Late-Stage Isotopic Carbon Labeling of Pharmaceutically Relevant Cyclic Ureas Directly from CO2

Article abstract of DOI:10.1002/anie.201804838

A robust, click-chemistry-inspired procedure for radiolabeling of cyclic ureas was developed. This protocol, suitable for all carbon isotopes (¹¹C, ¹³C, ¹⁴C), is based on the direct functionalization of carbon dioxide: the universal building block for carbon radiolabeling. The strategy is operationally simple and reproducible in different radiochemistry centers, exhibits remarkably wide substrate scope with short reaction times, and demonstrates superior reactivity as compared to previously reported systems. With this procedure, a variety of pharmaceuticals and an unprotected peptide were labeled with high radiochemical efficiency.

Full text of DOI:10.1002/anie.201804838

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
Chemie
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Accepted Article
Title: Late-stage isotopic carbon labeling of pharmaceutically relevant
cyclic ureas directly from CO2
Authors: Antonio Del Vecchio, Fabien Caillé, Arnaud Chevalier, Olivier
Loreau, Kaisa Horkka, Christer Halldin, Magnus Schou,
Nathalie Camus, Pascal Kessler, Bertrand Kuhnast, Frédéric
Taran, and Davide Audisio
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
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to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201804838
Angew. Chem. 10.1002/ange.201804838
Link to VoR: http://dx.doi.org/10.1002/anie.201804838
http://dx.doi.org/10.1002/ange.201804838

10.1002/anie.201804838
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Late-stage isotopic carbon labeling of pharmaceutically relevant
cyclic ureas directly from CO2
Antonio Del Vecchio,[a] Fabien Caillé,[b] Arnaud Chevalier,[a] Olivier Loreau,[a] Kaisa Horkka,[d] Christer
Halldin,[d] Magnus Schou,[d,e] Nathalie Camus,[a] Pascal Kessler,[c] Bertrand Kuhnast,[b] Frédéric Taran,[a]
Davide Audisio*[a]
Dedicated to Dr. Louis Pichat on the occasion of his 92nd birthday
often preferred to tritium because of a higher metabolic stability.
This natural radioisotope is generated as Ba[14C]CO3, which is
further converted to [14C]CO2, the universal precursor of all 14C
labeled compounds. Traditionally, [14C]CO2 functionalization
requires multi-step approaches and results in the production of
long lasting radioactive waste.7 Carbon-11 would be the most
general radioisotope for PET tracers but its narrow half-life
makes 11C labeled radiopharmaceuticals extremely challenging
to prepare.8 One major 11C primary precursor produced by
cyclotrons is [11C]CO2,9 an almost chemically inert molecule that
is not trivial to introduce directly into complex molecules as
pharmaceuticals. Due to such restrictions, the most frequently
used method for the introduction of 11C into organic molecules is
methylation.10 [11C]CO2 is transformed into a methylating agent
(typically [11C]CH3I or [11C]CH3OTf) by a series of reactions,
which are time and material consuming. Alternatives to
methylation are known but seldom applied to pharmaceutically
relevant molecules and biomolecules.11, 12, 13 The development of
methodologies capable of converting CO2 directly into the
desired scaffolds, in one single operation, at a late-stage of the
synthesis would be highly beneficial for the radiolabeling with
carbon isotopes.
Abstract:
A
robust, click chemistry inspired procedure for
radiolabeling of cyclic ureas was developed. This protocol, suitable
for all carbon isotopes (11C, 13C, 14C), is based on the direct
functionalization of carbon dioxide: the universal building block for
carbon radiolabeling. The strategy is operationally simple,
reproducible in different radiochemistry centers, exhibits
a
remarkably wide substrate scope with short reaction times, and
demonstrates superior reactivity compared to previously reported
systems. With this procedure, a variety of pharmaceuticals and an
unprotected peptide were labeled with high radiochemical efficiency.
Radioisotope labeling has a remarkable impact on our society
and particularly on public health: from the collection of precious
preclinical absorption, distribution, metabolism, excretion
(ADME) and toxicological data, required for drug development
and registration with long lived - isotopes,1 to the early
diagnosis of disease with non-invasive positron emission
tomography (PET) imaging with short lived + radiotracers.2
Late-stage labeling is the most effective strategy to introduce the
radioisotope into the desired organic molecule: allowing its
insertion at the last step of the synthesis it provides a beneficial
impact on the overall efficiency of the process. Recent
developments in late-stage tritium (3H)3,4 and fluorine-18 (18F)5,6
labeling clearly showcased the benefits of such an approach.
