Comparative and optimized studies on radiosynthesis of O-（2-[^18F]fluoroethyl）-L-tyrosine

O-（2-[^18F]fluoroethyl）_L-tyrosine （[^18F]FET）, one of radiolabelled amino acids, is a very promising brain tumor positron emission tomography （PET） imaging agent and holds clinical potential. This paper described out a comparative and optimized radiosynthesis of [^18F]FET, concerning three aspects of its two-step preparation method, including reaction components, heating methods and reaction models. As a result, good radiochemical yield （about 45%, no-decay-corrected） and radiochemical purity （more than 95%） were achieved, and total synthesis time of [^18F]FET was shortened within 20 min and radiation exposure time also decreased.     

Preparation and preliminary evaluation of [^55Co]（II）vancomycin

Co-55 （t1/2=17.53 h） was produced by 150 uA irradiation of a natural nickel target using 15 MeV protons. It was separated from the irradiated target material by two ion exchange chromatography steps with a radiochemical yield of 〉95% and was used for the preparation of [^55Co]vancomycin （[^55Co]VAN）. Optimization studies were performed using Co-57 due to its longer half-life. Cobalt-57 （t1/2=271.79 d） was produced by irradiation of a natural nickel target with 150 pA current of 22 MeV protons. The 57Co was separated from the irradiated target material using a no-carrier-added method with a radiochemical yield of 〉97%. Both products were controlled for radionuclide and chemical purity. The solutions of [^55Co]VAN were prepared （radiochemical yield〉80%） starting with 55Co acetate and vancomycin at room temperature after 30 min. A precise solid phrase extraction （SPE） method was developed using Si Sep-Pak in order to purify/reconstitute the final formulation for animal studies. [^55Co]VAN showed a radiochemical purity of more than 99%. The resultant specific activity was about 1.15 TBq/mmol. It is proved that the tracer is stable in the final product and in presence of human serum at 37℃ up to 24 h. Biodistribution study of [55Co]VAN in normal rats was undertaken for up to 72 h.     

Synthesis and biological evaluation of 18F-FB-NGA as a hepatic asialoglycoprotein receptor PET imaging agent

Abstract Asialoglycoprotein receptor （ASGP-R） is a hepatic membrane receptor that uniquely exists on the surface of mammalian hepatocytes, and has been used as target of liver functional imaging agents for many years. We labeled the Galactosyl-neoglycoalbumin （NGA） with 18F to get a PET molecular probe 18F-FB-NGA and evaluated its ability as a liver functional PET imaging agent. The 18F-FB-NGA was prepared with NGA by conjugation with N- succinimidyl-4-18F-fluorobenzoate （18F-SFB） and purified with PD-10 desalting column. The radiolabeling yield and radiochemical purity of 18F-FB-NGA were determined by radio-HPLC. Starting with 18F-F-, the total time for 18F-F/3 -NGA was about 120± 10 min. The decay-corrected radiochemical yield is about 25-30%. The radiochemical purity of purified 18F-FB-NGA was more than 98%. Labeled with 185-1850 MBq 18F-SFB, the specific activity of 18F -FB- NGA was estimated to be 7.8-78.3 TBq/mmol. Biodistribution of 18F-FB-NGA in normal mice was investigated after injection through the tail vein. The results showed that the liver accumulated 39.47±3.42 and 12.12±6.11%ID/g at 10 and 30 min after injection, respectively. Dynamic MicroPET images in mice were acquired with and without block after injection of the radiotracer, respectively. High liver activity accumulation was observed at 5 min after injection in normal group. On the contrary, the liver accumulation was significantly lower after block, indicating the specific binding to ASGP-R. J SF-FB-NGA is probably a potential PET liver imaging agent.     

Synthesis and biodistribution of [131I]IMPY

The synthesis and biodistribution of β-amyloid plaques imaging agent [^131I]-2- （4′-dimethylaminophenyl）-6-iodoimidazo[1,2-α] pyridine （[^131I]IMPY） were reported. The chemical structure of the labeling precursor 2-（4′-dimethylaminophenyl）-6- （tributylstannyl） imidazo[1, 2-α] pyridine and all its intermediates were verified by IR,HNMR and MS. The radioiodinated compound was prepared using iododestannylation reaction by hydrogen peroxide. Final radiochemical purity was above 95% determined by TLC. The in vivo biodistribution of [^131I]IMPY in normal mice showed excellent brain uptake and washout, indicating this thioflavin-T based small molecular probe has potential for in vivo imaging amyloid deposits.     

