11C-PK11195的自动化合成及其生物学分布

目的 研究N-[11C]甲基-N-(1-甲基丙基)-1-(2.氯苯基)异喹啉-3-氨甲酰(11C-PK11195)在国内现有合成模块上的自动化合成程序及其在小鼠体内的生物学分布.方法 以1-(2-氯苯基)-N-(1-甲基丙基)-异喹啉-3-氨甲酰去甲基前体与国产模块生产的11C-CH3I在TracerLabFXF-N自动化合成模块中进行甲基化反应,制备11C-PK11195,测定11C-PK11195的纯度和稳定性,观察11C-PK11195在小鼠体内的生物学分布[以每克组织百分注射剂量率(%ID/g)表示]和异常毒性,并进行健康家猫PET显像.结果 从11C-CO2生产到11C-PK11195合成结束总的合成时间约35 min,甲基化合成11C-PK11195的放化产率为(47±3.6)%,其放化纯和化学纯度均>98%,比活度为30～65 GBq/μmol,"C-PK11195注射液室温放置1 h内放化纯>95%.生物学分布实验表明,11C-PK11195在小鼠体内的清除较快,1 min时为(21.44±3.08)%ID/g,60 ndn下降到(1.35±0.54)%ID/g,肾为其主要的排泄器官.注射后1～5 min内,鼠脑放射性水平较高,随后脑内放射性快速下降;心、肺和肾组织中的放射性较高.猫PET显像示肝和肠道摄取最高,其次为肾、肺、大脑、心肌、胃、脾和膀胱,脑组织中放射性分布均匀.结论 该方法可制备出满足临床应用的11C-PK11195,其合成程序也适合于在国内其他模块中应用.11C-PK11195可望用于国内临床PET显像研究.在注射显像剂后30～40 min进行PET显像,可获得较佳PET图像.     

多巴胺D2受体乃131I-epidepride显像对帕金森病的临床研究

目的 评价多巴胺D2受体显像剂131I-(s)-(-)-N-[(1-乙基-2-吡咯烷基)甲基]-5-碘-2,3-二甲氧基苯甲酰胺(epidepride)对帕金森病(PD)的临床应用价值.方法 PD患者38例(H/YⅠ～Ⅳ级,病程4个月～6年),健康对照组12例,静脉注射131I-epidepride 18.5 MBq 3 h后行SPECT显像,并应用感兴趣区(ROI)技术计算纹状体/枕叶放射性(ST/OC)比值,分析ST/OC比值与PD患者临床严重程度的相关性.采用SPSS 10.0软件对数据进行校正t检验,配对t检验及Spearman相关分析.结果 对照组131I-epidepride显像示双侧纹状体内有高度放射性浓聚,纹状体显示清晰,双侧基本对称,额叶、颞叶、顶叶、枕叶及小脑放射性较低.与健康对照组比较,PD患者ST内131I-epide-pride浓聚增加,但差异无统计学意义.早期PD患者(H/Y Ⅰ级)病侧肢体的对侧ST放射性显著增加、体积增大(壳核尤为显著),与同侧ST相比差异有统计学意义(t=7.89,P＜0.05).ST/OC比值与PD临床严重程度(H/Y分级)无明显相关性(r=0.12,P＞0.05).结论 多巴胺D2受体131I-Epi-depride SPECT显像有助于了解PD患者ST内突触后膜的多巴胺D2受体变化,PD患者D2上调,在偏侧PD中以病变对侧壳核尤为显著.ST/OC比值与PD临床严重程度无相关性.     

猫多巴胺转运蛋白PET脑显像研究

目的:制备多巴胺转运蛋白显像剂~(18)F-FP-βCIT[~(18)F-N-(3-氟丙基)-2β-甲酯基-3β-(4’-碘苯基)去甲基托烷],并进行猫PET脑显像。材料和方法:~(18)F-FP-βCIT的制备应用一步法:用K_(222)催化发生亲核氟化反应,得到~(18)F-FP-βCIT。PET显像仪器为Siemens ECAT HR~+ PET仪,3只健康正常猫进行~(18)F-FP-βCIT PET脑动态显像,观察纹状体体区放射性计数随时间的变化,并进行半定量分析。结果:~(18)F-FP-βCIT总放化合成时间为60～90min,时间校正后放化产率为2％～10％,放化纯度平均为96.3％,tR=3.38±0.20min。PET显像示早期(15min内)猫脑皮质及纹状体可见显影,随显像时间延长,脑皮质放射性减退,而纹状体显影更为清晰,30min纹状体/小脑比值达2.59±0.16,60min、90min及120min时此比值分别为2.73±0.23、2.52±0.13、2.08±0.11。结论:~(18)F-FP-βCIT是一种理想的PET多巴胺转运蛋白显像剂,可利用PET进行猫的脑受体方面的研究。     

