Abstract:
To date, a wide variety of potential PET-apoptosis imaging radiopharmaceuticals targeting
apoptosis-induced cell membrane asymmetry and acidification, as well as caspase 3 activation
(substrates and inhibitors) have been developed with the purpose of rapidly assessing the response to
treatment in cancer patients. Many of these probes were shown to specifically bind to their apoptotic
target in vitro and their uptake to be enhanced in the in vivo-xenografted tumours in mice treated
by means of chemotherapy, however, to a significantly variable degree. This may, in part, relate to
the tumour model used given the fact that different tumour cell lines bear a different sensitivity to a
similar chemotherapeutic agent, to differences in the chemotherapeutic concentration and exposure
time, as well as to the different timing of imaging performed post-treatment. The best validated
cell membrane acidification and caspase 3 targeting radioligands, respectively 18F-ML-10 from the
Aposense family and the radiolabelled caspase 3 substrate 18F-CP18, have also been injected in
healthy individuals and shown to bear favourable dosimetric and safety characteristics. However,
in contrast to, for instance, the 99mTc-HYNIC-Annexin V, neither of both tracers was taken up to a
significant degree by the bone marrow in the healthy individuals under study. Removal of white
and red blood cells from the bone marrow through apoptosis plays a major role in the maintenance
of hematopoietic cell homeostasis. The major apoptotic population in normal bone marrow are
immature erythroblasts. While an accurate estimate of the number of immature erythroblasts
undergoing apoptosis is not feasible due to their unknown clearance rate, their number is likely
substantial given the ineffective quote of the erythropoietic process described in healthy subjects.
Thus, the clinical value of both 18F-ML-10 and 18F-CP18 for apoptosis imaging in cancer patients, as
suggested by a small number of subsequent clinical phase I/II trials in patients suffering from primary
or secondary brain malignancies using 18F-ML-10 and in an ongoing trial in patients suffering from
cancer of the ovaries using 18F-CP18, remains to be proven and warrants further investigation.
