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The Radiopharmaceutical Chemistry of Fluorine-18: Next-Generation Fluorinations

  • Anu J. Airaksinen
Chapter

Abstract

This chapter introduces “next-generation” methods for radiofluorination reactions with fluorine-18. We will primarily focus on two topics: (1) methods for the 18F-fluorination of heteroatoms and (2) methods for the transition metal-mediated 18F-fluorination of aromatic and allylic carbons. Fluorine forms bonds with several group 13–15 elements, including carbon (obviously), boron, nitrogen, aluminum, silicon, and phosphorous. For example, [18F]fluoride and aluminum form a stable [18F][AlF]2+ complex which can be incorporated into biomolecular targeting vectors using bifunctional chelators such as NOTA and NODA. With boron, [18F]fluoride readily forms organotrifluoroborate salts which can be synthesized using boronic esters in finely controlled carrier-added conditions or via 18F–19F isotopic exchange from trifluoroborate salts of the stable isotope. Both methods can be utilized for the synthesis of 18F-labeled radiopharmaceuticals with high radiochemical yields (RCYs) and high molar activities (GBq/μmol). Shifting gears a bit, transition metals can be used to catalyze the 18F-fluorination of sp2 carbons at aromatic and allylic positions using nucleophilic [18F]fluoride. Selective fluorinations of these positions have been notoriously challenging using conventional radiosynthetic methods, especially when products with high molar activity are needed (see the chapters on “ The Radiopharmaceutical Chemistry of Fluorine-18: Nucleophilic Fluorinations” and “ The Radiopharmaceutical Chemistry of Fluorine-18: Electrophilic Fluorinations”). Yet novel methods based on palladium- and nickel-aryl complexes as well as copper(II) salts have revolutionized this area, providing access to a wide variety of 18F-fluorinated aromatic and allylic substrates in moderate to high yields and formerly unattainable molar activities (GBq/μmol).

Keywords

Fluoride Aluminum fluoride Organotrifluoroborate salts Kit labeling Radiofluorination Pd(IV) complex Pd(II) complex Nickel(II) complex Copper(II)-mediated reactions 

Abbreviations

AMBF3

Alkylammoniomethyltrifluoroborate

DFO

Desferrioxamine

DMA

N,N-Dimethylacetamide

DMF

Dimethylformamide

DMSO

Dimethyl sulfoxide

DTPA

Diethylenetriaminepentaacetic acid

DOTA

1,4,7,10-Tetraazacyclododecane-1,4,7,10-tetraacetic acid

EDTA

Ethylenediaminetetraacetic acid

EtOH

Ethanol

HPLC

High-pressure liquid chromatography

Kryptofix 2.2.2

4,7,13,16,21,24-Hexaoxa-1,10-diazabicyclo[8.8.8]hexacosane

MPAEM

Methyl phenyl acetamido ethyl maleimide

NFSI

N-Fluorobenzenesulfonimide

NODA

1,4,7-Triazacyclononane-1,4-diiacetic acid

NOTA

1,4,7-Triazacyclononane-1,4,7-triacetic acid

PBS

Phosphate-buffered saline

PET

Positron emission tomography

PPTS

Pyridinium p-toluenesulfonate

PSMA

Prostate-specific antigen

QMA

Quaternary ammonium ion-exchange resin

RCY

Radiochemical yield

SNAr

Aromatic nucleophilic substitution

SPE

Solid-phase extraction

USP

United States Pharmacopeia

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Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Anu J. Airaksinen
    • 1
  1. 1.Department of Chemistry – RadiochemistryUniversity of HelsinkiHelsinkiFinland

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