Advances in the automated synthesis of 6-[18F]Fluoro-L-DOPA

Abstract

The neurotracer 6-[18F] FDOPA has been, for many years, a powerful tool in PET imaging of neuropsychiatric diseases, movement disorders and brain malignancies. More recently, it also demonstrated good results in the diagnosis of other malignancies such as neuroendocrine tumours, pheochromocytoma or pancreatic adenocarcinoma.The multiple clinical applications of this tracer fostered a very strong interest in the development of new and improved methods for its radiosynthesis. The no-carrier-added nucleophilic 18F-fluorination process has gained increasing attention, in recent years, due to the high molar activities obtained, when compared with the other methods although the radiochemical yield remains low (17–30%). This led to the development of several nucleophilic synthetic processes in order to obtain the product with molar activity, radiochemical yield and enantiomeric purity suitable for human PET studies.Automation of the synthetic processes is crucial for routine clinical use and compliance with GMP requirements. Nevertheless, the complexity of the synthesis makes the production challenging, increasing the chance of failure in routine production. Thus, for large-scale clinical application and wider use of this radiopharmaceutical, progress in the automation of this complex radiosynthesis is of critical importance.This review summarizes the most recent developments of 6-[18F]FDOPA radiosynthesis and discusses the key issues regarding its automation for routine clinical use.

A reliable and automated synthesis of 6-[18F]fluoro-L-DOPA and the clinical application on the imaging of congenital hyperinsulinism of infants

“…6-[ 18 F] uoro-L-DOPA [3], since its rst clinical application in the imaging of dopaminergic pathways of human brain [4], has been used to report a wide variety of diseases [5], including neuro-oncology [6,7], endocrinology [8], and Parkinson's disease [9,10], As a result, a range of methods have been developed for this valuable radiotracer. [11,12] The rst synthesis of radioactive L-DOPA (5-[ 18 F] uoro-L-DOPA) was accomplished by Firnau and co-workers in 1973 using diazonium uoroborate compound as precursor [13]. The same lab later reported the synthesis of this radiotracer by the reaction of L-DOPA and [ 18 F]F 2 , which afforded only a mixture of 2-, 5-and [ 18 F] uoro-L-DOPA [14].…”

Manufacturing 6-[18F]Fluoro-L-DOPA via Flow Chemistry-Enhanced Photoredox Radiofluorination

“…11−18 Given its advantageous diagnostic potential, since the 1980s, diverse methods have been developed for 6-[ 18 F]FDOPA synthesis, each with unique advantages and limitations (Scheme S1). 8,19 However, the complexity of current methods, involving expensive automated modules and HPLC instruments, impedes the widespread adoption of 6-[ 18 F]FDOPA. Therefore, simplified synthetic protocols are still in high demand for the cGMP synthesis of 6-[ 18 F]-FDOPA.…”

“…6-[ 18 F]­FDOPA, an FDA-approved radiopharmaceutical agent, finds extensive use in PET imaging for visualizing and measuring dopaminergic neuron activity . Its application extends beyond managing neurologic disorders like Parkinson’s disease, , with ongoing research and clinical trials in oncology. − Given its advantageous diagnostic potential, since the 1980s, diverse methods have been developed for 6-[ 18 F]­FDOPA synthesis, each with unique advantages and limitations (Scheme S1).…”

“…Its application extends beyond managing neurologic disorders like Parkinson’s disease, , with ongoing research and clinical trials in oncology. − Given its advantageous diagnostic potential, since the 1980s, diverse methods have been developed for 6-[ 18 F]­FDOPA synthesis, each with unique advantages and limitations (Scheme S1). , However, the complexity of current methods, involving expensive automated modules and HPLC instruments, impedes the widespread adoption of 6-[ 18 F]­FDOPA. Therefore, simplified synthetic protocols are still in high demand for the cGMP synthesis of 6-[ 18 F]­FDOPA. − To overcome the scope limitations of aryl 18 F-fluorination, we recently developed several radiolabeling methods including direct C–H/C– 18 F activation, radiodeoxyfluorination, and direct halide/ 18 F interconversion to construct C­(sp 2 )– 18 F bonds in electron-rich (hetero)­arene substrates via photocatalysis.…”

Correction to: Advances in the automated synthesis of 6-[18F]Fluoro-L-DOPA

“…Following publication of the original article (Neves et al 2021 ), some errors were identified in the article text:…”