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(Scheme10.6)[51]. Initially, sluggish RCYs of the desired
*X
3
125
I-labeled PARP-1 inhibitors
were observed using optimized conditions. However, when utilizing a 1:1 ratio of
Cu(pyridine)
(OTf)2 and electron-rich ligand 3,4,7,8-tetramethyl-1,10-phenanthroline
4
(L2), excellent RCCs and RCYs were restored. Mach and co-workers also conducted
a comparative radiolabeling study by preparing [
L2
B(OR)
Y
R
O
NH
N
O
N
F
125
[
I]Olaparib Derivative 1
211
[
At]Olaparib Derivative 1
RCC
RCY
RCC
RCY
=
=
=
=
89%
89%
92%
92%
Cu(pyridine)4(OTf)
2
125
Na[
I]
MeOH:H
23
°C,
N
O
*X
or
Na[
O (4:1)
2
10
min
/
2
211
At]
Y
O
NH
N
125
[
I]Olaparib Derivative 2
211
[
At]Olaparib Derivative 2
125
I]KX1 and [
L2
R
O
F
RCC
RCY
RCC
RCY
=
=
=
=
=
N
99%
99%
93%
93%
211
At]MM4, PARP-1
N
N
N
*X
O
I]
°C,
/
2
211
or
At]
Na[
min
10
O
Using Bpin Precursor
125
[
RCC = 99%
RCY = 99%
211
[
NH
RCC = 100%
RCY = 100%
I]KX1
At]MM4
N
Cu(pyridine)4(OTf)
NH
N
125
Na[
MeOH:MeCN (4:1)
23
N
Bpin
L2
N
O
NH
125
211
or
At]
Na[
Na[
N
N
I]
H
CH
COOH
,
2O2
3
100 °C, 30 min
*X
Using
RCC = 70%
RCY = 50%
211
[
RCC = 70%
RCY= 60%
Tin
125
[
At]MM4
Precursor
I]KX1
SnBu
Scheme 10.6 Radiosynthesis of
125
I- and
211
At-labeled PARP-1 inhibitors. Source:
Based on Reilly, S.W., Makvandi, M., Xu, K., and Mach, R.H. [50].
Chapter 10: Cu-Mediated Radiohalogenation of Organoboranes 335
inhibitors with applications in cancer imaging and radiotherapeutics, respectively,
77
Br
RCC = 92–99%
RCC = 99%
from both the boronic ester and stannane precursors (Scheme10.6). Compared to the
classical electrophilic organostannane radiohalogenation approach, Mach’s late-stage
radiolabeling method delivered higher RCCs and RCYs for both [
125
I]KX1 and [
211
At]MM4
under optimized reaction conditions.
Zhou and co-workers then disclosed the rst Cu-mediated organoborane radiobromination report in 2018[52]. In their study, they found Cu(pyridine)
most ecient Cu source for labeling aryl boronic acids and esters with
(OTf)2 to be the
4
77
Br at temperatures of 80–110 °C (Scheme10.7). The authors noted near-quantitative RCCs in
40 minutes during the optimization studies; however, large amounts of reagents were
required. Similar to the Cu-mediated heavy halide radiohalogenation studies by Gouverneur[46] and Mach[50], Zhou’s method was also found to tolerate aqueous reaction
media. Although the authors did not discuss why the scope was limited to para-substi-
tuted aryl boron precursors, this robust radiolabeling strategy aorded RCCs of 90%
or greater throughout the investigation in just 10–20 minutes. This technique was also
evaluated with a boronic ester precursor of an olaparib derivative, aording a RCC of
99%. Overall, the Zhou group found this method to be higher-yielding, as well as more
reliable and facile, than their previously reported nucleophilic[44] and electrophilic[53]
radiobromination strategies.
B(OR)
2
Cu(pyridine)4(OTf)
[77Br]Bromide
DMSO
80 °C, 20 min
R
2
10 Examples
R
Scheme 10.7 Cu-mediated radiobromination of organoboranes. Source: Zhou, D.,
Chu, W., Voller, T., and Katzenellenbogen, J.A. [52]. Reproduced with the permission
of Elsevier.
336 Handbook of Radiopharmaceuticals
O
NH
N
O
N
N
F
O
[77Br]Olaparib Derivative
77
Br
10.4 CONCLUSIONS
The overall advances made in Cu-mediated organoborane radiohalogenation have
undoubtedly helped bridge the synthetic gaps in
18
F-based PET tracer development and
heavy halide radiohalogenation. Development of radioligands with promising clinical
applications previously found to be synthetically challenging, and subsequently underutilized, may now be more synthetically accessible using this robust radiolabeling approach.
