多巴胺转运蛋白示踪药物~（18）F-FECNT的制备与临床前药理研究
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摘要
中枢神经系统的多巴胺转运蛋白(DAT)与多种神经精神类疾病有关,以DAT为靶点的诊断与治疗药物的设计颇受重视。DAT示踪药物对帕金森病(PD)的分子影像研究具有临床价值。本论文研制了用于DAT示踪的放射性药物氟[18F]-N-(2-氟乙基)-2β-甲酯基-3β-(4-氯苯基)去甲基托烷(18F-FECNT),并评价其作为PD显像药物的成药性。论文主要结果如下:
设计并制备了DAT示踪药物18F-FECNT标记前体化合物N-(2-甲磺酰乙基)-2β-甲酯基-3β-(4-氯苯基)去甲基托烷(MsOECNT)。以可卡因为起始原料,经酸性水解、分子内脱水、选择性1,4-加成反应等过程,制备了关键中间体2β-甲酯基-3β-(4-氯苯基)托烷(CClT),并通过衍生化法完成其立体结构测定。将CClT脱去N-位甲基,再进行羟乙基化制备了新化合化物N-(2-羟乙基)-2β-甲酯基-3β-(4-氯苯基)去甲基托烷(HOECClT),最后将HOECClT酯化获得了新的18F-FECNT标记前体化合物N-(2-甲磺酰乙基)-2β-甲酯基-3β-(4-氯苯基)去甲基托烷(MsOECNT)。此外,通过nor-CClT的氟乙基化反应制备了18F-FECNT的对照品FECNT。合成过程中对关键的合成步骤进行了优化,通过红外光谱、质谱、核磁共振谱、元素分析等技术确证了各步中间体及终产物的化学结构。建立了自动化的一步法、高产率的18F-FECNT放射合成方案。在催化剂K222作用下,4 mg的MsOECNT与K18F于1 ml无水乙腈中在90℃下反应20 min,直接生成了18F-FECNT,氟[18F]化产率为48%。通过高效液相色谱(HPLC)分享纯化,获得了高纯度的18F-FECNT注射液,其放射化学纯度为98.4%,最终放射化学产率为33%,总合成时间为80-100 min。标记反应过程实现了计算机自动化控制。
完成了18F-FECNT的作为一种DAT示踪药物的临床前主要药效与药理学研究,证实了18F-FECNT的临床应用潜力。18F-FECNT在正辛醇-水相中的分配系数为34.1(pH7.0),56.4(pH7.4)。生物分布结果表明,18F-FECNT能穿透无损的血脑屏障而进入脑组织并有较好的滞留特性(给药后5, 15, 30, 60, 120, 180 min的脑摄取值分别为2.22, 1.20, 1.02, 0.78, 0.71, 0.67 %ID),脑内的18F-FECNT在靶部位(纹状体)有较好的摄取与滞留,纹状体(ST)与小脑(CB)、海马、顶叶、颞叶的放射性摄取比值分别高达3.47, 3.55, 4.40, 3.47(给药后15min),与额叶、枕叶的比值分别为3.17, 3.35(30min)。纹状体对18F-FECNT的摄取能被DAT阻断剂特异性地阻断。放射自显影结果显示正常大鼠纹状体显影清晰,双侧对称(ST左/CB = 5.42,ST右/CB = 5.52),单侧纹状体经6-OHDA损毁的PD模型大鼠其未损毁侧放射性浓聚(ST未损毁侧/CB = 2.57),而损毁侧放射性摄取不明显(ST损毁侧/CB = 1.05)。上述系列研究表明DAT对18F-FECNT对结合具有高特异性与高选择性。体内的18F-FECNT主要通过肝脏和肾脏代谢。异常毒性结果小鼠可耐受剂量是人体注射用量的625倍以上,表明18F-FECNT对人安全。
完成了正常及PD模型大鼠的小动物PET显像研究,在活体内证实18F-FECNT用于PD显像的临床应用价值。正常大鼠纹状体显影清晰,双侧对称,脑内未见其它放射性浓聚区(ST/CB=2.18±0.16,ST左/ST右=1.00±0.05,n=3,给药后5-125 min)。动态分析结果双侧纹状体的放射性浓度在120 min内均高于小脑,ST/CB值最高达3.44(给药后25 min)。单侧纹状体经6-OHDA损毁的PD模型大鼠其未损毁侧显影清晰(ST未损毁侧/CB=2.01±0.23,n=3,5-125 min),而损毁侧不显影,其放射性浓度与小脑接近(ST损毁侧/CB=1.04±0.05,n=3)。单侧PD模型大鼠的动态分析结果未损毁侧纹状体在5-125 min内放射性浓度高于小脑,但相对摄取值低于正常大鼠,而损毁侧纹状体的放射性浓度始终与小脑接近,研究结果在活体动物内证实了18F-FECNT用于临床PD的影像学研究的可行性。
研究结果表明:18F-FECNT是良好的DAT示踪药物,对PD的分子影像学研究具有临床应用潜力。
Dopamine tranporter (DAT) in the central nervous sysytem is related to many neurological and psychiatric disorders. Great attention has been paid to theraputic and diagnostic drug design targeted to DAT. Molecular imaging with DAT tracer provides valuable information for Parkinson’s diease. In this study, a DAT imaging agent, [18F]-2β-carbomethoxy-3β-(4-chlorophenyl)-8-(2-fluoroethyl)nortropane (18F-FECNT), was developed and evaluated for molecular imaging for PD. The synthesis and characterization of a new precursor, a automated high-radiochemical yield radiosyntheisis of 18F-FECNT, a series of preclinical studies including microPET imaging were reported to meet the requirement of the clinical application.
A new mesylate precursor of 18F-FECNT, 2β-Carbomethoxy-3β-(4- chlorophenyl)-8-(2- mesyloxyethyl)nortropane (MsOECNT), was designed and synthesized. The synthesis began with hydrolysis of cocaine in hydrochloride solution and gave ecognine. Intramolecular dehydration of ecognine in POCl3 followed by treatment with methanol produced anhydraecognine methyl ester. The key intermediate, 2β-carbomethoxy-3β-(4- chlorophenyl)tropane (CClT), was obtained by selective 1,4-addition reaction of anhydraecognine methyl ester with p-chlorophenyl magnesium bromide followed by purification. The stereo structure of CClT was confirmed by single crystal x-diffraction. Demethylation of CClT afforded 2β-carbomethoxy-3β-(4-chlorophenyl)nortropane (nor-CClT). The new intermediate, 2β-carbomethoxy-3β-(4-chlorophenyl)-8-(2- hydroxyethyl)-nortropane (HOECNT), was prepared by hydroxyethylation of nor-CClT followed by purification by chromatography. Finally, MsOECNT was synthesized by mesylation of HOECNT with methanesulfonic anhydride. In addition, 2β-carbomethoxy-3β- (4-chlorophenyl)-8-(2-fluoroethyl)nortropane (FECNT) was synthesized by fluoroethylation of nor-CClT as the reference substance of 18F-FECNT. Structures of MsOECNT, FECNT and all intermediates were confirmed by IR, MS, 1HNMR and elemental analysis.
A one-step automated high-radiochemical-yield synthesis of 18F-FECNT from the mesylate precursor was established. [18F]fluorination was performed by heating 4 mg mesylate precursor and K18F in 1.0 ml anhydrous acetonitrile at 90℃for 20 min. The crude 18F-FECNT was obtained with a radio labeling yield of 48%. After purification by preparative high performance liquid chromatography (HPLC), the final 18F-FECNT product was obtained with a radiochemical purity of 98.4% and a decay corrected radiochemical yield of 33±9% (and the uncorrected radiochemical yield was 19±5%, n=5). The procedure of the [18F]fluorination was automated and the duration of the total radiosynthesis was 80-100 min.
