Pharmaceutical Manufacturing Handbook: Production and

86 RADIOPHARMACEUTICAL MANUFACTURING
going to change substantially the physicochemical properties of the molecule (reactivity,
hydrogen bonding, interactions with cognate receptors, metabolization, etc.).
It is not possible to assume that the biological behavior of a molecule and its fl uorinated
analog is going to be similar. On the contrary, it is advisable to fi nd substantial
differences in lipophilicity, biodistribution, protein binding, affi nity for receptors,
and so on. However, such modifi cations are in many cases very useful to permit the
use of a 18 F - fl uorinated analog as a PET radiopharmaceutical. In fact, that is the
case for the most widely use one: FDG. This compound, which accounts for probably
more than 90% of the PET studies performed in the world every day, is a glucose
analog that is taken up by the cells by GLUT transporters and metabolized just as
glucose at the very fi rst steps of glicolysis. But as a consequence of the change of
the C 2 OH group in natural glucose by a 18 F atom in FDG, the latter cannot be
isomerized (once phosphorilated) and suffers metabolic trapping being specifi cally
accumulated in tumoral cells.
Carbon - 11 has a very short half - life (just 20.4 min) but the chance to substitute
a carbon atom in any biological molecule by a positron - emitting 11 C is a very interesting
possibility. This has led to a substantial development of 11 C - labeled tracers.
The short half - life conditions everything and only PET centers equipped with a
cyclotron can have a clinical program with 11 C tracers. The production of the radiopharmaceutical
must in these cases be performed just before the imaging study and
is usually not started until the patient is already on the PET scanner.
The 12 11 C – C substitution will produce chemically identical molecules and give the
chance to study many biological processes by this noninvasive methodology and can
also be used in new - drug research and development (R & D).
Synthesis of PET Radiopharmaceuticals Albeit the requirements for the synthesis
of PET radiopharmaceuticals previously described, the synthesis process could conceptually
be reduced to a very simple scheme, as shown in Figure 6 .
The concept is really simple, but there are considerable diffi culties in each of the
steps. In many cases it is diffi cult to synthesize a properly designed cold precursor
that will permit a simple direct reaction with few secondary products. No modifi ca-
FIGURE 6 General reaction scheme for synthesis of PET radiopharmaceuticals. The precursor
molecule (A) is designed with the adequate protecting groups ( � ) and a reactive
leaving group ( Δ ). A reactive form of the radionuclide ( � ) is covalently joined to the precursor
at the reaction site, while the leaving group is eliminated. An intermediate radioactive
product (B) is obtained that is hence deprotected (2) to produce the fi nal radiopharmaceutical
(C). A fast and effi cient purifi cation process of C is needed to get read of unreacted cold
precursor, radionuclide, and intermediate products.