TOWARD IMAGING GLYCOTOOLS BY CLICK COUPLING - Click Chemistry in Glycoscience: New Developments and Strategies - page 197

OH

OH

EtOH O O

O O

OH

O N

N HO

HO

HO
HO

+

( ) 6

OH H 2 N 100°C

HN

X

X

O

O

92 X = F
93 X = 18 F

90 X = F
1 X = 18 F

91

RSH

SR

OH

O O

OH

N

HO
HO

HN

X

O

94

SCHEME 7.19 Oxime formation as a click coupling between a sugar and maleimide.

radiochemistry [89, 90]. Wuest and coworkers proposed oxime formation as a
click reaction to construct an FDG-based prosthetic group (Scheme 7.19) [91]. As
[ 18 F]FDG is available in all PET centers, it is obvious to use it as a precursor to
elaborate reactive species able to label peptides or proteins. The cold reference was
obtained by heating equimolecular amounts of free FDG 90 with N -(6-aminooxy)
hexyl maleimide 91 inaEtOH/H 2 O mixture (4:1) to give the oxime 92 . Purification
on a Sep-Pack cartridge gave pure 92 as an open-chain mixture of Z and E isomers as
shown by proton nuclear magnetic resonance spectroscopy 1 HNMR.The 18 F-labeled
compound 93 was obtained from [ 18 F]FDG 1 and maleimide 91 used in excess. Heat-
ing the mixture at 100 ◦ C for 15 minutes in 80% ethanol gave 45-69% radiochemical
yields in radiochemical purity up to 95%. The labeled oximes 93 have been used to
achieve another click reaction, that is, thiol 1,4-addition on the activated double bond
of the succinimide moiety to produce radiotracers 94 where R can be glutathione or
annexin A5.
The same approach has been used by Gambhir et al. using [ 18 F]FDG and RGD-
containing peptides (Scheme 7.20) [92]. In this case, the oxime 95 was directly built
from [ 18 F]FDG 1 reacting with the aminooxy function introduced at the N-terminus
of an RGD sequence by amide bond formation. Incubation of [ 18 F]FDG with the
peptide 16% ethanol in saline (120

L) in the presence of 0.4% TFA at 100 ◦ C for 30
minutes gave the conjugate 96 ( Z/E mixture) in 27.5 radiochemical yield. Conjugation
to c(RGDyK) proceeded the same way in 41.4% radiochemical yield. The method
has also been used for the synthesis of a [ 18 F]FDG-c(RGDfK) conjugate 97 by direct
reaction with the Boc-protected aminooxy function grafted at the

ε position of a

lysine residue (Scheme 7.20) [93].
The Wuest group also investigated this direct method to several aminooxy deriva-
tized peptides [94]. It was concluded that the method works well with small peptides
although it requires large amounts of peptide and tedious separation of the glucose-
peptide conjugate also formed in the ligation reaction.