However, while this versatile method enables organic transformations that are quite
challenging using traditional radiosynthetic techniques, replicating RCYs found in Cumediated radiohalogenation reports has been problematic since many of the protocols
have been carried out in a “manual” format[37]. Thus, in order to extend this radiolabeling concept to clinical applications, a dependable and reproducible Cu-mediated protocol
will be needed in order to tailor this method to automated radiosynthesis modules, due
to the high level of radioactivity in patient-scale PET studies. Moreover, these automated
synthetic and purication steps must also be in compliance with current Good Manufacturing Practice (cGMP) before translating this innovative radiosynthesis to the production
of PET tracers for clinical research in humans[54, 55]. Although much progress has been
achieved in Cu-mediated radiohalogenation of organoboranes, additional work in the
aforementioned areas must be achieved before this method can be used on a widespread
basis in radiosynthesis.
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F-uorination of aryl boronic esters provides eight radiotracers for PET applica-
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Chapter 10: Cu-Mediated Radiohalogenation of Organoboranes 339
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340 Handbook of Radiopharmaceuticals
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Chapter 10: Cu-Mediated Radiohalogenation of Organoboranes 341
Chapter 11
The Radiochemistry
ofZirconium
Jason P. Holland
Department of Chemistry, University of Zurich, CH-8057, Zurich,
Switzerland
11.1 INTRODUCTION
In the last two decades, the positron-emitting radionuclide zirconium-89
89
(
Zr, t
=78.41 hours) has been the subject of increasing fundamental and clinical
1/2
research activity centred around the development of radiolabelled antibodies, immunoglobulin fragments and other proteins for use in immuno-positron emission tomography
(immuno-PET). Interest in
preclinical and clinical studies, but also from the ease, eciency, and reproducibility of
the bioconjugation chemistry and radiochemistry required to make
tracers. Other advantages include the low cost of production, automated isolation from
the cyclotron target material (usually solid
radionuclide solutions across continents. This chapter explores some of the fundamental
properties of zirconium in aqueous environments, as well as the production, chemistry,
and radiochemistry associated with the synthesis of
89
Zr stems from the excellent image quality reported in both
89
Zr-labelled radio-
89
Y foils), and the possibility to ship stock
89
Zr-based radiotracers.
When asked to name one of the most abundant elements on Earth, most people
would be unlikely to suggest zirconium. Nevertheless, zirconium is the 18th most
abundant element in the Earth’s crust, with estimated concentrations in the range
13 0 –2 50 m g kg
(zirconium silicate, ZrSiO
Handbook of Radiopharmaceuticals: Methodology and Applications, Second Edition.
Edited by Michael R. Kilbourn and Peter J.H. Scott.
© 2021 John Wiley & Sons Ltd. Published 2021 by John Wiley & Sons Ltd.
−1
[1, 2]. The most prevalent minerals that contain Zr ions include zircon
) and zirconium dioxide (ZrO2). An interesting fact related to
4
nuclear chemistry is that in the geological sciences, zircon crystals play an important role
IZ
impure
K
2
4
1800
pure22
CO
22
4
(1743–1817)
(1779–1848)
in uranium-thorium-lead radiometric dating methods. Zircon crystals are exceedingly
hard (hardness of 7.5 on the Mohs scale) and are highly resistant to both mechanical and
chemical weathering. The relative concentrations of uranium, thorium and radiogenic
lead, and the analysis of ssion (or ion) tracks present in the zircon crystals allows geologists to estimate mineral ages from about 1 million years ago to over 4.4 billion years old
(the current estimated age of the Earth) with a precision of 0.1–1.0%.
Element 40 is a second-row d-block transition metal and resides in group 4 of the
Periodic Table. The rst discovery is credited to Martin Heinrich Klaproth in 1789, who
prepared ZrO
from zircon (Figure11.1a). The elemental form of Zr was allegedly isolated
2
by the prolic Swedish chemist Jöns Jacob Berzelius in 1824 (Figure11.1b). However,
due to the chemical similarities between zirconium and hafnium, pure forms of Zr were
not obtained until much later. The crystal bar process (also known as the thermal iodide
process or the Arkel-de Boer process) was invented by Anton Eduard van Arkel and Jan
Hendrik de Boer in 1925 (Eq.(11.1))[3].
K
)I Zr
870
2
Tungsten filament
rr(s) I
(11.1)
Subsequently, William J. Kroll invented the chloride process (also known as the Kroll
process) in 1940. This allowed pure forms of Zr(s) to be produced on large scales by adapting the methods used for isolating titanium (Eqs.(11.2) and (11.3)).
K
1200
OCCl ZrCl
(a)
Klaproth
(b)
22 2
Berzelius
~
(11.2)
Figure 11.1 (a) Engraving of the German chemist Martin Heinrich Klaproth
Source:Smithsonian Libraries. (b) Lithograph of the Swedish chemist Jöns Jacob
Berzelius Electronic images were obtained from the Smithsonian Libraries Digital
Collections (https://library.si.edu, accessed 16 January 2019). Source: Smithsonian
Libraries.
344 Handbook of Radiopharmaceuticals