Improved, one‐pot synthesis of 6‐[18F]fluorodopamine and quality control testing for use in patients with neuroblastoma

• Published in: Journal of labelled compounds & radiopharmaceuticals Vol. 61; no. 14; pp. 1069 - 1080
• Main Authors: Vāvere, Amy L., Neumann, Kiel D., Butch, Elizabeth R., Hu, Bao, DiMagno, Stephen G., Snyder, Scott E.
• Format: Journal Article
• Language: English
• Published: HOBOKEN Wiley 01.12.2018; Wiley Subscription Services, Inc
• Subjects: 6‐[18F]fluorodopamine; Bioaccumulation; Biochemical Research Methods; Biochemistry & Molecular Biology; Biological Transport; Cell Line, Tumor; Chemistry; Chemistry Techniques, Synthetic; Chemistry, Analytical; Chemistry, Medicinal; Computation; Computed tomography; Dopamine - analogs & derivatives; Dopamine - chemical synthesis; Dopamine - chemistry; Dopamine - metabolism; Fluorination; Fluorine isotopes; fluorine‐18; F‐DA; Humans; Image quality; Life Sciences & Biomedicine; Medical imaging; Neuroblastoma; Neuroblastoma - diagnostic imaging; Neuroblastoma - pathology; Neuroendocrine tumors; Norepinephrine; Norepinephrine transporter; Patients; PET; Pharmacology & Pharmacy; Photon emission; Physical Sciences; Positron emission; Positron emission tomography; Positron Emission Tomography Computed Tomography; Precursors; Quality Control; Radiochemistry; Regulatory agencies; Salts; Science & Technology; Single photon emission computed tomography; Synthesis; Tomography; Tumors; F-DA; neuroblastoma; HIGHLY EFFICIENT; AGENT; HEART; fluorine-18; POSITRON-EMISSION-TOMOGRAPHY; METABOLISM; NOREPINEPHRINE TRANSPORTER; PET/CT; 6-[F-18]fluorodopamine; EXPRESSION; PET; 6-[18F]fluorodopamine
• ISSN: 0362-4803; 1099-1344
• DOI: 10.1002/jlcr.3685

6‐[18F]Fluorodopamine ([18F]F‐DA) is taken into cells via the norepinephrine transporter (NET). Recent [18F]F‐DA positron emission tomography–computed tomography (PET‐CT) imaging of adult neuroendocrine tumors shows a dramatic improvement in sensitivity over the standard‐of‐care, meta‐iodobenzylguanidine (MIBG) single‐photon emission computed tomography (SPECT)–CT. A new precursor (ALPdopamine™) allows no‐carrier‐added synthesis resulting in high–molar activity [18F]F‐DA. Automated synthesis of [18F]F‐DA was performed in a single reactor using a two‐step procedure: 1) fluorination via thermolysis of a diaryliodonium salt precursor, followed by 2) acid hydrolysis. Phase transfer agents, Kryptofix 222 and two tetraalkylammonium salts, were investigated. Optimized synthesis of [18F]F‐DA was achieved in 56 to 60 minutes (26% end of synthesis [EOS], nondecay corrected). The product passed all Food and Drug Administration (FDA)–required quality control testing for human use. Accumulation of [18F]F‐DA in SK‐N‐BE(2)‐C (high NET expression) cells was significantly higher than in SH‐EP (minimal NET expression) cells (P < 0.0001). ALPdopamine provides an effective scaffold for the routine production of [18F]F‐DA for human use. Validation of uptake by neuroblastoma (NB) cell lines supports the use of [18F]F‐DA for imaging NB patients. A pediatric NB imaging trial using [18F]F‐DA PET has been approved (Investigational New Drug application (IND) no. 138638) based on the methods reported here. We expect [18F]F‐DA will be localized in NB tumors and that high‐quality functional images will be obtained within minutes after injection. An improved method for the nucleophilic synthesis of [18F]fluorodopamine, a highly promising PET radiopharmaceutical for imaging neuroendocrine tumors, is presented. The final product is demonstrated to meet established quality control requirements for human use. This optimized method is now in use for human subject research in patients with neuroblastoma.