Institute of Neuroscience and Psychology, College of Medical, Veterinary and Life Sciences, University of Glasgow, G12 8QQ Glasgow, UK.
Nucl Med Biol. 2011 May;38(4):493-500. doi: 10.1016/j.nucmedbio.2010.11.011. Epub 2011 Feb 4.
(123)I-NKJ64, a reboxetine analogue, is currently under development as a potential novel single photon emission computed tomography radiotracer for imaging the noradrenaline transporter in brain. This study describes the development of the radiosynthesis of (123)I-NKJ64, highlighting the advantages and disadvantages, pitfalls and solutions encountered while developing the final radiolabelling methodology.
The synthesis of (123)I-NKJ64 was evaluated using an electrophilic iododestannylation method, where a Boc-protected trimethylstannyl precursor was radioiodinated using peracetic acid as an oxidant and deprotection was investigated using either trifluoroacetic acid (TFA) or 2 M hydrochloric acid (HCl).
Radioiodination of the Boc-protected trimethylstannyl precursor was achieved with an incorporation yield of 92±6%. Deprotection with 2 M HCl produced (123)I-NKJ64 with the highest radiochemical yield of 98.05±1.63% compared with 83.95±13.24% with TFA. However, the specific activity of the obtained (123)I-NKJ64 was lower when measured after using 2 M HCl (0.15±0.23 Ci/μmol) as the deprotecting agent in comparison to TFA (1.76±0.60 Ci/μmol). Further investigation of the 2 M HCl methodology found a by-product, identified as the deprotected proto-destannylated precursor, which co-eluted with (123)I-NKJ64 during the high-performance liquid chromatography (HPLC) purification.
The radiosynthesis of (123)I-NKJ64 was achieved with good isolated radiochemical yield of 68% and a high specific activity of 1.8 Ci/μmol. TFA was found to be the most suitable deprotecting agent, since 2 M HCl generated a by-product that could not be fully separated from (123)I-NKJ64 using the HPLC methodology investigated. This study highlights the importance of HPLC purification and accurate measurement of specific activity while developing new radiosynthesis methodologies.
（123）I-NKJ64 是一种瑞波西汀类似物，目前正在开发中，作为一种潜在的新型单光子发射计算机断层扫描放射性示踪剂，用于成像大脑中的去甲肾上腺素转运体。本研究描述了（123）I-NKJ64 的放射合成开发，强调了在开发最终放射性标记方法学过程中遇到的优点、缺点、陷阱和解决方案。
使用亲电碘代脱锡法评估（123）I-NKJ64 的合成，其中使用过乙酸作为氧化剂对 Boc 保护的三甲基锡前体进行放射性碘代，并用三氟乙酸（TFA）或 2 M 盐酸（HCl）研究脱保护。
Boc 保护的三甲基锡前体的碘代反应产率为 92±6%。与 TFA 相比，用 2 M HCl 进行脱保护得到（123）I-NKJ64 的放射化学产率最高，为 98.05±1.63%。然而，当使用 2 M HCl（0.15±0.23 Ci/μmol）作为脱保护剂时，获得的（123）I-NKJ64 的比活度较低，而 TFA 的比活度为 1.76±0.60 Ci/μmol。对 2 M HCl 方法的进一步研究发现了一种副产物，鉴定为脱保护的原脱锡前体，其在高效液相色谱（HPLC）纯化过程中与（123）I-NKJ64 共洗脱。
（123）I-NKJ64 的放射合成产率为 68%，比活度为 1.8 Ci/μmol，产率较高。发现 TFA 是最合适的脱保护剂，因为 2 M HCl 生成的副产物不能用研究的 HPLC 方法从（123）I-NKJ64 中完全分离。本研究强调了在开发新的放射合成方法学过程中 HPLC 纯化和准确测量比活度的重要性。