A series of preclinical studies of 18F-FECNT was finished to testify its clinical potential. The octanol-water partition coefficients of 18F-FECNT were 34.1 and 56.4 at pH 7.0 and pH7.4 respectively. Biodistribution in mice showed that 18F-FECNT penetrated the blood-brain barrier (BBB) rapidly and had favorable retention in the brain. (2.22, 1.20, 1.02, 0.78, 0.71, 0.67 %ID at 5, 15, 30, 60, 120, 180min respectively post i.v. injection). In the brain, 18F-FECNT concentrated in the target area, the striatum (ST). The ratios of striatum to cerebellum (CB), hippocampus, parietal cortex and temporal cortex reached as high as 3.47, 3.55, 4.40 and 3.47, respectively, at 15 min post injection, while the ratios of striatum to frontal cortex, occipital cortex were 3.17, 3.35, respectively, at 30 min post injection. The selective striatum uptake of 18F-FECNT decreased dramatically to the background when the DAT was blocked withβ-CFT. The autoradiography showed that 18F-FECNT was concentrated in the striatum highly and symmetrically in normal rat brains (STleft/CB = 5.42,STright/CB = 5.52), while in left-sided lesioned PD rat brains, the striatal uptake of 18F-FECNT bilaterally decreased and no significant uptake was visible in the 6-OHDA lesioned-sided striatal areas (STunlesioned/CB = 2.57, STlesioned/CB = 1.05). These results indicated that 18F-FECNT had high affinity and selectivity to DAT. The major radioligand was metabolized by the hepatic system. Toxicity trial displayed that the acceptable dose per kilogram to mice was 625 times greater than that to human, which implied safty of 18F-FECNT for human.
The microPET imaging of the normal and PD rats was carried out to verify the clinical potential of 18F-FECNT in living animals. The normal rat’s striatum exhibited the highest uptake of the radio ligand and prolonged retention of the radioligand in the brain (ST/CB=2.18±0.16,STleft/STright=1.00±0.05). Radiouptake in the striatum remained highest in 5-125 min post injection and the ratio of ST to CB peaked to 3.44 at 25 min. As for the 6-OHDA lesioned PD rats, the highest uptake was observed in the unlesioned side striatum ( STunlesioned/CB = 2.01±0.23, 5-125 min), whereas no significant uptake was visible in lesioned side (STlesioned /CB = 1.04±0.05). Time-activity curves demonstrate that uptake of the unlesioned side striatum remained higher than CB but lower than the normal rat’s striatum in 5-125 min post injection, whereas the lesioned side keep similar to CB.
