Jiang Huailei, Jain Manoj K, Cai Hancheng
Department of Radiology, Mayo Clinic Jacksonville, FL, USA.
Karmanos Cancer Institute Detroit, MI, USA.
Am J Nucl Med Mol Imaging. 2021 Aug 15;11(4):290-299. eCollection 2021.
Radiotracer 3,4-dihydroxy-6-[F]fluoro-L-phenylalanine (L-6-[F]fluorodopa or [F]FDOPA) is widely used for PET imaging of dopamine metabolism in several diseases including Parkinson's Disease, brain tumor, neuroendocrine tumors, and focal hyperinsulinism of infancy. In 2019, [F]FDOPA was approved by US FDA for detection of dopaminergic nerve terminals in the striatum of adult patients with suspected Parkinsonian Syndromes. A convenient and reliable method is desired for fully automated production of [F]FDOPA under cGMP compliance to meet the increasing clinical need. In this study, we reported a cassette-based automated production of [F]FDOPA using a GE Fastlab 2 module and the quality control (QC) under fully cGMP compliant environment. Briefly, automated radiosynthesis of [F]FDOPA was processed via nucleophilic radio-fluorination using FDOPA Fastlab cassette and solid phase extraction (SPE) purification. The QC tests of [F]FDOPA, including appearance, pH, half-life, radiochemical purity and identity, enantiomeric purity, chemical impurities, molecular activity, radioactive concentration, filter integrity, endotoxin, and sterility, were conducted at the end of synthesis (EOS) and 8 h after EOS during the validation runs. Three consecutive productions of [F]FDOPA were reliably achieved with desired radiochemical yield and high radiochemical/enantiomeric purities and molar activity. The uncorrected radiochemical yields of [F]FDOPA were 9.3-9.8% with a total synthesis time of ~140 min. Both radiochemical and enantiomeric purities of [F]FDOPA were >99.9% and the molar activities were 2.1-3.9 Ci/μmole at EOS. The full QC results at EOS and 8 h after EOS showed that the produced [F]FDOPA met all release criteria for clinical use within 8 hours of expiration time. Three consecutive validation runs and QC results demonstrated the efficacy of cassette-based production of [F]FDOPA for routine clinical use.
放射性示踪剂3,4 - 二羟基 - 6 - [F]氟 - L - 苯丙氨酸（L - 6 - [F]氟多巴或[F]FDOPA）广泛用于多种疾病的多巴胺代谢的正电子发射断层显像（PET），这些疾病包括帕金森病、脑肿瘤、神经内分泌肿瘤以及婴儿期局灶性高胰岛素血症。2019年，[F]FDOPA被美国食品药品监督管理局（US FDA）批准用于检测疑似帕金森综合征成年患者纹状体中的多巴胺能神经末梢。为了在符合药品生产质量管理规范（cGMP）的情况下满足日益增长的临床需求，需要一种方便可靠的方法来全自动生产[F]FDOPA。在本研究中，我们报告了一种基于试剂盒的[F]FDOPA自动化生产方法，该方法使用GE Fastlab 2模块，并在完全符合cGMP的环境下进行质量控制（QC）。简而言之，[F]FDOPA的自动化放射性合成通过使用FDOPA Fastlab试剂盒进行亲核放射性氟化以及固相萃取（SPE）纯化来进行。在验证运行期间，在合成结束时（EOS）和EOS后8小时对[F]FDOPA进行质量控制测试，包括外观、pH值、半衰期、放射化学纯度和同一性、对映体纯度、化学杂质、分子活性、放射性浓度、过滤器完整性、内毒素和无菌性。连续三次成功生产出[F]FDOPA，获得了所需的放射化学产率以及高放射化学/对映体纯度和摩尔活性。[F]FDOPA的未校正放射化学产率为9.3 - 9.8%，总合成时间约为140分钟。在EOS时，[F]FDOPA的放射化学纯度和对映体纯度均>99.9%，摩尔活性为2.1 - 3.9 Ci/μmole。EOS时以及EOS后8小时的完整质量控制结果表明，所生产的[F]FDOPA在有效期8小时内符合所有临床使用放行标准。连续三次验证运行和质量控制结果证明了基于试剂盒生产[F]FDOPA用于常规临床使用的有效性。
