Biological Distribution and Metabolic Profiles of Carbon-11 and Fluorine-18 Tracers of VX- and Sarin-Analogs in Sprague–Dawley Rats,Chemical Research in Toxicology

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Biological Distribution and Metabolic Profiles of Carbon-11 and Fluorine-18 Tracers of VX- and Sarin-Analogs in Sprague–Dawley Rats
Chemical Research in Toxicology ( IF 3.7 ) Pub Date : 2020-12-29 , DOI: 10.1021/acs.chemrestox.0c00237
Thomas R Hayes ₁ , Chih-Kai Chao ₂ , Joseph E Blecha ₁ , Tony L Huynh ₁ , Kurt R Zinn ₃ , Charles M Thompson ₂ , John M Gerdes ₂ , Henry F VanBrocklin ₁

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Organophosphorus esters (OPs) were originally developed as pesticides but were repurposed as easily manufactured, inexpensive, and highly toxic chemical warfare agents. Acute OP toxicity is primarily due to inhibition of acetylcholinesterase (AChE), an enzyme in the central and peripheral nervous system. OP inhibition of AChE can be reversed using oxime reactivators but many show poor CNS penetration, indicating a need for new clinically viable reactivators. However, challenges exist on how to best measure restored AChE activity in vivo and assess the reactivating agent efficacy. This work reports the development of molecular imaging tools using radiolabeled OP analog tracers that are less toxic to handle in the laboratory, yet inhibit AChE in a similar fashion to the actual OPs. Carbon-11 and fluorine-18 radiolabeled analog tracers of VX and sarin OP agents were prepared. Following intravenous injection in normal Sprague–Dawley rats (n = 3–4/tracer), the tracers were evaluated and compared using noninvasive microPET/CT imaging, biodistribution assay, and arterial blood analyses. All showed rapid uptake and stable retention in brain, heart, liver, and kidney tissues determined by imaging and biodistribution. Lung uptake of the sarin analog tracers was elevated, 2-fold and 4-fold higher uptake at 5 and 30 min, respectively, compared to that for the VX analog tracers. All tracers rapidly bound to red blood cells (RBC) and blood proteins as measured in the biodistribution and arterial blood samples. Analysis of the plasma soluble activity (nonprotein/cell bound activity) showed only 1–6% parent tracer and 88–95% of the activity in the combined solid fractions (RBC and protein bound) as early as 0.5 min post injection. Multivariate analysis of tracer production yield, molar activity, brain uptake, brain area under the curve over 0–15 min, and the amount of parent tracer in the plasma at 5 min revealed the [¹⁸F]VX analog tracer had the most favorable values for each metric. This tracer was considered the more optimal tracer relative to the other tracers studied and suitable for future in vivo OP exposure and reactivation studies.

中文翻译：

Sprague-Dawley 大鼠中 VX 和沙林类似物的碳 11 和氟 18 示踪剂的生物分布和代谢特征

有机磷酯 (OP) 最初是作为杀虫剂开发的，但后来被重新用作易于制造、廉价且剧毒的化学战剂。急性 OP 毒性主要是由于对乙酰胆碱酯酶 (AChE) 的抑制，该酶是中枢和外周神经系统中的一种酶。使用肟再激活剂可以逆转 AChE 的 OP 抑制，但许多显示出较差的 CNS 渗透性，表明需要新的临床上可行的再激活剂。然而，在如何最好地测量体内恢复的 AChE 活性和评估再活化剂功效方面存在挑战。这项工作报告了使用放射性标记的 OP 模拟示踪剂开发分子成像工具，这些示踪剂在实验室中处理的毒性较小，但以与实际 OP 类似的方式抑制 AChE。制备了 VX 和沙林 OP 剂的碳 11 和氟 18 放射性标记模拟示踪剂。在正常 Sprague-Dawley 大鼠静脉内注射后（n= 3-4/示踪剂），使用无创 microPET/CT 成像、生物分布测定和动脉血分析对示踪剂进行评估和比较。通过成像和生物分布确定，所有这些都显示在大脑、心脏、肝脏和肾脏组织中的快速摄取和稳定保留。与 VX 模拟示踪剂相比，沙林模拟示踪剂的肺摄取量在 5 分钟和 30 分钟时分别升高了 2 倍和 4 倍。在生物分布和动脉血样本中测得的所有示踪剂都迅速与红细胞 (RBC) 和血液蛋白结合。早在注射后 0.5 分钟，血浆可溶性活性（非蛋白质/细胞结合活性）分析显示只有 1-6% 的母体示踪剂和 88-95% 的活性在组合的固体组分（RBC 和蛋白质结合）中。示踪剂产量、摩尔活性的多变量分析，¹⁸ F]VX 模拟示踪剂对每个指标都有最有利的值。相对于所研究的其他示踪剂，该示踪剂被认为是更佳的示踪剂，适用于未来的体内 OP 暴露和再激活研究。

更新日期：2021-01-18

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