设计并制备了DAT示踪药物18F-FECNT标记前体化合物N-(2-甲磺酰乙基)-2β-甲酯基-3β-(4-氯苯基)去甲基托烷(MsOECNT)。以可卡因为起始原料,经酸性水解、分子内脱水、选择性1,4-加成反应等过程,制备了关键中间体2β-甲酯基-3β-(4-氯苯基)托烷(CClT),并通过衍生化法完成其立体结构测定。将CClT脱去N-位甲基,再进行羟乙基化制备了新化合化物N-(2-羟乙基)-2β-甲酯基-3β-(4-氯苯基)去甲基托烷(HOECClT),最后将HOECClT酯化获得了新的18F-FECNT标记前体化合物N-(2-甲磺酰乙基)-2β-甲酯基-3β-(4-氯苯基)去甲基托烷(MsOECNT)。此外,通过nor-CClT的氟乙基化反应制备了18F-FECNT的对照品FECNT。合成过程中对关键的合成步骤进行了优化,通过红外光谱、质谱、核磁共振谱、元素分析等技术确证了各步中间体及终产物的化学结构。建立了自动化的一步法、高产率的18F-FECNT放射合成方案。在催化剂K222作用下,4 mg的MsOECNT与K18F于1 ml无水乙腈中在90℃下反应20 min,直接生成了18F-FECNT,氟[18F]化产率为48%。通过高效液相色谱(HPLC)分享纯化,获得了高纯度的18F-FECNT注射液,其放射化学纯度为98.4%,最终放射化学产率为33%,总合成时间为80-100 min。标记反应过程实现了计算机自动化控制。
完成了18F-FECNT的作为一种DAT示踪药物的临床前主要药效与药理学研究,证实了18F-FECNT的临床应用潜力。18F-FECNT在正辛醇-水相中的分配系数为34.1(pH7.0),56.4(pH7.4)。生物分布结果表明,18F-FECNT能穿透无损的血脑屏障而进入脑组织并有较好的滞留特性(给药后5, 15, 30, 60, 120, 180 min的脑摄取值分别为2.22, 1.20, 1.02, 0.78, 0.71, 0.67 %ID),脑内的18F-FECNT在靶部位(纹状体)有较好的摄取与滞留,纹状体(ST)与小脑(CB)、海马、顶叶、颞叶的放射性摄取比值分别高达3.47, 3.55, 4.40, 3.47(给药后15min),与额叶、枕叶的比值分别为3.17, 3.35(30min)。纹状体对18F-FECNT的摄取能被DAT阻断剂特异性地阻断。放射自显影结果显示正常大鼠纹状体显影清晰,双侧对称(ST左/CB = 5.42,ST右/CB = 5.52),单侧纹状体经6-OHDA损毁的PD模型大鼠其未损毁侧放射性浓聚(ST未损毁侧/CB = 2.57),而损毁侧放射性摄取不明显(ST损毁侧/CB = 1.05)。上述系列研究表明DAT对18F-FECNT对结合具有高特异性与高选择性。体内的18F-FECNT主要通过肝脏和肾脏代谢。异常毒性结果小鼠可耐受剂量是人体注射用量的625倍以上,表明18F-FECNT对人安全。
完成了正常及PD模型大鼠的小动物PET显像研究,在活体内证实18F-FECNT用于PD显像的临床应用价值。正常大鼠纹状体显影清晰,双侧对称,脑内未见其它放射性浓聚区(ST/CB=2.18±0.16,ST左/ST右=1.00±0.05,n=3,给药后5-125 min)。动态分析结果双侧纹状体的放射性浓度在120 min内均高于小脑,ST/CB值最高达3.44(给药后25 min)。单侧纹状体经6-OHDA损毁的PD模型大鼠其未损毁侧显影清晰(ST未损毁侧/CB=2.01±0.23,n=3,5-125 min),而损毁侧不显影,其放射性浓度与小脑接近(ST损毁侧/CB=1.04±0.05,n=3)。单侧PD模型大鼠的动态分析结果未损毁侧纹状体在5-125 min内放射性浓度高于小脑,但相对摄取值低于正常大鼠,而损毁侧纹状体的放射性浓度始终与小脑接近,研究结果在活体动物内证实了18F-FECNT用于临床PD的影像学研究的可行性。
研究结果表明:18F-FECNT是良好的DAT示踪药物,对PD的分子影像学研究具有临床应用潜力。
Dopamine tranporter (DAT) in the central nervous sysytem is related to many neurological and psychiatric disorders. Great attention has been paid to theraputic and diagnostic drug design targeted to DAT. Molecular imaging with DAT tracer provides valuable information for Parkinson’s diease. In this study, a DAT imaging agent, [18F]-2β-carbomethoxy-3β-(4-chlorophenyl)-8-(2-fluoroethyl)nortropane (18F-FECNT), was developed and evaluated for molecular imaging for PD. The synthesis and characterization of a new precursor, a automated high-radiochemical yield radiosyntheisis of 18F-FECNT, a series of preclinical studies including microPET imaging were reported to meet the requirement of the clinical application.
