Preliminary And Clinical Studies On Positron Emission Tomography: The Preparation And Preliminary Biological Evaluation Of ¹¹C-1-SPD

Purpose and design of the study1.Traditional Chinese pharmacy,a splendid pearl in the treasures of world traditional medicine,has a history of thousands of years,and it has played an important role in the development of Chinese nation.For a long time,traditional Chinese pharmacological research has been developed from scratch,and great achievements have been made.The elucidation of efficacy of traditional Chinese drugs and their underlying mechanisms,however,is still a great challenge.Therefore we should take full advantage of the current technology and use the multi- discipline crossing methods to help the innovation of traditional Chinese pharmacy. Basic researches for traditional Chinese drugs are of great importance for the elucidation of scientific principles of effects of traditional Chinese drugs,and for the development of modern new traditional Chinese drugs,and are helpful for investigating the new growth point for modern medicine and pharmacy.2."A better tool is needed for good work,a workman must sharpen his tools if to do his work well".Modern pharmacology,pharmacokinetics, toxicology,materia medica,and so on,all depend on the development of new methods and new technology,as well as traditional Chinese pharmacy.With the development of science and technology,multiple-discipline crossings are more and more common.With the repaid development of modern medical imaging,and its intercrossing and integration with other disciplines,the knowledge,techniques and methods in the field of medical imaging are more and more introduced into modern pharmacology to address issues in traditional Chinese pharmacology,such as CT,MR,fMR,SPECT,PET, PET/CT,which is necessary for the modernization of traditional Chinese medicine and pharmacology,and is essential for the development of traditional Chinese drug research,microPET is a device of imaging for small animal,its characteristic is:â‘ high resolution.â‘¡small volume, and low price.â‘¢it can fuse the anatomical and the functional images.â‘£it can reduce time and cost of the reserch in new drug.3.Neuropathy and psychosis show the relationship of multi-target between receptor and transmitter,as well as the traditional Chinese medicine,lf we want to use PET to explore the pharmacology,curative effect,pharmacokinetics of the traditional Chinese medicine,we must resolve the three problems:â‘ the selection and radiolabeling of positron-emitting radionuclide.â‘¡PET imaging and image reconstruction.â‘¢Selection Principle of the traditional Chinese medicine primer.In the shudy of the traditional Chinese medicine,L-Stepholidine(1-SPD) is one of the active ingredients of corydalis,which is a traditional Chinese herb.L-SPD has a dual pharmacological effect of D1 agonism and D2 blockade. So far,1-SPD is the only substance found to have this kind of dual effect. The dual pharmacological effect of 1-SPD will be a new research field for the development of new neuroleptic agents,and will be promising in the treatment of mental disorders and opioid addiction.Therefore,the second development of 1-SPD is of great value.4,On the whole,it has not been reported in literature to label an active ingredient of 1-SPD with ¹¹C.If the method to label an active ingredient of traditional Chinese herb with ¹¹C is investigated,and biological evaluation is conducted,these will be of great novelty,and will be beneficial to the investigation of in vivo mechanism of active ingredients of Chinese herbs.In addition,these studies of labeling methods may be used as preparatory studies for future possible PET or microPET assisted drug development.Based on factors relating to material selection in this project,L- Stepholidine is chosen to conduct an exploratory study.The pharmacokinetic study of 1- Stepholidine using PET will be conducted as first stage work,by which a new method may be provided for future in vivo investigations for active ingredients of Chinese herbs.The objectives of this study are as follow:1) To investigate method feasibility of labeled active ingredients of Chinese herb imaging with PET.2) To investigate in vivo distribution of ¹¹C labeled 1-SPD to provide reference for future possible second development. 3) To investigate the feasibility of PET imaging in the study of pharmacokinetics of active ingredients of Chinese herbs to conduct preparatory work for future possible PET or micro PET assisted drug development;To explore a new investigation method for the study of in vivo pharmacokinetics of traditional Chinese drugs by dynamically monitoring biological distribution in animals.5,Preliminary And Clinical Studies On Positron Emission Tomography was one important research of Batch of doctoral program of Imaging medicine and Nuclear medicine and Key Discipline of MH.To label an active ingredient of traditional Chinese herb with 11C was one branch of serial studies.The serial studies included ¹⁸F-ZMS(2006),¹¹C-HupA(2007), ¹¹C-1-SPD(2008),Trichosanthin,and so on.The