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product is isolated, reformulated, characterised, and stored for subsequent use. In the
NN
5
Simultaneous
second step, radiolabelling is performed to give access to the nal radiolabelled product. An alternative two-step approach involves pre-radiolabelling the chelate and then
performing the bioconjugation step using the radioactive intermediate. Although highly
successful, these two-step approaches have a number of disadvantages, including the
need to produce, isolate, characterise, and potentially store an intermediate product.
As an alternative, our group is exploring the possibility of combining the bioconjugation
and radiolabelling steps into a simultaneous, one-pot process using an emerging concept that combines photochemistry with radiochemistry (photoradiochemistry)[132, 133].
The approach involves a multicomponent reaction in which a photoactivatable chelate is
mixed with the radionuclide and the protein at the same time, and then irradiated with
ultraviolet light (Scheme11.4). Radiolabelling of ‘free’ chelates that are not bound to protein can typically be accomplished in just a few seconds or minutes due to the enhanced
rate of diusion of small molecules. At the same time, photochemical activation of a substrate containing an aryl azide group generates extremely reactive arylnitrene intermediates that rapidly isomerise and then undergo facile and chemoselective reactions with
primary amines (lysine residues). In contrast to traditional coupling methods that usually
functionalise lysine or cysteine residues using thermochemically initiated reactions, photochemical reactions occur at room temperature with greatly enhanced kinetics (estimates indicate upwards of three-orders of magnitude faster than standard approaches).
The speed of photochemical reactions means the photoradiochemical approach can
produce fully formulated radiolabelled antibodies from the native protein source in
<10 minutes. In addition, we found that, unlike traditional conjugation chemistries, this
photoradiochemical method is compatible with standard clinical formulations of many
antibodies. This discovery circumvents the need to pre-purify the protein from a GMPgrade source. Further development is required before photoradiochemical methods can
be translated to a clinical setting, but if the two examples highlighted in this section can
be combined,
89
Zr-based radiopharmaceuticals will have a bright future.
5
OO
OO
H
O
N
O
N
HO
photoradiolabelling
<10 min., pH~8
O
UV light ~365 nm
N
H
O
O
Lys
N
H
N
N
N
O
4
H
[89Zr]ZrDFO-azepin-trastuzumab
O
N
OH
O
N
N
H
3
DFO-ArN
O
N
H
O
H
N
N
OOH
3
Scheme 11.4 Illustration of the concept of the simultaneous, one-pot photoradio-
chemical conjugation and labelling of antibodies.
J.P.H. the Swiss National Science Foundation (SNSF Professorship PP00P2_163683 and
PP00P2_190093), the Swiss Cancer League (Krebsliga Schweiz; KLS-4257-08-2017), and the
University of Zurich (UZH) for nancial support. This project has received funding from the
Chapter 11: The Radiochemistry ofZirconium 365
European Union’s Horizon 2020 research and innovation programme/from the European
Research Council under the Grant Agreement No 676904, ERC-StG-2015, NanoSCAN.
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