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development of 15O-labeling strategies. Both radionuclides have short half-lives, resulting in three main inconveniences: (i) their use is restricted to organizations with access to
a cyclotron; (ii) rapid and ecient methods must be applied to the preparation of radiotracers to minimize radioactivity loss; and (iii) only fast processes can be investigated,
because the time window for image acquisition is short.
That said, the stable isotopes of nitrogen and oxygen are present in the majority of
biologically active molecules. Hence, a wide range of molecules can potentially be labeled
13
with
N or 15O. Additionally, the short half-life enables repeated experiments within
the same individual. These facts, combined with the development of smaller/cheaper
cyclotrons, may facilitate the incorporation of these radionuclides into the toolbox of
PET chemists. New strategies would help tackle the preparation of multi-radioisotopelabeled tracers as the driving force for the investigation of biologica processes, providing
crucial information on metabolism, mechanisms of diseases, and more.
The authors thank the Spanish Ministry of Science and Competitiveness for nancial
support (Project CTQ2017-87637-R).
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of [O-15]-H
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2
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142 Handbook of Radiopharmaceuticals
Chapter 7
Radiochemistry
withCarbon-11
Stephen Thompson, Steven Kealey, Selena Milicevic
Sephton and Franklin I. Aigbirhio
Molecular Imaging Chemistry Laboratory, Wolfson Brain Imaging
Centre, Department of Clinical Neurosciences, University of Cambridge, Cambridge, CB2 0SZ, UK
7.1 INTRODUCTION
7.1.1 History
In 1934, Lauritsen etal. found that when boron oxide was irradiated with deuterons, a
radionuclide with a half-life of 20 minutes was formed[1]. This was subsequently identied as carbon-11, formed by the
11
[
C]CO2 and [11C]CO[2]. In 1939, the 14N(p,α)11C reaction was rst described by Barkas[3],
whereby high-energy cyclotron-produced protons were bombarded on a nitrogen-14
target to produce carbon-11. Eighty years on, this remains the most common method
of producing
the world.
Carbon-11 decays into stable boron-11 and has a physical half-life of 20.4minutes.
Decay occurs primarily (99.8%) by positron emission, with the emitted positron having a
mean energy of 0.386 MeV and a mean range of 1.2 mm in water[4]. The remaining decay
(0.2%) occurs by electron capture. The utility of
tion is immediately obvious–the ubiquitous nature of carbon in biologically relevant molecules allows for a radioactive analogue (isotopologue) to be produced by substitution
of a stable
11
C and is used at positron emission tomography (PET) centres across
12/13
C for 11C. The rst chemical manipulation with 11C was reported by Long in
10
B(d,n)11C nuclear reaction and isolated in the form of
11
C as a radiolabel for biological applica-
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.
1939, in which [11C]CO2 was converted to potassium [11C]oxalate[5]. Later that year, Ruben
etal. reported the rst biological application of
ing photosynthesis[6]. The rst human experiments with
Tobias etal. with a study on [
11
C]CO uptake and bodily distribution following inhalation of
11
C in their study on [11C]CO2 uptake dur-
11
C were performed in 1945 by
the gas[7].
The availability of carbon-14 (half-life 5730 years) after World War II precipitated a
downturn in research activities with
cyclotrons in the 1960s and PET in the late 1970s has driven
11
C until the early 1960s. The emergence of medical
11
C radiochemistry research
to meet the demands for new or improved tracers at an expanding array of biological
targets[8]. This review chapter highlights core aspects of
11
C radiochemistry and notable
advances since the publication of the previous edition of Handbook of Radiopharmaceuticals in 2003[9].
7.1.2 Synthetic Considerations
In addition to the usual synthetic considerations, incorporation of cyclotron-derived 11C
into the molecule of interest is complicated by the inherent challenges of working with
radioactivity: i.e. need for shielding and automation, time restrictions, and small scale
of radiolabelling reactions with short-lived radionuclides. For a typical production of a
11
C-labelled PET tracer for clinical use, the radiosynthesis, purication, and quality control must be complete within approximately three half-lives (~1 hour) to have sucient
radioactivity in the nal dose for a successful PET scan. In practice, this restricts the
11
use of
requirement for rapid chemistry means a convergent synthetic approach is often pursued
in which the radiolabel is introduced late in the sequence, ideally in the nal step, to minimize loss of activity by radioactive decay.
occurring carbon (
1000 GBq· μmol
by
of
tunately, the nanomole amount of radiolabelling reagents lends itself to rapid chemical
reactions due to the large stoichiometric excess (10–1000 fold) of non-radioactive
reagents present in the reaction mixture (based on typical conditions involving 0.1–10 mg
of precursor with a molecular mass of 300 g·mol
reagent with a molar activity of 300 GBq·μmol
precursor eectively remains constant throughout the reaction, and the resultant pseudo
rst-order reaction kinetics allows reactions to occur within minutes.
C to centres with a cyclotron on-site, or to those centres in close proximity. The
The theoretical molar activity of
12/13
C) is 341 000 GBq· μmol−1. In practice, molar activities in the 100–
−1
range are observed for 11C-labelled tracers, meaning 11C is outnumbered
12/13
C in a ratio of ~1:1000. Even when accounting for isotopic dilution, the total amount
11
12/13
C +
C in the nal dose of a PET radiotracer is typically in the nanomole range. For-
11
C in the absence of isotopic dilution from naturally
−1
reacting with 10 GBq of 11C-labelling
−1
). Under these conditions, the amount of
7.1.3 Biological Considerations
The physical properties of carbon-11 are ideally suited to imaging biological processes as
its half-life is of a similar order of magnitude to many biological processes involving small
144 Handbook of Radiopharmaceuticals