Department of Radiology and Imaging Sciences, Indiana University School of Medicine, 1345 West 16th Street, L3-202, Indianapolis, IN 46202-2111, USA.
Steroids. 2011 Nov;76(12):1331-40. doi: 10.1016/j.steroids.2011.06.012. Epub 2011 Jul 3.
The translocator protein 18 kDa (TSPO) is an attractive target for molecular imaging of neuroinflammation and tumor progression. [(18)F]PBR06, a fluorine-18 labeled form of PBR06, is a promising PET TSPO radioligand originally developed at NIMH. [(11)C]PBR06, a carbon-11 labeled form of PBR06, was designed and synthesized for the first time. The standard PBR06 was synthesized from 2,5-dimethoxybenzaldehyde in three steps with 71% overall chemical yield. The radiolabeling precursor desmethyl-PBR06 was synthesized from 2-hydroxy-5-methoxybenzaldehyde in five steps with 12% overall chemical yield. The target tracer [(11)C]PBR06 was prepared by O-[(11)C]methylation of desmethyl-PBR06 with [(11)C]CH(3)OTf in CH(3)CN at 80°C under basic condition and isolated by HPLC combined with SPE purification with 40-60% decay corrected radiochemical yield and 222-740 GBq/μmol specific activity at EOB. On the similar grounds, [(18)F]PBR06 was also designed and synthesized. The previously described Br-PBR06 precursor was synthesized from 2,5-dimethoxybenzaldehyde in two steps with 78% overall chemical yield. A new radiolabeling precursor tosyloxy-PBR06, previously undescribed tosylate congener of PBR06, was designed and synthesized from ethyl 2-hydroxyacetate, 4-methylbenzene-1-sulfonyl chloride, and N-(2,5-dimethoxybenzyl)-2-phenoxyaniline in four steps with 50% overall chemical yield. [(18)F]PBR06 was prepared by the nucleophilic substitution of either new tosyloxy-PBR06 precursor or known Br-PBR06 precursor in DMSO at 140°C with K[(18)F]F/Kryptofix 2.2.2 for 15 min and HPLC combined with SPE purification in 20-60% decay corrected radiochemical yield, >99% radiochemical purity, 87-95% chemical purity, and 37-222 GBq/μmol specific activity at EOB. Radiosynthesis of [(18)F]PBR06 using new tosylated precursor gave similar radiochemical purity, and higher specific activity, radiochemical yield and chemical purity in comparison with radiosynthesis using bromine precursor.
转位蛋白 18 kDa（TSPO）是神经炎症和肿瘤进展的分子成像的一个有吸引力的靶标。[(18)F]PBR06 是 PBR06 的氟-18 标记形式，是最初由 NIMH 开发的有前途的 PET TSPO 放射性配体。[(11)C]PBR06 是 PBR06 的碳-11 标记形式，是首次设计和合成的。标准 PBR06 是由 2,5-二甲氧基苯甲醛经三步反应以 71%的总化学收率合成。放射性标记前体去甲-PBR06 是由 2-羟基-5-甲氧基苯甲醛经五步反应以 12%的总化学收率合成。目标示踪剂[(11)C]PBR06 是通过在碱性条件下，用[(11)C]CH(3)OTf 在 CH(3)CN 中对去甲-PBR06 进行 O-[(11)C]甲基化反应在 80°C 下制备的，并通过 HPLC 结合 SPE 纯化，在 EOB 时获得 40-60%的放射性化学收率和 222-740GBq/μmol 的比活度。基于同样的原因，还设计并合成了[(18)F]PBR06。先前描述的 Br-PBR06 前体是由 2,5-二甲氧基苯甲醛经两步反应以 78%的总化学收率合成的。一种新的放射性标记前体 tosyl-PBR06，以前未描述的 PBR06 的对甲苯磺酸盐同系物，是由乙基 2-羟基乙酸、4-甲基苯磺酰氯和 N-(2,5-二甲氧基苄基)-2-苯氧基苯胺经四步反应以 50%的总化学收率合成的。[(18)F]PBR06 是通过在 140°C 下用 K[(18)F]F/Kryptofix 2.2.2 在 DMSO 中对新的 tosyl-PBR06 前体或已知的 Br-PBR06 前体进行亲核取代反应制备的，15 分钟后通过 HPLC 结合 SPE 纯化，放射性化学收率为 20-60%，放射性纯度>99%，化学纯度 87-95%，EOB 时比活度为 37-222GBq/μmol。与使用溴前体的放射性合成相比，使用新的 tosylated 前体进行 [(18)F]PBR06 的放射性合成具有相似的放射性纯度，以及更高的比活度、放射性化学收率和化学纯度。
