| PurposeAMPA receptors are ion channels located at the excitatory synapses of the central nervous system.And the abnormal expressions and the protein function play an important role in the pathogenesis of epilepsy.In this paper,we intend to develop a novel positron drug targeting AMPA receptor,which named [11C]AMPA-1905,and do some evaluation for the probe in vitro and rodents imaging,so as to provide new molecular imaging probe research ideas for the location of epileptic foci in drugrefractory epilepsy.Method(1)Analyzing the targeted functional molecules of AMPA receptors through the literature research,and screening out the potential target molecules.(2)Using organic chemical synthesis reaction,and through multi-step chemical transformation to obtain the labeling precursor and standard ligand.(3)Realizing the automated synthesis of the [11C]AMPA-1905 by optimizing conditions such as alkali,solvent,and reaction temperature,then determining its radiochemical yield,radiochemical purity,molar activity and in vitro stability.(4)Determining the biodistribution(n=12)and the metabolic stability(n=2)of the [11C]AMPA-1905 in the CD-1 mice.(5)Using the specific targeted drug,which is Tarampanel,to study the specificity of the probe in the mice(n = 6),and analyzing the specific binding ability of the [11C]AMPA-1905.(6)Imaging in CD-1 mice(n = 2)and SD rat(n =1)to detect the activity of [11C]AMPA-1905 in the brain,and detect the distribution of [11C]AMPA-1905 in different brain regions of rats.Result(1)The target molecule AMPA-1905 was obtained after screening and analysis.(2)After a total of 4 steps of organic chemical synthesis,the labeled precursor and standard ligand were obtained,and the yields were 36% and 18%,respectively.(3)The [11C]AMPA-1905 had a non-decay-corrected radiochemical yield of 22%-28%(n = 6),radiochemical purity> 99%,molar activity greater than 37.0 GBq / μmol,and good stability in vitro.(4)The data of the biodistribution in normal mice suggested that: the [11C]AMPA-1905 had a low blood-brain barrier penetration in the mouse brain,and the liver system was the main excreted pathway.(5)The results of the experiments for the metabolic stability in vivo showed that [11C]AMPA-1905 was metabolized quickly in mice.(6)In vivo inhibition experiment exhibited that the block of the inhibitor Tarampanel did not reduce the radioactive signal of [11C]AMPA-1905 in the brain of mice,indicating that the PET tracer had a not ideal specific in the mice.(7)the brain uptake of the [11C]AMPA-1905 reached a peak at 1 min,and the SUV value was ~ 0.6,indicating that the tracer has a low blood-brain barrier penetration ability in mice.(8)The uptake of the [11C]AMPA-1905 by rats reached a peak within 1 min,and the SUV was 1.4,indicating that the tracer had a good permeability of the blood-brain barrier in rats.Secondly,Radioactive signals of [11C] AMPA-1905 were uniform in cerebral cortex,thalamus,hippocampus,striatum and cerebellum without different.ConclusionThe AMPA-targeted PET tracer,named [11C]AMPA-1905,can be effectively labeled and synthesized with high radiochemical yield,ideal radiochemical purity and molar activity.The probe has a good stability in vitro and has been successfully applied to PET imaging of rodent brains.The results showed that the probe could quickly cross the blood-brain barrier and had a higher uptake in the rat brain(SUV1min = 1.4).However,the probe’s the rapid brain clearance and low target specificity in rodents have limited its ability to study AMPA receptors.Therefore,further modification of the molecular framework is required to improve the above shortcomings. |