Synthesis and radioiodinated labeling of p—iodophenyl pentadecanoic acid

A new method for the preparation of p-iodophenyl pentadecanoic acid(IPPA) has been developed.The synthesis are described,and physical properties of IPPA are characterized by IR,1HNMR,elementary analysis and MS.^125I-IPPA can be easily prepared by two methods:direct labeling and solid-phase iodo-exchange labeling,and the yields of labeling are 80% and 65%,respectively,The radiochemical purities are higher than 98% after being extracted with chloroform and hexane.     

Synthesis of 2-[~(18)F]fluoro-3-[2(S)-2-azetidinylmethoxy]pyridine as a radioligand for imaging nicotinic acetylcholine receptors

Nicotinic acetylcholine receptors (nChRs) are involved in the various pharmacological effects or disease states. In order to study the central nChRs by PET or SPECT, some radioligands have been investigated. In this paper, the procedure for synthesis of 2-[18F]fluoro-3-[2(S)-2-azetidinylmethoxy]pyridine (2-[18F]-A-85380), a potential PET ligand for in vivo imaging nicotinic acetylcholine receptor was described. 2-[18F]-A-85380 was prepared from the precursor, 2-nitro-3-[(1-(tert-butoxycarbonyl)-2-(S)-azetidinyl)methoxy]pyridine(4), which was synthesized with commercial (S)-2-azetid- inecarboxylic acid as starting material. The whole procedure for radiosynthesis and purification was executed in about 1h and 45-55% of the added fluorine-18 was found in the purified 2-[18F]-A-85380, with specific activity of 1.0-2.2×1011 Bq/μmol.     

Preparation of 6—[^18F]fluoro—L—DOPA and its biodistribution in normal and unilateral PD model rats

No-carrier-added 6-[18F]fluoro-L-DOPA (6-FDOPA) was synthesized via a multistep procedure from a commercial available precursor, 6-nitroveratraldehyde. The total synthesis time was 75min, with a radiochemical yield of (10±3)%, high radiochemical purity (>99%) and high enantiomeric purity (>95%). The biodistri-butions of 6-FDOPA in normal and unilateral PD model rats were measured. The results from normal rats showed the expected high concentration of radioactivity in striatum and low distributions in cerebrum, cortex and cerebellum. The ratio of the radioactivity in striatum to cerebellum reached a peak value (5.9) at 60min. In unilateral PD model rats, whose substania nigra of the right side had been damaged by pre-treated with 6-OHDA, the radioactive concentration in striatum of the damaged side was significantly lower than that of the undamaged side or that of both sides in striatum of control groups.     

Synthesis of [^18F]－N－3－fluoropropyl－2β－carbomethoxy－3β－（4－iodophenyl） nortropane（[^18F0－FP－β－CIT

The ligand of N-(3-fluoropropyl)-2β-carbomethoxy-3β(4‘-iodophenyl) nortropane(FP-β-CIT) and mesylate precursor were synthesized by hydrolysis of cocaine,followed by dehydration,esterification,Grignard reaction,N-demethylation,iodination,N-alkylation with 3-bromopropanol and methylsulfonylation,Finally,^18F-FP-β-CIT was prepared by nucleophilic fluorinatioin of the mesylate with K^18F/K2.2.2 (Kryptofix).The labeling yiedl of ^18F-FP-β-CIT is 25%-30%,The total radiochemical yield of this compound ,calculated from the end of bombardment(EOB) with decay correction,is 10%-12% with a synthesis time of 100-110min.The radiochemical purity of ^18F-FP-β-CIT is greater than 90%,and this compound in aqueous solution is also stable for more than 4 hours at room temperature,It is stable enough for for clinical study.     

Study on radiolabeling of 1,2,3-triazole analogs with fac-[188Re（CO）3 （H2O）3 ]+ via click chemistry

Click chemistry was used to study on radiolabeling of 1,2,3-triazole analogs with fac-[188 Re(CO) 3 (H 2 O) 3]+ . CuSO 4 /L-sodium ascorbate was chosen as the catalyst system, three terminal alkynes were conjugated with two different azides respectively, and then the new prepared fac-[188 Re(CO) 3 (H 2 O) 3]+ was coordinated to the six triazoles. The results showed that the radiochemical yields (RCY) of the conjugation of fac-[188 Re(CO) 3]+ with six triazoles were over 90%, and the triazoles showed high stability in phosphate-buffered saline and new-born calf serum. The preliminary biological evaluation results showed that the new 188 Re-labeling method via click chemistry could have general application in labeling bioactive molecules in high radiochemical yield and high specific activity for further SPECT research.     