Al18F-NOTA-FAPI-04的自动化合成与体内显像

目的:自动化合成Al¹⁸F-1,4,7-三氮杂环壬烷-1,4,7-三乙酸(NOTA)-成纤维细胞激活蛋白抑制剂(FAPI)-04,并进行体内显像,评估其诊断肿瘤的效能。方法:利用All-in-one型自动合成模块合成Al¹⁸F-NOTA-FAPI-04,并进行质量分析;取3只正常BALB/c小鼠和3只4T1小鼠乳腺癌荷瘤小鼠进行PET/CT显像,观察体内Al¹⁸F-NOTA-FAPI-04分布情况;对1例肝细胞肝癌患者(男,51岁)进行Al¹⁸F-NOTA-FAPI-04和18F-FDG PET/CT显像,评估其对肝癌的诊断效能。结果:自动化合成Al¹⁸F-NOTA-FAPI-04的时间约为35 min,合成产率约为(25.2±1.9)%(衰减校正后,n=3),产品为无色透明溶液,pH值为7.0~7.5,其比活度为(46.11±3.07)GBq/μmol(衰减校正后,n=3),放化纯大于99.0%,室温放置6 h后放化纯仍大于98.0%。小鼠体内显像示Al¹⁸F-NOTA-FAPI-04的生理性摄取主要在胆道系统和膀胱中,且高度浓聚于肿瘤病灶区域;肝细胞肝癌患者PET/CT显像示Al¹⁸F-NOTA-FAPI-04和18F-FDG PET/CT在胸骨旁淋巴结、膈上前组淋巴结、肝门区淋巴结、胰十二指肠韧带区淋巴结、腹主动脉旁淋巴结的靶本比值(TBR)分别为4.1、8.9、5.4、4.8、2.2和1.0、2.8、5.0、2.1、1.1。结论:基于All-in-one型自动合成模块合成Al¹⁸F-NOTA-FAPI-04,合成时间较短、产率高、稳定性好,高度浓聚于病灶区域,其PET图像对比度高,诊断性能优异。     

18F-RGD环肽二聚体的自动化合成及小动物PET显像

目的 应用国产多功能18F标记模块制备4-[18F]氟-3-三氟甲基苯甲酰基-谷氨酸-(RGD -苯丙氨酸-赖氨酸)环肽二聚体(4-18 F-TFMB-E[c(RGDfk)2]),并用micro PET观察其在肿瘤模型鼠内的生物分布.方法 基于PET-MF-2V-IT-I多功能合成模块,采用“一锅法”完成4-18F-TFMB-E[ c(RGDfk)2]的制备和纯化.荷人胰腺癌BxPC-3裸鼠给药后行micro PET活体显像.结果 4-18 F-TFMB-E[ c(RGDfk)2]放化产率为(27.4±2.3)％(衰减校正后),总合成时间为30 min,无需HPLC法分离,放化纯＞98％.荷人胰腺癌BxPC-3裸鼠注射4-18 F-TFMB-E[c(RGDfk)2]后30、60和120 min后肿瘤摄取值(％ID/g)分别为4.03±0.32、3.31±0.20和2.72±0.17;注射后30 min肿瘤与对侧肌肉摄取值比值大于6(对侧肌肉摄取值为0.47 ±0.12).4-18F-TFMB-E[c (RGDfk)2]主要经肝、肠排泄.结论 4-18F-TFMB-E[ c(RGDfk)2]自动化合成速度快、效率高,胰腺癌肿瘤模型显影清晰.     

