Automated synthesis of [(18)F]DCFPyL via direct radiofluorination and validation in preclinical prostate cancer models.
Automated synthesis of [(18)F]DCFPyL via direct radiofluorination and validation in preclinical prostate cancer models.
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DOI：
10.1186/s13550-016-0195-6
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发表时间：
2016-12
期刊：
影响因子：
3.2
通讯作者：
Wuest F
中科院分区：
文献类型：
--
作者：
Bouvet V;Wuest M;Jans HS;Janzen N;Genady AR;Valliant JF;Benard F;Wuest F
前列腺特异性膜抗原（PSMA）在前列腺癌中经常过度表达和上调。迄今为止，各种用于PSMA PET成像的18F和68ga标记的尿素基放射性示踪剂已经开发并进入临床试验。在这里，我们描述了一种通过直接放射氟化自动合成[18F]DCFPyL的方法，并在前列腺癌临床前模型中进行了验证。[18F]采用单反应器TRACERlab FXFN自动合成装置，通过直接亲核异芳取代反应合成了DCFPyL。[18F]DCFPyL的放射药理学评价包括内化实验、LNCaP （PSMA+）和PC3 （PSMA−）荷瘤BALB/c裸鼠的动态PET成像、生物分布研究和代谢谱分析。此外，采用可逆双组织室室模型分析，定量分析[18F]DCFPyL在LNCaP和PC3肿瘤模型中的药代动力学。自动放射性合成可在55分钟内提供放射性示踪剂[18F]DCFPyL，经衰减校正的放射化学产率为23±5% (n = 10)，包括HPLC纯化。动态PET分析显示LNCaP肿瘤的放射性吸收迅速且高（SUV5min 0.95），随时间增加（SUV60min 1.1）。LNCaP肿瘤的放射性摄取在非放射性DCFPyL的存在下被阻断（SUV60min 0.22）。作为参考组织的肌肉随着时间的推移显示出快速和持续的清除（SUV60min 0.06）。血液中放射性的快速清除导致肿瘤与血液的比值在10分钟后为1.0，在60分钟后为8.3。随着时间的推移，PC3肿瘤也显示出持续的放射性清除（SUV60min 0.11）。PET数据的动力学分析显示，当K1 = 0.12, k2 = 0.18, k3 = 0.08, k4 = 0.004 min−1时，两组织间室模型最适合，证实了[18F]DCFPyL在PSMA+ LNCaP细胞中的分子捕获。[18F]DCFPyL可在单反应器自动合成装置中通过直接放射性氟化合成路线制备，制备方法简单，放射化学产率高。[18F]DCFPyL的放射药理学评估证实psma介导的高肿瘤摄取结合优越的清除参数。区室模型分析指出了一个基于PSMA结合和随后内化的两步分子捕获机制，导致PSMA+ LNCaP肿瘤中的放射性保留。本文的在线版本（doi:10.1186/s13550-016-0195-6）包含补充材料，可供授权用户使用。
Prostate-specific membrane antigen (PSMA) is frequently overexpressed and upregulated in prostate cancer. To date, various 18F- and 68Ga-labeled urea-based radiotracers for PET imaging of PSMA have been developed and entered clinical trials. Here, we describe an automated synthesis of [18F]DCFPyL via direct radiofluorination and validation in preclinical models of prostate cancer. [18F]DCFPyL was synthesized via direct nucleophilic heteroaromatic substitution reaction in a single reactor TRACERlab FXFN automated synthesis unit. Radiopharmacological evaluation of [18F]DCFPyL involved internalization experiments, dynamic PET imaging in LNCaP (PSMA+) and PC3 (PSMA−) tumor-bearing BALB/c nude mice, biodistribution studies, and metabolic profiling. In addition, reversible two-tissue compartmental model analysis was used to quantify pharmacokinetics of [18F]DCFPyL in LNCaP and PC3 tumor models. Automated radiosynthesis afforded radiotracer [18F]DCFPyL in decay-corrected radiochemical yields of 23 ± 5 % (n = 10) within 55 min, including HPLC purification. Dynamic PET analysis revealed rapid and high uptake of radioactivity (SUV5min 0.95) in LNCaP tumors which increased over time (SUV60min 1.1). Radioactivity uptake in LNCaP tumors was blocked in the presence of nonradioactive DCFPyL (SUV60min 0.22). The muscle as reference tissue showed rapid and continuous clearance over time (SUV60min 0.06). Fast blood clearance of radioactivity resulted in tumor-blood ratios of 1.0 after 10 min and 8.3 after 60 min. PC3 tumors also showed continuous clearance of radioactivity over time (SUV60min 0.11). Kinetic analysis of PET data revealed the two-tissue compartmental model as best fit with K1 = 0.12, k2 = 0.18, k3 = 0.08, and k4 = 0.004 min−1, confirming molecular trapping of [18F]DCFPyL in PSMA+ LNCaP cells. [18F]DCFPyL can be prepared for clinical applications simply and in good radiochemical yields via a direct radiofluorination synthesis route in a single reactor automated synthesis unit. Radiopharmacological evaluation of [18F]DCFPyL confirmed high PSMA-mediated tumor uptake combined with superior clearance parameters. Compartmental model analysis points to a two-step molecular trapping mechanism based on PSMA binding and subsequent internalization leading to retention of radioactivity in PSMA+ LNCaP tumors. The online version of this article (doi:10.1186/s13550-016-0195-6) contains supplementary material, which is available to authorized users.