Compounds which are useful, in particular, for radiotherapy or i

Details Compounds which are useful, in particular, for radiotherapy or i Compounds which are useful, in particular, for radiotherapy or i

1988-12-15

1992-03-17

Lovering, Richard D.

Drug, bio-affecting and body treating compositions

Radionuclide or intended radionuclide containing; adjuvant...

436504, A61K 4300, A61K 4902

Patent

active

050966944

DESCRIPTION:

BRIEF SUMMARY
The technical field of the present invention is that of targeted therapy and of medical imaging, in particular of cancer.
The present invention relates especially to the treatment of disseminated cancers using targeted cytotoxic radioisotopes.
According to the invention, the target for the ionizing radiation administered is the DNA of malignant cells. The sterilizing effect of the radiation is due predominantly to the induction of double breaks in the DNA.
The use of radioisotopes which disintegrate emitting Auger electrons is very opportune for this purpose. Due to the short range of AUGER electrons, the efficacy of such radioisotopes in relation to cellular inactivity is completely lost when they are not linked to, or at the very most at a distance of a few atoms from, the DNA.
In contrast, such radioisotopes become very effective when they are linked to molecules that are incorporated in DNA or that bind to DNA.
.sup.125 I and .sup.80m Br have already been proposed for this purpose. However, .sup.125 I is not ideal for this application in vivo in view of its half-life of 60 days.
For example, the turnover of estrogen/estrogen receptor complexes takes place on a scale measured in hours and not in days, which means that only a small fraction of the radioactivity administered to the patient will reach the target cells at the appropriate time, and that the patient will be exposed needlessly to a large amount of radioactivity.
Bromine-80.sup.m, on the other hand, has a half-life of 4.4 hours, which makes it obligatory in practice to treat the patient in the immediate vicinity of the cyclotron. In addition, Br-80.sup.m produces only an average of 6 to 7 AUGER electrons per disintegration.
It has been discovered, according to the invention, that iodine-123, which has a half-life of 13.21 hours and produces about twenty AUGER electrons per disintegration, does not have the drawbacks of iodine-125 and of bromine-80.sup.m. Its half-life is sufficiently short for the patient not to be exposed needlessly to doses of radioactivity during an extended period, but is sufficiently long to enable radiopharmaceutical products to be synthesized and dispatched to treatment centers located far from the production cyclotron, taking into account the fact that up to 48 hours' journey time and 24 hours of treatment must be anticipated.
In effect, the maximum specific activities for one radioactive halogen atom incorporated per molecule are as follows:


______________________________________ for Br-80.sup.m 0 h 712,415 Ci/mmol ##STR1## 24 h 48 h 72 h 16,259 Ci/mmol 371 Ci/mmol 8 Ci/mmol for I.sup.123 0 h 237,292 Ci/mmol ##STR2## 24 h 48 h 72 h 67,373 Ci/mmol 19,129 Ci/mmol 5,431 Ci/mmol for I.sup.125 0 h 2,177 Ci/mmol ##STR3## 24 h 48 h 72 h 2,152 Ci/mmol 2,127 Ci/mmol 2,103 ______________________________________ Ci/mmol Ci (curie)
In addition, the activity decreases very rapidly after 72 hours for I.sup.123, whereas it persists with I.sup.125, allowing needless contamination.
Thus, the subject of the present invention is a compound which is useful, in particular, for the treatment by targeted radiotherapy or the imaging of cancer, which compound consists of a molecule capable of binding to or passing close to the DNA of target cells, the said molecule being radiolabeled with iodine-123.
As a molecule capable of binding to or passing close to the DNA of target cells, there may be mentioned nucleoside analogs, the nucleoside being substituted on its base with a radionuclide that emits I.sup.123 AUGER electrons, corresponding to the formula ##STR4## in which
B* denotes one of the substituted bases adenine, thymine, guanine, cytosine or uracil, labeled with a radionuclide that emits I.sup.123 AUGER electrons
R and R' denote H or a protective group such as acetyl or benzoyl.
Nucleoside analog is hence understood to mean a substance having the structure of a natural nucleoside but in which the base of the sugar portion can have an unnatural substitution.
These small-sized substances can enter the cell through

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