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Radiolabelling
CUSTOM CARBON-14
RADIOLABELLING
investing to meet new challenges
One consequence of an increasing demand from regulators for robust
quantitative data on the behaviour of new drugs in man and for information on
the fate of pharmaceuticals in the environment, has been an increase in demand
for carbon-14 labelled compounds. This article focuses on the new uses for
C-14 compounds, factors impacting on their preparation and how C-14 custom
labelling suppliers are responding to meet new demands.
W
hile traditional drug metabolism stud- more expensive than their non-labelled analogues
By Dave Roberts
ies continue to play a key role in for the reasons set out below. Taking short cuts in
understanding the pharmacokinetics, the radiolabelled synthesis may result in savings,
metabolism and ultimate fate of small molecules, however, these are often insignificant compared to
new technology has opened the door to study com- the cost of a study and may compromise the ulti-
pounds directly in man. Use of accelerator mass mate value of the information and data generated.
spectrometry (AMS) enables detection of very
small levels of C-14 allowing its use in humans at Carbon-14 for quantification
very low doses that pose no radiation risk. This, in Carbon-14 remains the isotope of choice as a
part, has led to new initiatives by the FDA and tracer being biologically equivalent to carbon-12,
EMEA encouraging fast track first-in-man studies. having a low background in the biosphere (1ppt:
Recent FDA guidance on the safety testing of 1 atom in 10
12
) and importantly facilitating easy
potentially toxic metabolites has provided another quantification. Its soft H9252-emission does not
growth driver for C-14. require shielding but is easily detectable allowing
Regulatory authorities require that studies fol- mass balance determination of the parent com-
low official guidance and meet statutory quality pound and importantly its metabolites (even of
standards such as GLP, GCP and GMP. When unknown structure) and gives good definition for
using a C-14 compound it is vitally important to autoradiography. Its half-life of 5,760 years
ensure there are no impurities present that may means it is unnecessary to correct for decay dur-
give the appearance of persistent drug residues, ing the experiment and provides good counting
lead to artefacts or spurious results. Such adverse efficiency using liquid scintillation counting
data may impact on a drug’s future marketability (LSC). Other advantages include minimal chance
and could lead to costly additional studies. of isotope exchange and minimal isotope effects
With increasing demand for quality C-14 com- on metabolic transformations.
pounds suitable for human studies, several of the The new accelerator mass spectrometer (AMS)
leading custom labelling suppliers have invested in technology relies upon the ratio of C-14/C-12 for
additional capacity, facilities, processes and analyt- quantification. AMS enables detection of very
ical capability. low levels of C-14, several orders of magnitude
Radiolabelled compounds are considerably below that of LSC, requiring a typical dose of
Drug Discovery World Winter 2009/10 53
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