6-[18F]fluoro-L-DOPA: a well-established neurotracer with expanding application spectrum and strongly improved radiosyntheses

Abstract

For many years, the main application of [(18)F]F-DOPA has been the PET imaging of neuropsychiatric diseases, movement disorders, and brain malignancies. Recent findings however point to very favorable results of this tracer for the imaging of other malignant diseases such as neuroendocrine tumors, pheochromocytoma, and pancreatic adenocarcinoma expanding its application spectrum. With the application of this tracer in neuroendocrine tumor imaging, improved radiosyntheses have been developed. Among these, the no-carrier-added nucleophilic introduction of fluorine-18, especially, has gained increasing attention as it gives [(18)F]F-DOPA in higher specific activities and shorter reaction times by less intricate synthesis protocols. The nucleophilic syntheses which were developed recently are able to provide [(18)F]F-DOPA by automated syntheses in very high specific activities, radiochemical yields, and enantiomeric purities. This review summarizes the developments in the field of [(18)F]F-DOPA syntheses using electrophilic synthesis pathways as well as recent developments of nucleophilic syntheses of [(18)F]F-DOPA and compares the different synthesis strategies regarding the accessibility and applicability of the products for human in vivo PET tumor imaging.

Figure 1

Selected radiotracers applicable in (brain-)tumor imaging.

Figure 2

Isotopic exchange reaction pathway for the synthesis of 5-[¹⁸F]F-DOPA [34].

Figure 3

Examples for different demetallation synthesis routes for production of carrier-added [¹⁸F]F-DOPA ([¹⁸ F]7) via desilylation (A) [42], demercuration (B) [44], and destannylation (C) [95].

Figure 4

Isotopic exchange reaction for the synthesis of carrier-added [¹⁸F]F-DOPA [59].

Figure 5

Most common precursors for no-carrier-added nucleophilic radiofluorination reactions producing [¹⁸F]F-DOPA.

Figure 6

Chiral phase-transfer catalyst O-ally-N-9-anthracenylmethyl-cinchonidinium bromide 18.

Figure 7

Synthesis pathway for the enzymatic preparation of [¹⁸F]F-DOPA according to Kaneko et al. [77].

Figure 8

Schematic depiction of the synthesis pathway utilizing NiPBPGly 25 and (S)-NOBIN 26 as a novel substrate/catalyst pair for the enantioselective radiosynthesis of [¹⁸F]F-DOPA by Krasikova et al. [80].

Figure 9

Automated radiosynthesis procedure for [¹⁸F]F-DOPA using the chiral phase transfer catalyst 18 [83].

Figure 10

Schematic depiction of the automated synthesis pathway using the chiral phase-transfer catalyst 31 [86].

Figure 11

Schematic depiction of an oxidative fluorination approach using the nickel complex 32 and a hypervalent iodine oxidant 33 giving the Boc-protected [¹⁸F]F-DOPA-analogue [ ¹⁸ F]34 [90].