT myocardial perfusion imaging with 13N-Ammonia were compared in Chinese miniswine model of acute myocardial ischemia to evaluate the imaging performance of 11 C-MD A in acute myocardial ischemia model.(3)Attempts were made to synthesize fluoro-18 labeled N-fluoromethyl dopamine and N-fluoroethyl dopamine with different precursors and synthetic routes.Results:(1)The radiochemical yield of 11C-MPEA was 26%(n = 10,form 11C-CO2).Radiochemical purity,chemical purity and specific activity measured by Radio-HPLC method were 98.75%,97.60%and 60 GBq/mmol,respectively.The lipid partition coefficient was 1.9 ± 0.09,in the n-octanol-PBS system,and the fat solubility was strong.Biodistribution in kunming mice showed the uptake of 11C-MPEA in the myocardium was lower than that in the lungs and the liver.The uptake ratio of heart to lung was 1/2.08 at 10 min after injection,and the uptake ratio of heart to liver was 1/2.94.(2)The radiochemical yield of 11C-m-MTyr was 13%(n = 10,from 11C-CO2).Radiochemical purity,chemical purity and specific activity measured by Radio-HPLC method were 98.47%,97.10%and 35 GBq/mmol,respectively.The lipid partition coefficient was 1.4±0.07,in the n-octanol-PBS system.This value is within the range of blood-brain-barrier(1.5?2.6),but the marker in the brain and myocardial intake are not high.Biodistribution with kunming mice showed the myocardial uptake was lower than those of lung and liver.Ratio of heart to lung uptake was 1/2.56 at 10 min after injection,and ratio of heart to liver uptake was 1/2.76.(3)The radiochemical yield of 11C-p-MTyr was 33%(n = 10,from 11C,CO2).Radiochemical purity,chemical purity and specific activity measured by Radio-HPLC method were 98.69%,97.34%and 80 GBq/mmol,respectively.The lipid partition coefficient was 1.6±0.1.This value is within the range of blood-brain-barrier(1.5?2.6),but the marker in the brain and myocardial intake are not high.Biodistribution with kunming mice showed the uptake of 11C-p-MTyr in the myocardium was lower than that in the lungs and the liver.The uptake ratio of heart to lung was 1/1.85 at 10 min after injection,and the uptake ratio of heart to liver was 1/5.PET/CT myocardial imaging of New Zealand white rabbits appeared vague and could not provide valid image.(4)The radiochemical yield of 11C-MDA was 21%(n = 10,from 11C-CO2).Radiochemical purity,chemical purity and specific activity measured by Radio-HPLC method were 99.09%,98.58%and 50 GBq/mmol,respectively.The lipid partition coefficient was-0.47±0.03 suggesting the agent has high hydrophilicity and easy to enter myocardial tissue.Biodistribution with kunming mice showed the myocardial uptake twice as high as that of non-target lungs,while liver uptake was higher then myocardial uptake,but less effect on myocardial imaging.PET/CT imaging in the New Zealand white rabbit showed clear left ventricular image and radioactive signal uniformly distributed in ventricular wall.Image of the right ventricular developed partially.Heart to lung uptake ratio was 3.26.Radioactivity uptake of liver was high.Cardiac image became blurred after inhibition with hydrochloric acid imipramine.Radioactivity uptake of ventricular wall significantly reduced or impaired.Heart to lung uptake ratio reduce to 1.21.(5)When diagnose acute myocardial ischemia in Chinese miniswine acute myocardial ischemia model,myocardial neuroimaging with 11C-MDA were more sensitive than myocardial perfusion imaging with 13N-Ammonia.For acute myocardial ischemia-reperfusion and cardiac sympathetic nerve recovery,the two kinds of imaging agents showed different characteristics.11C-MDA responded well to the damage and recovery of myocardial receptor,showing clearly the evolvement of the states of myocardial receptor from light damage to heavy damage followed by slow recovery within 6 month after model creation.However,in 13N-Ammonia imaging,blood perfusion had already recovered 1 month after model creation.(6)N-fluoromethyl dopamine was unstable at room temperature,easily defluorinated to N-methyl dopamine.N-fluoroethyl dopamine was relatively stable at room temperature.However,radio labeled target compound was not obtained.Conclusion:(1)Four carbon-11 labeled beta-phenethylamine derivatives were synthesized in the present study.Due to different position and number of hydroxyl group in benzene ring,the four imaging agents showed different performance.11C-MPEA showed high liposolubility,poor access to myocardial tissue and might easily overcome the blood-brain barrier to reach to the brain tissue;water-solubility and liposolubility of 11C-m-MTyr and 11 C-p-MTyr were not high and their abilities to enter the brain and heart tissue were low;11C-MDA has high solubility in water and is easy to enter the myocardial tissue.(2)11C-MPEA?11C-m-MTyr and 11C-p-MTy may not be suitable to be applied in myocardial PET imaging.Performance of 11C-MDA in myocardial PET imaging was excellent.Myocardial image of normal Chinese miniswine with 11C-MDA showed clear outline and the agent was evenly uptaken by ventricular wall.(3)Comparison of PET/CT myocardial neuroimaging with 11C-MDA and PET/CT myocardial perfusion imaging with 13N-Ammonia in Chinese miniswine acute ischemia model showed myocardial ischemia neuroimaging with 11C-MDA showed larger range of ischemia than that of 13N-Ammonia myocardial perfusion imaging.11C-MDA imaging has high sensitivity and is able to discover small changes in heart early.Moreover the agent can be used for ischemia memory imaging. |
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