Carbon is ubiquitously present in nature and it is the overriding
choice for isotopic radiolabeling of pharmaceuticals and
agrochemicals. Two radioisotopes with diametrically opposite
physical properties are commonly used: carbon-14 (- emitter,
half-life 5730 years) and carbon-11 (+ emitter, half-life 20.4 min).
Carbon-14 is a favoured isotope in drug development and is
Urea is a fundamental functional group in organic chemistry
commonly found in pharmaceuticals and dyes (Scheme 1a).14
Despite its chemical and metabolic stability, no general and
efficient labeling protocol has been reported so far. Cyclic ureas
have been traditionally labeled using [11C and 14C]-phosgene,15
a highly toxic radioactive reagent, which can be synthesized only
in a rather limited number of laboratories on a routine basis.
More recently, a number of methods have been described using
carbon monoxide [11C and 14C]CO and metal catalysts or
16
selenium at high pressures (scheme 1b).11,
Alternatives
utilizing directly [11C and 14C]CO2 in presence of 2-tert-
butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2- diaza
phosphorine (BEMP) and POCl3 display limited functional group
tolerance.17
[a]
A. Del Vecchio, Dr. A. Chevalier, O. Loreau, Dr. N. Camus, Dr. F.
Taran, Dr. D. Audisio
In this communication, we describe a one-pot operationally
simple labeling procedure for the synthesis of cyclic ureas using
a sequential Staudinger/Aza-Wittig (SAW) approach directly
from [11C and 14C]CO2. This example of late-stage labeling
proved to be broad in scope, highly tolerant towards functional
groups, suitable for all isotopes of carbon and effective for the
labeling of drugs and an unprotected peptide.
Service de Chimie Bio-organique et de Marquage
CEA-DRF-JOLIOT-SCBM, Université Paris-Saclay
91191, Gif sur Yvette, France
E-mail: davide.audisio@cea.fr
Dr. F. Caillé, Dr. B. Kuhnast
UMR 1023 IMIV, Service Hospitalier Frédéric Joliot, CEA, Inserm,
Université Paris Sud, CNRS, Université Paris-Saclay, Orsay, France
Dr. P. Kessler
[b]
[c]
Service d’Ingénierie Moléculaire des Protéines
CEA-DRF-JOLIOT-SIMOPRO, Université Paris-Saclay
91191, Gif sur Yvette, France
[d]
[e]
K. Horkka, Prof. Dr. C. Halldin, Dr. M. Schou
Psychiatry Section, Department of Clinical Neuroscience Karolinska
Institutet,
S-171 76, Stockholm, Sweden
Dr. M. Schou
PET Science Centre, Precision Medicine and Genomics, IMED
Biotech Unit, AstraZeneca, Karolinska Institutet,
S-171 76, Stockholm, Sweden
Supporting information for this article is given via a link at the end of
the document.
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10.1002/anie.201804838
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Table 1. Optimization of the Staudinger/aza-Wittig with
stoichiometric CO2.
Entry
*CO2
Phosphine
Temperature
Time
Yield
(%)
1
2
3
4
5
6
7
8
[
[
[
[
[
[
[
[
13C]CO2
13C]CO2
13C]CO2
13C]CO2
13C]CO2
13C]CO2
14C]CO2
11C]CO2
PPh3
65 °C
25 °C
25 °C
25 °C
25 °C
25 °C
25 °C
25 °C
2h
2h
90
80
PPh3
PPh2Me
PPh2Me
PPhMe2
PPhMe2
PPhMe2
PPhMe2
2h
95
1h
84
1h
95
5 min
5 min
5 min
95
90[a]
79[b]
[a] radiochemical yield; [b] radiochemical conversion. Carbon-13 and -14
experiments were performed in presence of stoichiometric amounts of [13
C
and 14C]CO2; for carbon-11 labeling, precursor 1a and the phosphine were
Scheme 1. a) Relevant examples of cyclic ureas; b) synthetic strategies to
access radiolabeled ureas.
typically in a 100-fold excess compared to [11C]CO2 (see SI for details).
