Beyond azide–alkyne click reaction: easy access to 18F-labelled compounds via nitrile oxide cycloadditions

Abstract

Radiofluorinated 4-fluorobenzonitrile oxide and N-hydroxy-4-fluorobenzimidoyl chloride rapidly react with different alkenes and alkynes under mild conditions. These cycloadditions are suitable for the preparation of low-molecular weight radiopharmaceuticals and, in a strain-promoted variant, can enable easy labelling of sensitive biopolymers.

Exploring the Potential of Norbornene‐Modified Mannosamine Derivatives for Metabolic Glycoengineering

“…A commercially available mixture of exo‐ and endo ‐bicyclo[2.2.1]hept‐5‐ene‐2‐carbaldehyde ( exo ‐ 6 and endo ‐ 6 ) was separated by silica gel column chromatography, and the isomers were reduced to exo‐ (bicyclo[2.2.1]hept‐5‐en‐2‐yl)methanol ( 7 ) and its endo isomer 8 , respectively (Scheme ) . Both 7 and 8 were then activated by treatment with disuccinimidyl carbonate ( 9 ). The corresponding activated carbonates 10 and 11 were treated with mannosamine hydrochloride ( 12 ), and the sugars were peracetylated for facilitated purification as well as increased cell permeability, yielding Ac 4 ManNNorboc exo ( 4 ) and Ac 4 ManNNorboc endo ( 5 ).…”

“…exo ‐(Bicyclo[2.2.1]hept‐5‐en‐2‐yl)methyl succinimidyl carbonate ( 10 ) was synthesized as described previously by Neumaier et al …”

18F‐Labeling of Sensitive Biomolecules for Positron Emission Tomography

“…[148] Similarly, these authors also investigated reaction of suitable dipolarophiles with 4- [18 F]fluorobenzonitrile oxide 177 (prepared from [18 F]FBA and oxime 176 ) and N -hydroxy-4- [18 F]fluorobenzimidoyl chloride to yield the corresponding labeled [3+2] cycloaddition product 178 (Figure 33). [149] RCCs >95% were obtained in some cases with sample small molecules. The methodology was extended to synthesize labeled model dipeptides 179 - 181 in ca.…”

18F-Labeling Using Click Cycloadditions

“…In further studies, the same group used 4-[ 18 F]fluorobenzonitrile oxide instead of C-(4-[ 18 F]fluorophenyl)-N-phenyl nitrone as 1,3-dipol for milder reaction conditions [20] (Table 3). 4-[ 18 F]fluorobenzonitrile oxide was obtained in 92% RCY within 10 min from the reaction of 4-[ 18 F]fluorobenzaldehyde (RCY: 30–50%, 50 min [99]) with hydroxylamine and subsequent treatment with phenyl iodine bis(trifluoroacetate).…”

“…Consequently, 4-[ 18 F]fluorobenzonitrile oxide was further treated with chloramine T (CAT) in situ forming the more stable building block N-hydroxy-4-[ 18 F]fluorobenzimidoyl chloride. With the use of high precursor (peptides) amounts, the latter enabled excellent RCY of the 18 F-labeled dipeptides of up to 88% within 10 min at room temperature [20]. Under optimized conditions low precursor amounts of 5 nmol (cyclononyne) and 50 nmol (norbornene- β -Ala-Phe-OMe) still allowed RCY of 56% and 47%, respectively.…”