Custom carbon-14:Layout 1 14/1/10 19:57 Page 55
Radiolabelling
synthesis of the desired radiolabelled compound The synthetic route provides control over the
starting from a single C-14 atom precursor. specific labelling position allowing study of the
C-14 is a reactor-produced isotope requiring metabolic fate of different parts of a molecule, pro-
lengthy exposure of a nitrogen precursor to high viding confidence in the fate of the parent and
flux neutron beam (
14
N(n,p)
14
C reaction) fol- facilitating metabolite identification.
lowed by isolation and purification to barium [C-
14] carbonate for distribution. C–14 compounds may need
Given valuable C-14 starting material and the repurification
high cost of licensed radioactive waste disposal, it Compounds labelled with C-14 have a liability to
is imperative to carry out a practical trial run of the decompose under the influence of their own radia-
entire synthetic route with unlabelled reagents (the tion; termed radiolysis, this effect is independent of
overall radiochemical yield can be reduced dramat- chemical stability. The primary effect when the dis-
ically even if a small quantity of impurities are integrating radioactive atom transmutates results
present) prior to performing the radiosynthesis. in total disintegration of a single molecule and may
This demonstrates that the synthesis is practical produce reactive fragments. The secondary effect is
and minimises radioactive waste production. The from the H9252-radiation that may produce ions and
requirement for high specific activity often pre- radicals, which can react with other molecules or
cludes dilution with unlabelled material and thus interact with solvent if present. Knowledge of radi-
the radiochemist is typically working to prepare olysis is empirical and cannot be predicted with
~100mg of final product. confidence prior to synthesis of the compound.
Each labelling project is unique and while ideal- However, the effect of radiolysis can be mitigated,
ly the radiolabel would be introduced in the last but not eliminated, by storage at low temperature
synthetic step, in practice, as the label position is under an inert gas. Storage in a solvent in solution,
often required in the core of the molecule, the label such as ethanol, may help. Thus, there may be a
often has to be introduced early in the synthetic need for regular purity checks to ascertain if re-
sequence. The challenge for the radiochemist thus purification is required prior to the study. Purity
becomes one of synthetic chemistry: to devise the checks are especially important if studies are
most efficient route in terms of radiochemical yield planned over several months to ensure the materi-
and number of synthetic steps from barium car- al is within specification prior to each study.
bonate. Radiochemists start much further back in Discolouration is not necessarily an indication of
the synthesis than traditional medicinal chemists as decomposition as free radicals may get trapped in
basic building blocks must be freshly prepared and the crystal lattice leading to marked colouration
in any event must derive from C-14 barium car- with no impurities detectable. Figure 2
bonate. For example, synthetic reasons often dic-
tate use of simple single carbon precursors such as
potassium [C-14] cyanide as starting material.
The radiochemist may employ process type
chemistry, for example, when preparing aromatic
moieties. Consider the sequence to a fluo-
robenezene starting with barium carbonate ⇒ bar-
ium carbide ⇒ acetylene ⇒ benzene ⇒
nitrobenezene ⇒ aniline ⇒ fluorobenzene: six
steps each involving handling volatile radioactive
materials. Further complexity occurs when consid-
ering the additional issues of isomerism arising
from the position of the C-14 atom. In the case
above the aromatic moiety may have molecules
with differing numbers of C-14 atoms, depending
upon at which stage the carbon-14 is diluted with
unlabelled material. As a result this uniformly
labelled material will exhibit multiple mass ions in
the mass spectrometer. Detection sensitivity may
require a single mass ion and in this case an alter-
native route must be followed to produce singly
labelled material.
Drug Discovery World Winter 2009/10 55
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