Production of multimeric prostate-specific membrane antigen small-molecule radiotracers using a solid-phase 99mTc preloading strategy
Production of multimeric prostate-specific membrane antigen small-molecule radiotracers using a solid-phase 99mTc preloading strategy
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DOI：
10.2967/jnumed.107.040303
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发表时间：
2007-08-01
影响因子：
9.3
通讯作者：
Frangioni, John V.
中科院分区：
文献类型：
--
作者：
Misra, Preeti;Humblet, Valerie;Frangioni, John V.
前列腺特异性膜抗原（PSMA）的小分子配体具有改善前列腺癌影像学的潜力。然而，高电荷配体很难用Tc-99m标记和纯化。在这项研究中，我们提出了一种金刚烷三聚体小分子，它与PSMA具有纳摩尔结合，并且具有12个负电荷。方法：为了将该分子转化为临床可行的SPECT诊断，我们开发了一种简单的，基于墨盒的固相预标记策略，在25分钟内，将易于获得且价格低廉的tc -99m-高技术酸盐转化为化学纯复合物，在纯有机溶剂中具有反应性n -羟基琥珀酰亚胺（NHS）酯。这种稳定的中间体可以用Tc-99m一步标记任何含胺的小分子或微粒，具有高比活性，不需要高效液相色谱（HPLC）。结果：tc -99m-高技术酸酯固相转化为Tc-99m-MAS(3)-NHS （MAS3为s -乙酰巯基乙酰三丝氨酸）可在25 min内完成，放射化学纯度为bb0 99%，无配体存在。该中间体经一步共轭得到金刚烷-三聚GPI（2[（3-氨基-3-羧基丙基）（羟基）（膦基）甲基]戊烷-1,5-二酸），收率高达95%，无需HPLC纯化。最后的分子特异性结合在表面表达PSMA的活的人类肿瘤细胞上。对GPI单体、GPI三聚体及其tc -99m衍生物进行了定量比较。结论：我们的研究描述了一种简单的基于盒的tc -99m-高技术酸盐转化为有用的，预加载的NHS酯中间体，仅需25分钟即可制备并获得bb0 99%的放射化学纯度。利用这种化学方法，我们生产了一种高特异性活性、tc -99m标记、psma靶向的小分子，并展示了活的人类前列腺癌细胞的伽马射线放射显像。
Small-molecule ligands specific for prostate-specific membrane antigen (PSMA) have the potential to improve prostate cancer imaging. However, highly charged ligands are difficult to label with Tc-99m and to purify. In this study, we present an adamantane-trimerized small molecule that has nanomolar binding to PSMA and also has 12 negative charges. Methods: To convert this molecule into a clinically viable SPECT diagnostic, we have developed a simple, cartridge-based, solid-phase prelabeling strategy that, within 25 min, converts readily available and inexpensive Tc-99m-pertechnetate into a chemically pure complex, with a reactive N-hydroxysuccinimide (NHS) ester, in neat organic solvent. This stable intermediate can label any amine-containing small molecule or pepticle with Tc-99m in 1 step, with high specific activity and without the need for high-performance liquid chromatography (HPLC). Results: Solid-phase conversion of Tc-99m-pertechnetate to Tc-99m-MAS(3)-NHS (MAS3 is S-acetylmercaptoacetyltriserine) could be completed in 25 min, with >99% radiochemical purity and with no coligands present. This intermediate was then conjugated to adamantane-trimerized GPI (2[(3-amino-3-carboxypropyl)(hydroxy)(phosphinyl)methyl]pentane-1,5-dioic acid) in 1 step with >95% yield and no need for HPLC purification. The final molecule bound specifically to living human tumor cells expressing PSMA on their surface. Quantitative comparison was made among GPI monomer, GPI trimer, and their Tc-99m-derivatives. Conclusion: Our study describes a simple cartridge-based conversion of Tc-99m-pertechnetate to a useful, preloaded NHS ester intermediate that takes only 25 min to prepare and results in >99% radiochemical purity. Using this chemistry, we produced a highspecific-activity, Tc-99m-labeled, PSMA-targeted small molecule and demonstrate gamma-ray radioscintigraphic imaging of living human prostate cancer cells.