多巴胺转运蛋白显像剂18F-β-FP-CIT的合成与质量控制

目的研制多巴胺转运蛋白显像剂18F-N-3-氟丙基-2-β-甲酯基-3-β-(4-碘苯基)降托烷(18F-β-FP-CIT).方法 18F-β-FP-CIT经两步法制备1,3-二溴丙烷在相转移催化剂氨基聚醚钾复合物(K/K222)+18F-存在下发生亲核氟化反应,生成18F-氟丙基溴,后者与前体2β-甲酯基-3β-(4-碘苯基)降托烷 (nor-β-CIT)反应生成18F-β-FP-CIT.测定18F-β-FP-CIT主要质量控制指标.结果 18F-β-FP-CIT平均总放化产率约为8%,总放化合成时间约为90～110 min,放射化学纯度大于99%,其他主要质量控制指标达到放射性药物质量要求.结论合成的18F-β-FP-CIT注射液可用于动物和人体PET研究.     

18F-fallpride:一种多巴胺D2受体PET显像剂

18F-fallypride是一种新的多巴胺D2受体PET显像剂,它与多巴胺D2受体亲和力高(Ki=0.03nmol/L)、亲脂性适宜(logKw=2.43),适于纹状体及纹状体外多巴胺D2/D3受体显像.对其合成、药理作用及体内过程、临床应用等进行了综述.     

在线自动化制备多巴胺转运蛋白显像剂11C-β-CFT

目的建立适于在线自动化制备多巴胺转运蛋白显像剂11C-甲基-N-2β-甲基酯-3β-(4-氟-苯基)托烷(β-CFT)的方法.方法将11C-碘代甲烷转换成11C-三氟甲基磺酰甲烷(Triflate-甲烷),与前体2β-甲基酯-3β-(4-氟-苯基)去甲基托烷(nor-β-CFT)反应,在线转移到反相C-18柱上纯化,最后将11C-β-CFT洗脱于收集瓶.正常大鼠给药后不同时间处死,测定其生物分布.2例帕金森病(PID)患者分别用11C-β-CFT和多巴胺D2受体显像剂11C-雷氯必利(Raclopride)显像.结果在线自动化制备的11C-β-CFT放化纯＞98%,比活度＞2TBq/mmol,校正合成效率为(92.4±3.1)%,从11C-碘代甲烷到11C-β-CFT的合成时间为4 min.放射性在正常大鼠体内主要分布于肝、肾和脑;颅内纹状体摄取放射性最高,与小脑的比值在5、15、30min分别为2.15、4.18和3.15.2例PD患者显像结果表明,11C-β-CFT对PD的诊断比11C-Raclopride灵敏.结论在线自动化制备11C-β-CFI效率高,速度快,放化纯高.初步显像结果表明,其可满足临床需要.     

^18F-FECNT的生物分布特性及小动物PET显像研究

目的探讨多巴胺转运蛋白（DAT）显像剂^18F-N-（2-氟乙基）-2β-甲酯基-3β-（4-氯苯基）去甲基托烷（FECNT）的体内生物分布特性,并进行小动物PET显像研究,以评价其临床应用潜力。方法自制^18F-FECNT注射液,进行正常小鼠脑内分布、DAT阻断实验、正常和单侧帕金森病（PD）模型大鼠小动物PET脑显像。结果正常ICR小鼠在给药后5,15,30,60,120,180min的进脑量分别达2．22,1．20,1．02,0．78,0．71,0．67百分注射剂量率（％ID）。给药后5～60min内,药物在纹状体（ST）部位浓聚,纹状体／小脑（ST／CB）比值在5,15,30,60min时分别为2．56,3．47,2．78,1．63。120min后ST的放射性浓度下降至与其他脑组织相近。脑内DAT经β-CFF阻断的小鼠,其ST未见放射性浓聚。正常大鼠小动物PFT显像图中ST显影清晰（ST／CB=2．18±0．16,n=3）,双侧对称;PD模型大鼠未损毁侧ST放射性浓聚（ST未损毁侧／CB=2．01±0．23,n=3）,而损毁侧ST放射性摄取不明显,与小脑相当（ST损毁侧／CB=1．04±0．05）。结论^18F-FECNT能透过无损的血脑屏障浓聚于ST,对DAT具有高亲和性与特异性,是一种有临床应用潜力的DAT显像剂。     