Encouraged by the exceptionally short time required to reach full
conversion, we next looked at its application to 11C-labeling. In
stark contrast to 14C, [11C]CO2 is generated using a cyclotron in
nanomolar amounts, thus forcing a complete modification of the
stoichiometry of the reaction and the use of 1a and phosphine in
large excess compared to [11C]CO2. We were pleased to
observe that this protocol was easy to implement and [11C]-2a
was obtained in 79% radiochemical conversion (RCC), without
need of CO2 trapping agents.19 The radiosynthesis was carried
out in automated modules and proved to be compliant with GMP
procedures.
At the outset, we aimed to develop a general approach to
radiolabel cyclic ureas and we reasoned that click chemistry
might be a source of inspiration. Azides play a central role in
click chemistry and the Staudinger ligation shows high substrate
compatibility and is effective even in complex biological media.18
The o-azidoaniline 1a was identified as an ideal building block.
When 1a was reacted in presence of a phosphine and CO2 the
resulting iminophosphorane undergoes an aza-Wittig reaction to
generate an intermediate isocyanate and subsequent
intramolecular nucleophile addition delivers the cyclized urea
product. Since in radiochemistry CO2 is the limiting reagent, the
optimization of the reaction was performed using a Tritec
manifold to precisely deliver stoichiometric amounts of 13C-
labeled gas (see SI for details). From preliminary screening
experiments, dimethylphenylphosphine (PMe2Ph) was identified
as a superior reducing agent (Table 1 and SI).
We next investigated the substrate scope in the presence of a
variety of substituted aromatic o-azido anilines, synthesized
according to literature procedures (Scheme 2).20 A whole range
of benzoimidazolones 2a-n were labeled in good to excellent
yields both with carbon-13 and carbon-11. Not surprisingly,
electron rich anilines proved to be competent substrates for the
transformation (2e-f). The presence of halogens (2b-d) and
sterically hindered substituents in ortho to the reactive azide (2i-
k) did not affect the transformation, while electron-withdrawing
groups allowed to obtain the product in moderate yields (2g and
2h).
When secondary anilines were used, the desired products 2l-n
were obtained in 52% to 78% yields for carbon-13 and 55% to
62% RCC for carbon-11. The use of simple, reproducible and
easy to implement protocols is highly desirable in radiochemistry
and particularly for positon emitters, where isotope manipulation
is restricted by the use of automated facilities. In this respect,
the current technology was successfully implemented in two
PET centers, with different automated systems, clearly
highlighting the robusteness of this protocol (see SI for details).
Compared to less nucleophilic and more sterically hindered
Ph3P and MePh2P (Table 1, entry 1-4), PMe2Ph was highly
effective delivering the desired benzoimidazolone 13C-2a in only
5 minutes at room temperature (see Table 1, entry 6 and SI for
more details). Solvent screening revealed that MeCN and DMF
were both suitable for the transformation. Under the optimized
reaction conditions in presence of radiolabeled [14C]CO2, 1a was
converted into the labeled urea 14C-2a in a remarkable 95%
radiochemical yield (RCY). It is worth noting that the
transformation required only a stoichiometric amount of [14C]CO2
and a single purification step, thus minimizing the radioactive
waste generated and representing
environmentally sustainable radiolabeling.
a
rare example of
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Scheme 3. Late stage labeling of aliphatic ureas with carbon isotopes. The
position of the azide on the o-azido aniline precursor is highlighted in bold. [a]
Isolated yield; [b] radiochemical conversion.
The promising functional group orthogonality of this approach
together with the successful implementation to both carbon-13
and carbon-11 prompted the evaluation of the isotopic labeling
of pharmaceutically relevant ureas (Scheme 4). Oxatomide, an
orally active antihistaminic, was labeled in 86% yield with
carbon-13 and 66% radiochemical yield (RCY) with 14C,21 while
11C-4a was obtained ready-to-inject in 45% RCY (molar activity:
75 GBq/µmol) within 30 minutes from the end of bombardment
(EOB). Domperidone, a commercially available antiemetic drug,
was successfully labeled in 57% RCY from [14C]CO2 and 43%
RCY from [11C]CO2. The 5-HT7 antagonist 4c, whose fluorinated
analogue was previously labeled with the short-lived PET
isotope fluorine-18,22 was obtained in 89% and 39% RCY
respectively using carbon-14 and carbon-11 isotopes.
