high purity (>95%) with specific activities of 0.0197 and 0.0192 mCi mg
−1 for 20
and 100 nm particle sizes, respectively.
In the effort to develop the most optimal synthetic strategies for the preparation
of radiopharmaceuticals, the requirement of a copper catalyst in these reactions is
problematic. Excessive intake of this metal is known to exert in vivo toxicity [20–
22] and therefore it requires complete removal in a fast and facile manner. Another
important consideration is that radiotracers based on peptides and proteins may
often be—given their abundance of electron donating groups—naturally primed for
coordinating metals such as copper in a manner which is often non-specific and
difficult to predict. This may of course have a detrimental impact on important
binding properties such as target affinity and specificity towards the epitope of
interest. Lastly, the necessity of a catalyst represents an additional reaction
parameter which requires thorough optimisation and, therefore, is another hurdle in
the research and development process. The simplification of these reactions by
removal of the catalyst is therefore highly desirable.
13.2 The Evolution of Copper-Free Click Chemistry
Reactions
A notable advancement in the effort to circumvent the requirement of a metal
catalyst in click chemistry reactions was pioneered by Bertozzi et al. in 2004 [23].
Inspired by early literature on this topic [24], it was recognised that ‘activating’
alkynes via their insertion into a ring-strained structure offered an attractive method
for tagging azide-modified structures despite the lack of a copper(I) catalyst.
Reactions of this type are now referred to as strain-promoted [3+2] azide-alkyne
cycloadditions (SPAAC; Fig. 13.2a) [25–31].
While early SPAAC reactions exhibited lower rates of reaction in comparison to
analogous copper-catalysed cycloaddition reactions, this obstacle was overcome
with the recognition that electron-withdrawing substituents (such as fluorine atoms)
in positions adjacent to the strained alkyne group [32] or dibenzoannulation [33]
effectively enhance the rate of these reactions. For example, in reactions with
benzyl azide (or a similar aliphatic azide), a ‘first generation’ cyclooctyne species
(OCT) yielded a rate constant of 2.4 Â 10
−3 M
−1 s
−1 , while the more
highly-strained alkyne dibenzoazacyclooctyne (DBCO; Fig. 13.2b) revealed a
greatly enhanced rate constant of 310 Â 10
−3 M
−1 s
−1 [33–35]. SPAAC reactions
have now been used widely for the synthesis of radiolabeled imaging agents for
PET and SPECT applications. Notably, in 2011, Bouvet et al. reported an [
18 F]labeled prosthetic group based on DBCO ([
18 F]-FB-DBCO; Fig. 13.2b) which was
used successfully for radiolabelling a variety of azide-containing precursors
including the complex natural product geldanamycin and obtained excellent
radiochemical yields under mild reaction conditions [36].
254
J. C. Knight and B. Cornelissen
−1 for 20
and 100 nm particle sizes, respectively.
In the effort to develop the most optimal synthetic strategies for the preparation
of radiopharmaceuticals, the requirement of a copper catalyst in these reactions is
problematic. Excessive intake of this metal is known to exert in vivo toxicity [20–
22] and therefore it requires complete removal in a fast and facile manner. Another
important consideration is that radiotracers based on peptides and proteins may
often be—given their abundance of electron donating groups—naturally primed for
coordinating metals such as copper in a manner which is often non-specific and
difficult to predict. This may of course have a detrimental impact on important
binding properties such as target affinity and specificity towards the epitope of
interest. Lastly, the necessity of a catalyst represents an additional reaction
parameter which requires thorough optimisation and, therefore, is another hurdle in
the research and development process. The simplification of these reactions by
removal of the catalyst is therefore highly desirable.
13.2 The Evolution of Copper-Free Click Chemistry
Reactions
A notable advancement in the effort to circumvent the requirement of a metal
catalyst in click chemistry reactions was pioneered by Bertozzi et al. in 2004 [23].
Inspired by early literature on this topic [24], it was recognised that ‘activating’
alkynes via their insertion into a ring-strained structure offered an attractive method
for tagging azide-modified structures despite the lack of a copper(I) catalyst.
Reactions of this type are now referred to as strain-promoted [3+2] azide-alkyne
cycloadditions (SPAAC; Fig. 13.2a) [25–31].
While early SPAAC reactions exhibited lower rates of reaction in comparison to
analogous copper-catalysed cycloaddition reactions, this obstacle was overcome
with the recognition that electron-withdrawing substituents (such as fluorine atoms)
in positions adjacent to the strained alkyne group [32] or dibenzoannulation [33]
effectively enhance the rate of these reactions. For example, in reactions with
benzyl azide (or a similar aliphatic azide), a ‘first generation’ cyclooctyne species
(OCT) yielded a rate constant of 2.4 Â 10
−3 M
−1 s
−1 , while the more
highly-strained alkyne dibenzoazacyclooctyne (DBCO; Fig. 13.2b) revealed a
greatly enhanced rate constant of 310 Â 10
−3 M
−1 s
−1 [33–35]. SPAAC reactions
have now been used widely for the synthesis of radiolabeled imaging agents for
PET and SPECT applications. Notably, in 2011, Bouvet et al. reported an [
18 F]labeled prosthetic group based on DBCO ([
18 F]-FB-DBCO; Fig. 13.2b) which was
used successfully for radiolabelling a variety of azide-containing precursors
including the complex natural product geldanamycin and obtained excellent
radiochemical yields under mild reaction conditions [36].
254
J. C. Knight and B. Cornelissen