11C-Raclopride的快速制备及生物学评价

目的 建立快速制备11C-雷氯必利(Raclopride)的方法,并对其进行生物学评价.方法 采用固相萃取法制备11C-Raclopride,即用11C-三氟甲基磺酰基甲烷(CH3-Triflate)与去甲基(Nor)-Raclopride反应得粗产品,用水稀释粗产品,将其转移到Sep-Pak C18反相柱,冲洗反相柱,再用乙醇淋洗得11C-Raclopride.研究正常SD大鼠体内11C-Raclopride分布,并行阻断剂(螺环哌啶酮)阻断后显像.制备食蟹猴帕金森病(PD)模型,行PET显像.结果 11C-Raclopride放化纯＞95%,比活度＞8 GBq/μmol,合成效率为60%,从11CO2到11C-Raclopride的合成时间为16 min.大鼠注射11C-Raclo pride 30 min后纹状体/小脑、纹状体/额叶皮质放射性摄取比值分别为4.67和6.20.Raclopride和螺环哌啶酮明显阻断了纹状体摄取11C-Raclopride,而Nor-Raclopride则不明显.PD模型猴11C-Raclo-pride PET显像示实验侧放射性高于对侧,出现D2受体上调.结论 固相萃取法制备11C-Raclopride速度快,放化纯高.动物显像表明11C-Raclopride能满足临床需求.     

Construction and evaluation of multitracer small-animal PET probabilistic atlases for voxel-based functional mapping of the rat brain.

Automated voxel-based or predefined volume-of-interest (VOI) analysis of rodent small-animal PET data is necessary for optimal use of information because the number of available resolution elements is limited. We have mapped metabolic ((18)F-FDG), dopamine transporter (DAT) (2'-(18)F-fluoroethyl(1R-2-exo-3-exe)-8-methyl-3-(4-chlorophenyl)-8-azabicyclo[3.2.1]-octane-2-carboxylate [(18)F-FECT]), and dopaminergic D(2) receptor ((11)C-raclopride) small-animal PET data onto a 3-dimensional T2-weighted MRI rat brain template oriented according to the rat brain Paxinos atlas. In this way, ligand-specific templates for sensitive analysis and accurate anatomic localization were created. Registration accuracy and test-retest and intersubject variability were investigated. Also, the feasibility of individual rat brain statistical parametric mapping (SPM) was explored for (18)F-FDG and DAT imaging of a 6-hydroxydopamine (6OHDA) model of Parkinson's disease. METHODS: Ten adult Wistar rats were scanned repetitively with multitracer small-animal PET. Registrations and affine spatial normalizations were performed using SPM2. On the MRI template, a VOI map representing the major brain structures was defined according to the stereotactic atlas of Paxinos. (18)F-FDG data were count normalized to the whole-brain uptake, whereas parametric DAT and D(2) binding index images were constructed by reference to the cerebellum. Registration accuracy was determined using random simulated misalignments and vectorial mismatching. RESULTS: Registration accuracy was between 0.24 and 0.86 mm. For (18)F-FDG uptake, intersubject variation ranged from 1.7% to 6.4%. For (11)C-raclopride and (18)F-FECT data, these values were 11.0% and 5.3%, respectively, for the caudate-putamen. Regional test-retest variability of metabolic normalized data ranged from 0.6% to 6.1%, whereas the test-retest variability of the caudate-putamen was 14.0% for (11)C-raclopride and 7.7% for (18)F-FECT. SPM analysis of 3 individual 6OHDA rats showed severe hypometabolism in the ipsilateral sensorimotor cortex (P 相似文献   

Phase 1 clinical study of 123I-IBF, a new radioligand for evaluating dopamine D2 receptor with SPECT (I); biodistribution and dosimetry

A Phase 1 clinical study of 123I-IBF, (S)-5-iodo-7- N-[(1-ethyl-2-pyrrolidinyl)methyl]carboxamido-2,3-dihydrobenzofuran, developed for evaluation of dopamine D2 receptor (D2-R) with SPECT, was performed in 12 healthy male volunteers. No side effects due to 123I-IBF (i.v. 167 MBq) injection were observed. In sequential whole-body images, the radioactivity was distributed mainly in the liver, lungs and brain, and decreased gradually. No significant retention of radioactivity was seen in any organ at 24 hr after injection. The absorbed dose of 123I-IBF, calculated based on the whole-body pharmacokinetics, was equal to or less than those of other brain perfusion imaging agents. No significant problems were observed in terms of the safety, pharmacokinetics or absorbed dose of 123I-IBF.     