Flibanserin, a medication approved for the treatment of pre-
menopausal women with hypoactive sexual desire disorder
(HSDD), was easily labeled in 64% and 48% RCY using carbon-
14 and carbon-11 respectively. Finally, CGP12177A, a tracer for
-adrenergic receptor was obtained in 35% isolated RCY and a
molar activity of 32 GBq/µmol. In comparison with the previously
reported
radiosynthesis
of
11C-CGP12177A
using
[11C]phosgene,23 the SAW approach afforded higher yields and
a shorter process without the use of hazardous chemicals. In all
cases, the ready-to-inject labeled drugs were isolated in high
chemical and radiochemical purities. In addition, the azide
precursors were easily synthetized in two linear steps from
commercially available anilines.
Scheme 2. Late stage labeling of benzoimidazolones with carbon isotopes.
The position of the azide on the o-azido aniline precursor is highlighted in bold.
[a] Isolated yield; [b] radiochemical conversion.
A variety of aliphatic ureas were also succesfully labeled using
this procedure. Six membered derivatives 3a-d were isolated in
good to excellent yields. Interestingly, the presence of the
guanine ring did not affect the efficiency of the transformation
(3e). Five membered derivative 3f was obtained in 51% and
99% with carbon-13 and -11, respectively. Notably, tricyclic urea
3g was obtained from the corresponding benzimidazole
precursor.
Scheme 4. Late-stage carbon isotope labeling of pharmaceutically relevant
ureas. RCY: radiochemical yield. The position of the azide on the o-azido
aniline precursor is highlighted in bold.
The use of radiolabeled peptides and proteins as imaging tools
for drug development and clinical diagnostics has recently
attracted considerable attention.24 In 2017, two major
contributions from Buchwald and Hooker24b using H[11C]CN as
labeled building block and from Antoni and Skrydstrup24c utilizing
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[11C]CO were reported. Both methods use efficient metal
catalysts for the insertion of the desired tag on series of peptides.
[5]
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Scheme 5. Late stage labeling of peptide 5. The position of the azide on the o-
azido aniline precursor is highlighted in bold. [a] Isolated yield; [b]
radiochemical conversion.
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sequence, we applied it to a designed peptide sequence bearing
the desired azido-amine group and most of the classical reactive
moieties displayed by amino acids (alcohols, carboxylic acids,
amine, indole). To our delight, we observed a very clean
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In conclusion, we have shown that a late-stage carbon labeling
Staudinger aza-Wittig reaction can access functionalized
molecules particularly challenging to obtain with conventional
procedures. The advantages of the current method are its
implementation to all isotopes of carbon (11C, 13C, 14C), a simple
and easy to reproduce protocol, a broad substrate scope
showcased by the labeling of drug candidates and a preliminary
insertion of the carbon tag into an unprotected peptide.
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Acknowledgements
This project has received funding from the European Union’s
Horizon 2020 research and innovation programme under the
Marie Sklodowska-Curie grant agreement N°675071. The
authors thank David-Alexandre Buisson and Elodie Marcon for
the excellent analytical support. We thank Dr. Catriona
Wimberley for kind proofreading.
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Keywords: Late stage isotopic labeling • Carbon-11 • Carbon-
14 • Heterocycles • Carbon dioxide
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COMMUNICATION
Antonio Del Vecchio,[a] Fabien Caillé,[b]
Arnaud Chevalier,[a] Olivier Loreau,[a]
Kaisa Horkka,[d] Christer Halldin,[d]
Magnus Schou,[d,e] Nathalie Camus,[a]
Pascal Kessler,[c] Bertrand Kuhnast,[b]
Frédéric Taran,[a] Davide Audisio*[a]
Page No. – Page No.
Label with a click: A click chemistry inspired Staudinger / Aza-Wittig approach to
carbon labeling was developed. This protocol, suitable for all carbon isotopes (11C,
13C, 14C), is based on the direct functionalization of carbon dioxide, the universal
building block for carbon radiolabeling. A variety of pharmaceuticals and an
unprotected peptide were labeled with high radiochemical efficiency.
Late-stage isotopic carbon labeling of
pharmaceutically relevant cyclic
ureas directly from CO2
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