Nucleophilic Synthesis of 6-l-[18F]FDOPA. Is Copper-Mediated Radiofluorination the Answer?

Raisa N Krasikova

doi:10.3390/molecules25194365

Abstract

Positron emission tomography employing 6-l-[18F]fluoro-3,4-dihydroxyphenylalanine (6-l-[18F]FDOPA) is currently a highly relevant clinical tool for detection of gliomas, neuroendocrine tumors and evaluation of Parkinson’s disease progression. Yet, the deficiencies of electrophilic synthesis of 6-l-[18F]FDOPA hold back its wider use. To fulfill growing clinical demands for this radiotracer, novel synthetic strategies via direct nucleophilic 18F-radiloabeling starting from multi-Curie amounts of [18F]fluoride, have been recently introduced. In particular, Cu-mediated radiofluorination of arylpinacol boronates and arylstannanes show significant promise for introduction into clinical practice. In this short review these current developments will be discussed with a focus on their applicability to automation.

Highlights

Positron Emission Tomography (PET), based on the use of tracers labeled with short-lived positron-emitting radionuclides, is a well-established methodology for non-invasive molecular imaging of living subjects, used in both pre-clinical and clinical settings, in the fields of oncology and neurology
Since its introduction in 1983 [6] for the in vivo assessment the central dopaminergic function of presynaptic neurons, 6-l-[18 F]FDOPA is regarded as the “gold standard” for the detection and post-treatment monitoring of Parkinson’s disease (PD) [7,8]
The hypervalent I(III) reagents described above are not commercially available and must be prepared on site through multistep synthesis involving complex purification steps; the structural complexity and presence of impurities often leads to limited shelf life of precursors, which precludes their implementation in routine synthesis of 6-l-[18 F]FDOPA for clinical applications

Summary

Introduction

Positron Emission Tomography (PET), based on the use of tracers labeled with short-lived positron-emitting radionuclides, is a well-established methodology for non-invasive molecular imaging of living subjects, used in both pre-clinical and clinical settings, in the fields of oncology and neurology. The number of requests for clinical 6-l-[18 F]FDOPA PET and PET/CT studies has been increasing dramatically in the recent years, despite of relatively high cost of single radiotracer dose and costs of studies themselves The use of this radiotracer is held back, to a great extent, by the absence of a simple and efficient production method, that could, to the [18 F]FDG, provide Curie-level amounts of tracer using fully automated nucleophilic radiofluorination reactions, utilizing [18 F]fluoride that is available from water cyclotron targets. One approach to improve the productivity and Am of electrophilic method has been a post-target generation approach based on the conversion of nucleophilic [18 F]fluoride into [18 F]F2 gas in an electrical discharge chamber, introduced by Solin’s group [28,29] This advanced methodology allowed production of radiotracers with Am exceeding 15 GBq/μmol at the end of synthesis and in clinically useful amounts [30].

18 O-water target

Iodonium Salts

Organostannanes

Summary and Conclusions