Synthesis, radiolabeling and animal studies of [^131I]MPPI： A 5-HT1A imaging agent

The synthesis and biological evaluation of serotonin （5-HT1A） imaging agent [^131I]- 4-iodo-N-{2-[4-（2-methoxyphenyl）-piperazin-l-yl]-ethyl}-N-pridin-2-yl-benzamide （[^131I]MPPI） are reported. The chemical structure of aimed compound and intermediates were confirmed by IR, ^1HNMR, and MS. Radiochemical purity was above 99% determined by TLC. Biodistribution of [^131I]MPPI in rats displayed high uptake in hippocampus and low uptake in cerebellum. The ratio of the uptake of [^131I]MPPI in hippocampus to that in cerebellum was 2.90 at 30 rain post injection. The radioactivity in thyroid was 0.069 and 0.128% ID/g organ at 5 min and 120 rain, respectively, and it was increased with time, which suggests that in vivo deiodination may be the major route of metabolism. Ex vivo autoradiography of brain section displayed significant decrease of radioactivity in hippocampus when pretreated with 8-OH-DPAT, a selective 5HT1A agonist, compared with control. These findings strongly suggested that ^131I-MPPI could be used as an in vivo marker for studies of pharmacology of the 5-HT1A receptor system in animals.     

肿瘤显像剂O-(18F-氟代正烷基)-L-酪氨酸的合成

O-(2-18F-氟代乙基)-L-酪氨酸(FET)和O-(3-18F-氟代丙基)-L-酪氨酸(FPT)由两步法制备。18F-分别与二对甲苯磺酸乙二酯(TsOCH2CH2OTs)和二对甲苯磺酸丙二酯(TsOCH2CH2CH2OTs)发生亲核取代反应,生成对甲苯磺酸-2-18F-氟代乙酯(18F CH2CH2OTs)和对甲苯磺酸-3-18F-氟代丙酯(18FCH2CH2CH2OTs),后两者再分别与L-酪氨酸二钠反应生成FET和FPT,总反应时间小于90 min。终产物FET和FPT用乙腈沉淀法分离纯化,未校正总放化产率分别为4.7%和8%。用HPLC法分离纯化,未校正总放化产率分别为20%和30%。FET和FPT注射液放化纯度大于95%,各质量控制指标符合放射性药物质量要求。     

简便、快速自动化合成肿瘤显像剂18F-氟代乙酸盐和1-H-1-(3-18F-2-羟基丙基)-2-18F-硝基咪唑

用"一锅法"和TRACERlab FXF-N自动化合成仪系统合成了18F-氟代乙酸盐(18F-FAC)和1-H-1-(3-18F-2-羟基丙基)-2-硝基咪唑(18F-FMISO).以溴代乙酸苄酯为前体,在同一反应瓶中经亲核氟化、NaOH水解两步反应及Sep Pak小柱分离纯化制备了18F-FAC注射液,总合成时间小于40 min,未经校正的放化产率和放化纯度分别大于45%和99%.以1-(2'-硝基-1'-咪唑基)-2-O-四氢吡喃基-3-O-甲苯磺酰基丙二醇为原料,用类似方法制备了18F-FMISO注射液,总合成时间小于40min,未经校正的放化产率和放化纯度分别大于40%和95%.采用"一锅法"自动化合成18F-FAC和18F-FMISO注射液,操作简便,该工艺可用制备2-18F-2-脱氧-D-葡萄糖(18F-FDG)的全自动化合成模块来制备18F-FAC和18F-FMISO注射液.     

6-[~(18)F]氟-L-多巴的合成

以硝基藜芦醛为原料 ,采用亲核取代合成法 ,利用手性相转移催化烷基化等多步反应制备了6 [18F]氟 L 多巴 (18FDOPA) ,并用手性流动相和反相C18柱的HPLC法测定对映纯度。结果表明 ,18FDOPA总的合成时间少于 12 0min ,经衰减校正后总放化产额约为 6 3% ,对映纯度和放化纯度分别大于 95 %和 99%     

取代杯[6]芳烃的制备及在18F-FET制备中的应用

本工作制备了相转移催化剂取代杯[6]芳烃：对磺酸杯[6]芳烃和对叔丁基杯[6]芳烃,并以其为催化剂进行了¹⁸F-FET的制备。结果表明,对磺酸杯[6]芳烃作催化剂不仅能够催化FET前体的¹⁹F取代反应,而且能够催化FET前体对（对甲苯磺酸酯）乙基苯甲酰（BOC）氨基酸酯的¹⁸F标记反应,放化产率为11%。而对叔丁基杯[6]芳烃对催化FET前体的¹⁹F取代反应和¹⁸F的标记反应均没有催化活性。对磺酸杯[6]芳烃的催化作用可能与它的磺酸基参与络合反应,增大了杯[6]芳烃极性等因素有关。虽然对磺酸杯[6]芳烃催化FET前体的放化产率远低于Kryptofix 2.2.2,但该研究对优化条件找出更好的取代杯[6]芳烃催化剂具有重要的指导意义。     

