GMP production of 6-[18F]Fluoro-l-DOPA for PET/CT imaging by different synthetic routes: a three center experience

Abstract

Background The radiofluorinated levodopa analogue 6-[18F]F-l-DOPA (3,4-dihydroxy-6-18F-l-phenylalanine) is a commonly employed radiotracer for PET/CT imaging of multiple oncological and neurological indications. An unusually large number of different radiosyntheses have been published to the point where two different Ph. Eur. monographs exist depending on whether the chemistry relies on electrophilic or nucleophilic radiosubstitution of appropriate chemical precursors. For new PET imaging sites wishing to adopt [18F]FDOPA into clinical practice, selecting the appropriate production process may be difficult and dependent on the clinical needs of the site. Methods Data from four years of [18F]FDOPA production at three different clinical sites are collected and compared. These three sites, Aarhus University Hospital (AUH), Odense University Hospital (OUH), and Herlev University Hospital (HUH), produce the radiotracer by different radiosynthetic routes with AUH adopting an electrophilic strategy, while OUH and HUH employ two different nucleophilic approaches. Production failure rates, radiochemical yields, and molar activities are compared across sites and time. Additionally, the clinical use of the radiotracer over the time period considered at the different sites are presented and discussed. Results The electrophilic substitution route suffers from being demanding in terms of cyclotron operation and maintenance. This challenge, however, was found to be compensated by a production failure rate significantly below that of both nucleophilic approaches; a result of simpler chemistry. The five-step nucleophilic approach employed at HUH produces superior radiochemical yields compared to the three-step approach adopted at OUH but suffers from the need for more comprehensive synthesis equipment given the multi-step nature of the procedure, including HPLC purification. While the procedure at OUH furnishes the lowest radiochemical yield of the synthetic routes considered, it produces the highest molar activity. This is of importance across the clinical applications of the tracer discussed here, including dopamine synthesis in striatum of subjects with schizophrenia and congenital hyperinsulinism in infants. Conclusion For most sites either of the two nucleophilic substitution strategies should be favored. However, which of the two will depend on whether a given site wishes to optimize the radiochemical yield or the ease of the use.

Early acquisition of [18F]FDOPA PET/CT imaging in patients with recurrent or residual medullary thyroid cancer is safe—and slightly better!

“…Patients fasted for at least 6 h prior to tracer injection. [ 18 F]FDOPA was synthesized using a standardized method at the PET Centre at Aarhus University Hospital as described by Andersen et al ( 2021 ). After an intravenous injection of 393.8 ± 45.2 MBq [ 18 F]FDOPA co-administered with saline, PET scans were performed at both 15 and 60 min p.i.…”

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.…”

“…20−25 To overcome the scope limitations of aryl 18 Ffluorination, we recently developed several radiolabeling methods including direct C−H/C− 18 F activation, 26 radiodeoxyfluorination, 27 and direct halide/ 18 F interconversion 28 to construct C(sp 2 )− 18 F bonds in electron-rich (hetero)arene substrates via photocatalysis. In particular, the direct 19 F/ 18 F conversion method has held the potential to offer a simple and robust protocol for PET probe screening/preparation: this methodology not only immediately facilitated new PET agent discovery 29 but also allowed for the simple and high-yield synthesis of the widely used PET agents including 6-[ 18 F]FDOPA if more translational investigation could be followed. 28 Therefore, the photoredox-mediated halide/ 18 F interconversion strategy, as an innovative and powerful technique, could be used to prepare new and clinically relevant PET agents that are synthetically inaccessible or cumbersome to achieve by conventional methods if a practical radiosynthesis method was developed.…”

“…We expect that a suitable flow device could enhance the photoredox radiofluorination due to increased light flux. By adopting the reported 19 F/ 18 F exchange labeling conditions (Scheme 1), a series of flow reactors and setups including Q-cell, plastic chips, and flow-Q-cell were tested. After screening, we found that flow chemistry promoted the RCY under LED light irradiation compared with direct LED irradiation of the open-air radiolabeling setup (Table S1).…”