Occupancy of dopamine D2 receptors in the mouse brain measured using ultra-high-resolution single-photon emission tomography and [123]IBF

Functional imaging of small animals, such as mice and rats, using ultra-high-resolution positron emission tomography (PET) and single-photon emission tomography (SPET) should be a valuable tool in studies of drug occupancy of cerebral binding sites. In this study we aimed to demonstrate the feasibility of using ultra-high-resolution SPET to measure the occupancy of dopamine D2 receptors by a competing drug, using the dopamine D2 receptor-specific radioligand iodine-123 5-iodo-7-N-[(1-ethyl-2-pyrrolidinyl) methyl] carboxamido-2,3-dihydrobenzofuran ([123I]IBF). Fourteen normal male mice (CD-1) were jugular vein-cannulated and a bolus infusion protocol was used to deliver 360 MBq [123I]IBF into the mouse (bolus-to-infusion ratio 1.8:1). The mice were scanned using an ultra-high-resolution triple-headed SPET system equipped with pinhole collimators. After sustained equilibrium had been achieved, varying doses of raclopride, a potent dopamine D2 receptor antagonist, were injected through the tail vein and the tracer was allowed to regain equilibrium. A simple equilibrium ratio of striatum to cerebellum provided a measure of D2 receptor binding both before and after injection of raclopride. Following raclopride administration, the system returned to equilibrium with lower specific binding in the striatum, while the counts in the cerebellum were unaffected. Receptor occupancy was 5.2% +/- 2.9% (control), 52.1% +/- 11.1% (0.3 mg/kg), 79.3% +/- 4.8% (1.0 mg/kg), and 94.7% +/- 2.2% (3.0 mg/kg), which gave an ED50=0.26 +/- 0.03 mg/kg using a single receptor site saturation model. This study has demonstrated clearly that ultra-high-resolution SPET of small animals is capable of measuring displacement and occupancy of dopamine D2 receptors by competing ligands.     

Multimodality imaging of tumor xenografts and metastases in mice with combined small-animal PET, small-animal CT, and bioluminescence imaging.

Recent developments have established molecular imaging of mouse models with small-animal PET and bioluminescence imaging (BLI) as an important tool in cancer research. One of the disadvantages of these imaging modalities is the lack of anatomic information. We combined small-animal PET and BLI technology with small-animal CT to obtain fusion images with both molecular and anatomic information. METHODS: We used small-animal PET/CT and BLI to detect xenografts of different cell lines and metastases of a melanoma cell line (A375M-3F) that had been transduced with a lentiviral vector containing a trimodality imaging reporter gene encoding a fusion protein with Renilla luciferase, monomeric red fluorescent protein, and a mutant herpes simplex virus type 1 thymidine kinase. RESULTS: Validation studies in mouse xenograft models showed a good coregistration of images from both PET and CT. Melanoma metastases were detected by 18F-FDG PET, 9-[4-(18)F-fluoro-3-(hydroxymethyl)butyl]guanine (18F-FHBG) PET, CT, and BLI and confirmed by ex vivo assays of Renilla luciferase and mutant thymidine kinase expression. 18F-FHBG PET/CT allowed detection and localization of lesions that were not seen on CT because of poor contrast resolution and were not seen on 18F-FDG PET because of higher background uptake relative to 18F-FHBG. CONCLUSION: The combination of 18F-FHBG PET, small-animal CT, and BLI allows a sensitive and improved quantification of tumor burden in mice. This technique is potentially useful for the study of the biologic determinants of metastasis and for the evaluation of novel cancer treatments.     