serial studies had been Sponsored by 985 Key Project of neurology and State Key Laboratory of Nuclear Medicine(WK006001,WK006002).This subject was the important part of the serial studies.Results of the studyPartâ… .Synthesis and quality control of ¹¹C-radiolabeled 1-SPDObjective:To expore the method and quality control of ¹¹C -radiolabeled 1-SPD.Methods:¹¹CO₂ was produced by CTI RDS 111 cyclotron, converted ¹¹CO₂ to ¹¹C- CH₃I by CH₃I die-block,and then converted it to ¹¹C-Triflate—CH₄,imported ¹¹C-Triflate—CH₄ to 1-SPD which was dissolved in Dimethyl sulfoxide[(CH3)₂SO],reacted at common temperature and then obtained the product.Compared with ¹²C-1-SPD which was produced at the same condition.The labeled product was analyzed by HPLC on a reverse-phase C18 column.Contents and analytical methods of quality control for ¹¹C-1-SPD were investigated and the main quality criteria were achieved through strict control of the determining parameters by standard procedures.Results:The Synthesis time of ¹¹C-1-SPD was 15 to 20 min with chemical purity＞90%,and PH values 6.5±0.3,radiochemieal purity＞95% in 2 hours.All quality criteria of ¹¹C-1-SPD met the requirements of the positron radio-pharmaceuticals.Conclusion:¹¹C-1-SPD injections can be used to further study in the animal or human study. Partâ…¡.Pharmacokinetics and biodistribution of ¹¹C-1-SPD in the normal animalObjective:To exolpre the pharmacokinetics and biodistribution of the new agent,¹¹C-1-SPD in vivo.Methods:Take the sample of blood and organs in different time,5 min,15 min,30 min,60 min,90 min after injecting ¹¹C-1-SPD by vail in mice and measure the cpm,then the%ID/g was calculated.Analysed the pharmacokinetics by taking the blood sample from tail of rats and analysed the biodistribution in the different regions of brain,such as frontal lobe,apical lobe,temporal lobe,occipital lobe,cerebellum,hippocampus,striatum,thalamencephalon and brain stem in the rats.Results:¹¹C-1-SPD was of the characteristic that quickly discharge from the blood,,metabolism through the liver,kidney was the main eccrisis organ,which was 1.323±0.153%ID/g at 5 min and decreasing graduately,it was 1.484±0.350ID/g in liver at 5 min. Pharmacokinetics of ¹¹C-1-SPD in the rats corresponded to two-compartment model.The half-time was 26.2min,apparent volume of distribution was 0.36ml/mg,clearance rate was 0.07ml/min/mg.Conclsions:¹¹C-1-SPD could quickly discharge and decrease to the low level from background of issues in vivo.There was not significant difference of ¹¹C-1-SPD that distribute in the different brain regions,there were more distribution in brain.Pharmacokinetics of ¹¹C-1-SPD in the rats corresponded to two-compartment model.Partâ…¢.Biodistribution of ¹¹C-1-SPD in rats assessed by PET/CT(dedicated PET/CT) ImagingObjective:To exolpre the feasibility to assess the biodistribution of ¹¹C-1-SPD in vivo by PET/CT(dedicated PET/CT) Imaging.Methods:Perform PET/CT scan in different time,5 min,15 min,30 min,45min,60 min,90 min after injecting ¹¹C-1-SPD by vail in rats and transfer the information of brain,heart,lung,liver,kidney,intestine,bladder to the Multi Modality Workststion.Obtain the Distribution Volume Ratios(DVR)of the above tissues.Results:¹¹C-1-SPD was keeping in a relative higher level in liver and kidney at 5min.metabolism through the liver,kidney was the main eccrisis organ.The distribution of ¹¹C-1-SPD in liver, kidney,intestine,bladder was 1.37±0.42%,1.10±0.19%,0.89±0.18 %,0.97±0.111%respectively at 5min and was 0.65±0.11%,0.54±0.05 %,5.49±1.44%,9.86±1.88%respectively at 90min.Conclsions: PET/CT(clinical type) imaging could observe the distribution and metabolism of ¹¹C-1-SPD dynamic and directly.On account of resolution and FOV of the PET/CT(dedicated PET/CT),we could not draw the conclusion that PET/CT imaging can take the place of biodistribution experiment ex vivo.Conclusions(Partâ… -Partâ…¢):1.Synthesis of ¹¹C-1-SPD was of high radiochemical purity and good stability in vitro.All quality criteria of ¹¹C-1-SPD met the requirements of the positron radionuclide-radiolabeled pharmaceutical, and can be used to further study.2.¹¹C-1-SPD could quickly discharge and decrease to the low level in vivo.Pharmacokinetics of ¹¹C-1-SPD in the rats corresponded to two-compartment model.There was not significant difference of ¹¹C-1-SPD that distributed in the different brain regions of normal rats.If the data could be repeated by other departments,the distribution and pharmacokinetics of ¹¹C-1-SPD in brain and body could offer references to second exploitation of drugs.3.Try to assesse the biodistribution of ¹¹C-1-SPD in rats by PET/Cr(dedicated PET/CT) Imaging,but on account of resolution and FOV of the PET/CT(dedicated PET/CT),we could not draw the conclusion that PET/Ctimaging can take the place of biodistribution experiment ex vivo.We firstly bring forward a proposal to establish "toolbox" of Translation Medicine in the research of traditional chinese herb.4.Synthesis of ¹¹C-1-SPD and pharmacokinetics study by PET/CT (dedicated PET/CT)in small animals had not been reported in literature.