羟基磷灰石对153Sm-HEDTMP的吸附性能研究

研究了各种因素对153Sm-HEDTMP（羟乙基乙二胺三甲撑膦酸）在羟基磷灰石（HA）上吸附的影响，结果表明，室温下153Sm-HEDTMP在HA上吸附20min即可达到平衡，温度对吸附量影响不明显。过量配体会使配合物吸附量降低；吸附量在酸性条件下较高，153Sm3＋在HA上的吸附能力最强，饱和吸附容量可达720 µmol•g－1；153Sm-HEDTMP饱和吸附容量为61µmol•g－1，153Sm-HEDTMP的吸附好于153Sm-EDTMP，Ca2＋对吸附有强烈的促进作用。EDTMP和HEDTMP对配合物的解吸率较高；生理盐水解吸作用不明显。     

国产氟多功能模块合成雌激素受体显像剂16α-[18F]氟-17β-雌二醇

采用国产氟多功能模块,以3-甲氧基甲基-16,17-O-磺酰基-表雌三醇-O-环状砜（3-O-(Methoxymethyl) -16,17-O-sulfuryl-16-epiestriol,MMSE）为前体,在国产氟多功能合成模块的密封体系下,经¹⁸F标记合成雌激素受体显像剂16α-[¹⁸F]氟-17β-雌二醇（¹⁸F-FES）。结果显示：合成的¹⁸F-FES,不校正合成效率为8.2%,校正合成效率为12.8%;合成时间约为70 min,标记物¹⁸F-FES放化纯度大于98%,体外稳定性良好。以上结果表明,国产氟多功能模块可制备¹⁸F-FES溶液,制备的¹⁸F-FES溶液符合放射性药物的质量要求。     

简便快速自动化合成报告基因表达PET显像剂18F-FHBG

用一锅法和TRACERlab FXF-N合成仪自动化合成9-(4-18F-3-羟甲基丁基)鸟嘌呤(188F-FHBG).以N2-(对甲氧苯基二苯基甲基)-9-[(4-甲苯磺酰基)-3-对甲氧苯基二苯基甲氧基-甲基丁基]鸟嘌呤为前体,在同一反应瓶中经亲核氟化、水解两步反应及SEP-PAK小柱分离纯化制备18 F-FHBG注射液,总合成时间<40 min,未校正放化产率为7%-12%(n>10),放化纯度>95%.用SEP-PAK分离纯化的一锅法,操作简便,很容易实现18F-FHBG的自动化合成.     

乳腺癌雌激素受体分子影像探针16α-[18F]氟-17β-雌二醇的自动化合成

采用改进的Explora FDG4模块,基于"两步-两锅"式的放射化学反应处理过程和简便的固相萃取(SPE)方式分离纯化,成功发展了18F-FES的快速、可靠的自动化合成方法.第一步是前体3-O-(甲氧甲基)-16,17-O-磺酰基-16-表雌二醇(MMSE)与活化的18F离子间的亲核放射氟化反应,100℃加热回流反应10 min,生成标记中间体,使用基于硅胶柱的SPE方式分离该标记中间体,除去未反应的起始物.第二步是标记中间体的酸性水解反应,90℃加热反应10 min,生成目标产物18F-FES,使用基于C18和Al2O3组成的串联柱的SPE方式分离、纯化所得的18F-FES.总合成时间～70 min,放射化学产率为35%(衰变校正后),放射化学纯度＞95%.     

5-HT_(1A)受体拮抗剂~(11)C-WAY-100635的自动化合成

为自动化合成用于5-羟色胺(5-HT_(1A))受体显像~(11)C标记的N-[2-[4-(2-甲氧基苯基)-1-哌嗪基]乙基]-N-2-吡啶基环己烷甲酰胺(~(11)C-WAY-100635),采用自动化合成模块,以去甲基WAY-100635为前体,经甲基化,HPLC纯化和Sep-Pak Plus C18柱去除有机溶剂制得~(11)C-WAY-100635注射液。结果显示,合成方法共耗时约40 min,~(11)C-WAY-100635注射液的未校正放化产率10%~20%,放化纯度97%;静脉注射日本大耳白兔~(11)C-WAY-100635(约111 MBq)后,脑组织放射性摄取显著,且明显高于头颅等其他组织。自动化合成5-HT_(1A)受体显像剂~(11)C-WAY-100635方法简单,反应时间较短,放化纯度高,产率稳定可靠,可在临床中推广应用。