自动化合成18F-FDDNP及其生物学分布

目的研究高效、简单的自动化合成脑内老年斑沉积显像剂2-(1-{6-[2-18F-乙基](甲基)氨}-2-萘-乙叉)丙二腈(18F-FDDNP)的方法及其小鼠生物学分布.方法采用化学过程控制单元(CPCU)控制整个过程,18F-在乙腈溶液中与前体2-(1-{6-[2-p-甲苯磺酰氧乙基](甲基)氨}-2-萘-乙叉)丙二腈直接反应生成18F-FDDNP,混合物装柱,产品被C-18柱吸附,用水冲洗柱,用少量乙醇淋出,加水稀释.NH小鼠给药后不同时间处死,分别取不同器官称重并测放射性计数.结果18F-FDDNP放化产率为35.7%(不校正),合成时间为20min,无需HPLC分离,放化纯＞95%.注射18F-FDDNP后,放射性主要分布在肝内,脑摄取较高,但清除较慢.结论自动化合成18F-FDDNP速度快,效率高.     

Small-animal PET imaging of human epidermal growth factor receptor type 2 expression with site-specific 18F-labeled protein scaffold molecules.

Human epidermal growth factor receptor type 2 (HER2) is a well-established tumor biomarker that is overexpressed in a wide variety of cancers and that serves as a molecular target for therapeutic intervention. HER2 also serves as a prognostic indicator of patient survival and as a predictive marker of the response to antineoplastic therapy. The development of (18)F-labeled biomolecules for PET imaging of HER2 (HER2 PET) is very important because it may provide a powerful tool for the early detection of HER2-positive tumor recurrence and for the monitoring of HER2-based tumor treatment. METHODS: In this study, anti-HER2 monomeric and dimeric protein scaffold molecules [Z(HER2:477) and (Z(HER2:477))(2), respectively] were radiofluorinated at a reasonable radiochemical yield (13%-18%) by use of site-specific oxime chemistry. The resulting radiofluorinated protein scaffold molecules were then evaluated as potential molecular probes for small-animal HER2 PET by use of a SKOV3 tumor-bearing mouse model. RESULTS: The 4-(18)F-fluorobenzaldehyde conjugated aminooxy-protein scaffolds [(18)F-N-(4-fluorobenzylidene)oxime (FBO)-Z(HER2:477) and (18)F-FBO-(Z(HER2:477))(2)] both displayed specific HER2-binding ability in vitro. Biodistribution and small-animal PET imaging studies further revealed that (18)F-FBO-Z(HER2:477) showed rapid and high SKOV3 tumor accumulation and quick clearance from normal tissues, whereas (18)F-FBO-(Z(HER2:477))(2) showed poor in vivo performance (low tumor uptake and tumor-to-normal tissue ratios). The specificity of (18)F-FBO-Z(HER2:477) for SKOV3 tumors was confirmed by its lower uptake on pretreatment of tumor-bearing mice with the HER2-targeting agents Z(HER2) and trastuzumab. Moreover, small-animal PET imaging studies revealed that (18)F-FBO-Z(HER2:477) produced higher-quality tumor imaging than (18)F-FBO-(Z(HER2:477))(2). (18)F-FBO-Z(HER2:477) could clearly identify HER2-positive tumors with good contrast. CONCLUSION: Overall, these data demonstrate that (18)F-FBO-Z(HER2:477) is a promising PET probe for imaging HER2 expression in living mice. It has a high potential for translation to clinical applications. The radiofluorination method developed can also be used as a general strategy for the site-specific labeling of other proteins with (18)F. The protein scaffold molecules used here are attractive for the further development of PET probes for other molecular targets.     

No-carrier-added N-(3-[18F]fluoropropyl)spiroperidol: biodistribution in mice and tomographic studies in a baboon

Two potential radioligands, no-carrier-added (NCA) N-(2-[18F]fluoroethyl)spiroperidol (3) and N-(3-[18F]fluoropropyl)spiroperidol (4) have been synthesized for PET imaging of dopamine receptors in humans. Compounds 3 and 4 were synthesized by N-alkylation of spiroperidol with NCA 1-bromo-2-[18F]-fluoroethane (2b), 1-[18F]fluoro-3-iodopropane (2c) and 1-bromo-3-[18F]fluoropropane (2d) respectively. The biodistribution of 4 in mice showed that the mouse brain uptake of radioactivity was similar to that of [18F]-N-methylspiroperidol (1.1% of the administered dose), but the activity in bone (femur) increased with time. The kinetic distribution of compound 4 in baboon brain was similar to that of [18F]-N-methylspiroperiodol, and the striatal accumulation of radioactivity was also blocked stereoselectively by butaclamol. The ratio of striatum to cerebellum radioactivities at 3 hr after injection was 5.9. Analysis of the metabolic stability of 4 in mouse brains for 1 hr indicated that, like [18F]-N-methylspiroperidol, it is relatively stable to metabolic transformation in the central nervous system. These results suggest that compound 4 may be a useful radioligand for PET studies of the dopamine receptor in humans.     