A new mesylate precursor of 18F-FECNT, 2β-Carbomethoxy-3β-(4- chlorophenyl)-8-(2- mesyloxyethyl)nortropane (MsOECNT), was designed and synthesized. The synthesis began with hydrolysis of cocaine in hydrochloride solution and gave ecognine. Intramolecular dehydration of ecognine in POCl3 followed by treatment with methanol produced anhydraecognine methyl ester. The key intermediate, 2β-carbomethoxy-3β-(4- chlorophenyl)tropane (CClT), was obtained by selective 1,4-addition reaction of anhydraecognine methyl ester with p-chlorophenyl magnesium bromide followed by purification. The stereo structure of CClT was confirmed by single crystal x-diffraction. Demethylation of CClT afforded 2β-carbomethoxy-3β-(4-chlorophenyl)nortropane (nor-CClT). The new intermediate, 2β-carbomethoxy-3β-(4-chlorophenyl)-8-(2- hydroxyethyl)-nortropane (HOECNT), was prepared by hydroxyethylation of nor-CClT followed by purification by chromatography. Finally, MsOECNT was synthesized by mesylation of HOECNT with methanesulfonic anhydride. In addition, 2β-carbomethoxy-3β- (4-chlorophenyl)-8-(2-fluoroethyl)nortropane (FECNT) was synthesized by fluoroethylation of nor-CClT as the reference substance of 18F-FECNT. Structures of MsOECNT, FECNT and all intermediates were confirmed by IR, MS, 1HNMR and elemental analysis.
A one-step automated high-radiochemical-yield synthesis of 18F-FECNT from the mesylate precursor was established. [18F]fluorination was performed by heating 4 mg mesylate precursor and K18F in 1.0 ml anhydrous acetonitrile at 90℃for 20 min. The crude 18F-FECNT was obtained with a radio labeling yield of 48%. After purification by preparative high performance liquid chromatography (HPLC), the final 18F-FECNT product was obtained with a radiochemical purity of 98.4% and a decay corrected radiochemical yield of 33±9% (and the uncorrected radiochemical yield was 19±5%, n=5). The procedure of the [18F]fluorination was automated and the duration of the total radiosynthesis was 80-100 min.
A series of preclinical studies of 18F-FECNT was finished to testify its clinical potential. The octanol-water partition coefficients of 18F-FECNT were 34.1 and 56.4 at pH 7.0 and pH7.4 respectively. Biodistribution in mice showed that 18F-FECNT penetrated the blood-brain barrier (BBB) rapidly and had favorable retention in the brain. (2.22, 1.20, 1.02, 0.78, 0.71, 0.67 %ID at 5, 15, 30, 60, 120, 180min respectively post i.v. injection). In the brain, 18F-FECNT concentrated in the target area, the striatum (ST). The ratios of striatum to cerebellum (CB), hippocampus, parietal cortex and temporal cortex reached as high as 3.47, 3.55, 4.40 and 3.47, respectively, at 15 min post injection, while the ratios of striatum to frontal cortex, occipital cortex were 3.17, 3.35, respectively, at 30 min post injection. The selective striatum uptake of 18F-FECNT decreased dramatically to the background when the DAT was blocked withβ-CFT. The autoradiography showed that 18F-FECNT was concentrated in the striatum highly and symmetrically in normal rat brains (STleft/CB = 5.42,STright/CB = 5.52), while in left-sided lesioned PD rat brains, the striatal uptake of 18F-FECNT bilaterally decreased and no significant uptake was visible in the 6-OHDA lesioned-sided striatal areas (STunlesioned/CB = 2.57, STlesioned/CB = 1.05). These results indicated that 18F-FECNT had high affinity and selectivity to DAT. The major radioligand was metabolized by the hepatic system. Toxicity trial displayed that the acceptable dose per kilogram to mice was 625 times greater than that to human, which implied safty of 18F-FECNT for human.
The microPET imaging of the normal and PD rats was carried out to verify the clinical potential of 18F-FECNT in living animals. The normal rat’s striatum exhibited the highest uptake of the radio ligand and prolonged retention of the radioligand in the brain (ST/CB=2.18±0.16,STleft/STright=1.00±0.05). Radiouptake in the striatum remained highest in 5-125 min post injection and the ratio of ST to CB peaked to 3.44 at 25 min. As for the 6-OHDA lesioned PD rats, the highest uptake was observed in the unlesioned side striatum ( STunlesioned/CB = 2.01±0.23, 5-125 min), whereas no significant uptake was visible in lesioned side (STlesioned /CB = 1.04±0.05). Time-activity curves demonstrate that uptake of the unlesioned side striatum remained higher than CB but lower than the normal rat’s striatum in 5-125 min post injection, whereas the lesioned side keep similar to CB.
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