Chemistry Reference
In-Depth Information
recent developments In the chemIstry
of [
18
f]fluorIde for pet
Dirk Roeda and Frédéric Dollé
CEA, I2BM, Service Hospitalier Frédéric Joliot, Orsay, France
3.1
IntroductIon
Molecular imaging in medicine and biology provides noninvasive views inside tissues of a living organism in order to obtain
information at the molecular level. In this endeavour, positron emission tomography (PET) has always tried to stay as close
as possible to the 'tracer principle' of George de Hevesy (Nobel prize 1943), which states that 'a radioactive atom might
be used as a “representative” tracer of stable atoms of the same element whenever and wherever it accompanied them in
biological systems.' The element fluorine, although as inorganic fluoride probably an essential element for humans, is not
known to play any role in human physiological processes in an organically bound form. Why then does the positron emitting
radioisotope fluorine-18 occupy such a prominent place in PET and associated radiochemistry [1], while
a priori
its principal
alternative carbon-11 has the potential to label any carbon-containing compound? There are several answers to this question,
but the convenience of the 110-minute physical half-life is preponderant. This time span is long enough to allow for relatively
elaborate radiochemical processing and short enough to ensure that the radiation dose to a patient is not too high. It also
makes distribution of radiofluorinated products possible over considerable geographical distances. Indeed, if fluorine-18 had
the half-life of carbon-11 (20 minutes), it most probably would not have the status it has today nor would carbon-11. A true
tracer, in the sense of de Hevesy, is however possible with fluorine-18 in the field of medicinal drugs and related compounds
that show a fluorine atom in their structure. The numbers of this type of substance are growing continuously, and a good deal
of
18
F-PET studies have been done with radiotracers based on it, notably in
in vivo
(neuro)receptor studies. An example is
the central benzodiazepine antagonist [
18
F]flumazenil (
1
) (Figure 3.1) [2].
But
18
F-PET does not stop there. A C-F entity in an organic molecule resembles sizewise a C-H or a C-OH group, and the
latter two can sometimes be replaced by a fluorine atom without changing too much the
in vivo
behaviour of the molecule,
especially where it concerns mechanisms of transport into tissue cells, and this in spite of the considerably greater electro-
negativity of fluorine. Three of the most successful PET radiopharmaceuticals are based on this design principle, namely
2-[
18
F]fluoro-2-deoxy-D-glucose (
2
) (C-H for C-
18
F in 2-deoxy-D-glucose or C-OH for C-
18
F in D-glucose), 3'-[
18
F]fluoro-
3'-deoxythymidine (
3
) (C-H for C-
18
F in 3'-deoxythymidine or C-OH for C-
18
F in thymidine) and 6-[
18
F]fluoro-L-DOPA (
4
)
(aromatic C-H for C-
18
F in L-DOPA). These tracers are used to measure glucose metabolism, cell proliferation and dopamine
storage respectively.
The third option in fluorine-18 radiopharmaceutical design, in addition to the above true labelling and mimicry of H or
OH, is to provide the molecule of interest with a prosthesis that can accommodate the fluorine-18 atom. This technique,
called prosthetic labelling, is first of all applied in the labelling of macromolecules (e.g., proteins, peptides, oligonucleo-
tides) but also in the derivation of small molecules such as in [
18
F]LBT-999 (
6
) (dopamine transporter ligand) [3, 4] and in
particular by the replacement of a methoxy- by a [
18
F]fluoroalkoxy group [5] like in [
18
F]DPA-714 (
7
) (TSPO ligand) [6-8]