PET imaging of colorectal cancer in xenograft-bearing mice by use of an 18F-labeled T84.66 anti-carcinoembryonic antigen diabody.

In this study, we investigated the 18F-labeled anti-carcinoembryonic antigen (CEA) T84.66 diabody, a genetically engineered noncovalent dimer of single-chain variable fragments, for small-animal PET imaging of CEA expression in xenograft-bearing mice. METHODS: 18F labeling of the anti-CEA T84.66 diabody (molecular mass, 55 kDa) was achieved with N-succinimidyl-4-18F-fluorobenzoate (18F-SFB). The biodistribution of the 18F-fluorobenzyl-T84.66 diabody (18F-FB-T84.66 diabody) was evaluated in athymic nude mice bearing subcutaneous LS 174T human colon carcinoma and C6 rat glioma tumors. Serial small-animal PET imaging studies were performed to further evaluate in vivo targeting efficacy and pharmacokinetics. RESULTS: Radiolabeling required 35 +/- 5 (mean +/- SD) min starting from 18F-SFB, and the tracer 18F-FB-T84.66 diabody was synthesized with a specific activity of 1.83 +/- 1.71 TBq/mmol. The decay-corrected radiochemical yield was 1.40% +/- 0.16% (n = 4), and the radiochemical purity was greater than 98%. The radioimmunoreactivity was 57.1% +/- 2.0%. The 18F-FB-T84.66 diabody showed rapid and high tumor uptake and fast clearance from the circulation in the LS 174T xenograft model, as evidenced by both small-animal PET imaging and biodistribution studies. High-contrast small-animal PET images were obtained as early as 1 h after injection of the 18F-FB-T84.66 diabody, and only a background level of activity accumulation was found in CEA-negative C6 tumors. The tracer exhibited predominantly renal clearance, with some activity in the liver and spleen at early time points. CONCLUSION: The 18F-labeled diabody represents a new class of tumor-specific probes for PET that are based on targeting cell surface antigen expression. The 18F-FB-T84.66 diabody can be used for high-contrast small-animal PET imaging of CEA-positive tumor xenografts. It may be translated to the clinic for PET of CEA-positive malignancies.     

Comparison of [18F]FDOPA, [18F]FMT and [18F]FECNT for imaging dopaminergic neurotransmission in mice

INTRODUCTION: The clinically established positron emission tomography (PET) tracers 6-[(18)F]-fluoro-l-DOPA ([(18)F]FDOPA), 6-[(18)F]-fluoro-l-m-tyrosine ([(18)F]FMT) and 2beta-carbomethoxy-3beta-(4-chlorophenyl)-8-(2-[(18)F]-fluoroethyl)-nortropane ([(18)F]FECNT) serve as markers of presynaptic integrity of dopaminergic nerve terminals in humans. This study describes our efforts to adopt the methodology of human Parkinson's disease (PD) PET studies to mice. METHODS: The PET imaging characteristics of [(18)F]FDOPA, [(18)F]FMT and [(18)F]FECNT were analyzed in healthy C57BL/6 mice using the dedicated small-animal PET tomograph quad-HIDAC. Furthermore, [(18)F]FECNT was tested in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD. RESULTS: [(18)F]FDOPA and [(18)F]FMT failed to clearly visualize the mouse striatum, whereas PET experiments using [(18)F]FECNT proved that the employed methodology is capable of delineating the striatum in mice with exquisite resolution. Moreover, [(18)F]FECNT PET imaging of healthy and MPTP-lesioned mice demonstrated that the detection and quantification of striatal degeneration in lesioned mice can be accomplished. CONCLUSIONS: This study shows the feasibility of using [(18)F]FECNT PET to analyze noninvasively the striatal degeneration in the MPTP mouse model of PD. This methodology can be therefore considered as a viable complement to established in vivo microdialysis and postmortem techniques.