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Radionuclide production

As from the beginning of the 2000s, a technological revolution dramatically modified the prospects of nuclear medicine.

This technological revolution was the introduction of PET imaging with 18FDG in the routine practice of nuclear oncology. At the same time a substantial progress has been achieved in radionuclide therapy development as well, especially in radioimmunotherapy and radiopeptide therapy. All these developments open large prospects both in diagnostic imaging and radionuclide therapy with the availability of a lot of carrier molecules which are currently evaluated in preclinical and clinical studies. Beyond oncology, new innovative radiopharmaceuticals are expected to be validated in the coming years, in cardiology and neurology.

In this context, some new needs show up for original and innovative positron, beta- and alpha-emitting radionuclides.

1- PET imaging

For PET imaging, fluorine-18 is undoubtedly the radionuclide of choice, due to its favourable radiophysical characteristics. A lot of new carrier candidates, including FLT, F-MISO, FES, F-choline and F-DOPA, have been clinically evaluated and some of them could be approvedjavascript:toggle_preview();
Mode prévisualisation for a routine use in the coming years. However, the short physical half life (110 minutes) of fluorine-18 requires its production in a cyclotron located at a short distance of each user centre. That’s why there is more and more interest for positron-emitting radionuclides with short half-lives but which can be produced in a generator and especially for [*gallium-68*] (physical half-life: 68 minutes) for which the father is germanium-68 (with a long half-life of 271 days). Such a generator 68Ge/68Ga has the great advantage to be used for a few months in a nuclear medicine department but germanium-68 needs to be produced in a cyclotron with a high intensity due to its low production yield.

Moreover, fluorinated molecules have a small size and consequently fast kinetics after intravenous injection, which is compatible with the relative short physical half life of fluorine-18. However, for larger carrier molecules, such as antibodies or more generally immunoconstructs, blood kinetics is much slower and maximal tumor accretion is observed relatively late, some days after intravenous injection. This time interval is not compatible with the 110 minutes half-life of fluorine-18. For this new imaging application named immuno-PET, new radionuclides with longer half-lives are needed. [*Iodine-124*] is a positron-emitting radionuclide with a physical half-life of 4.2 days which favorably fits with the blood kinetics of antibodies for immuno-PET imaging.

[*Copper-64*] (half-life: 12.7 hours) is another positron-emitting radionuclide of great interest which is also considered for routine production.

Another clinical application which needs some radionuclides with half-lives longer than that of fluorine-18, even for small molecules with fast blood kinetics, is the pre-therapeutic dosimetric calculation. For this application, the innovative approach consists in taking into consideration some pairs of positron- and beta-emitting radionuclides.

Given the present clinical routine use of iodine-131 and yttrium-90 for the labeling of immunoconstructs and peptides, the favorite pairs of radionuclides are iodine-124/iodine-131 and yttrium-86/yttrium-90. However, for the latter pair, a high energy gamma ray emitted at a high rate by yttrium-86 is a real drawback for the routine use of this radionuclide.

Another highly requested pair of radionuclides is copper-64/copper-67 due to the favorable characteristics of both radionuclides.

In cardiology, thallium-201 and technetium-99m MIBI (Cardiolite®) radiopharmaceuticals have been used in clinical practice for some decades, for the diagnosis of myocardial ischemia. However the low energy of the gamma rays emitted by these radionuclides requires an attenuation correction to be introduced which has some limitations. These limitations result in a relative high percentage of false positive results which can lead to some useless invasive coronarography procedures.

[*Rubidium-82*] is a positron-emitting radionuclide which behaves like thallium-201 and is taken-up by the myocardial muscle. The high energy (511 keV) annihilation photons allow to achieve a reliable attenuation correction. Consequently it has been clearly shown that the diagnostic specificity of rubidium-82 imaging is significantly higher than that of thallium-201 or technetium-99m MIBI SPECT imaging. Rubidium-82 has a very short physical half-life (75 sec) and is produced, in a generator, by decay of strontium-82 which has a 25.5 day physical half-life. This very short half-life of rubidium-82 allows to perform both rest and stress imaging tests in less than 30 minutes as compared with a few hours for thallium-201 or technetium-99m MIBI SPECT imaging.

Strontium-82/rubidium-82 generators have been used in the US for more than a decade but currently, the production capability of high activity of strontium-82 is seriously limited in the production centers. ARRONAX cyclotron, with a high energy/high intensity of proton beam will allow to produce up to 600 generators a year.

2- Radionuclide therapy

The three currently used radionuclides for therapy are iodine-131, yttrium-90 and lutetium-177. They cover a range of beta energy which fits well with the range of small tumor sizes which are appropriate for this treatment modality. However iodine-131 emits a relatively high percentage of high energy gamma rays which requires some medical staff radiation safety constraints including some confining of patients in shielded rooms for a few days. These constraints seriously limit the number of patients who could have benefit of radionuclide therapy. Moreover yttrium-90, a high energy beta-emitter, is taken up by bone/bone marrow after release from its chelator coupled to the carrier molecule resulting in bone marrow irradiation which limits the injected activity. Additionally yttrium-90 does not emit gamma rays for pre-therapeutic imaging and yttrium-86 has too high energy gamma rays for routine imaging.

A radionuclide with favorable radiophysical and biological characteristics is [*copper-67*] (physical half-life: 61.5 hours) which has been preclinically and clinically evaluated for more than 2 decades. As compared with iodine-131 and yttrium-90, copper-67 has shown the highest therapeutic index in a few clinical studies. However its industrial production has been, up to now, limited by the lack of high energy (70 MeV), high intensity (a few hundreds of microamps) cyclotrons necessary for the production of high activities for clinical studies. ARRONAX cyclotron will be able to produce such high activities.

Finally alpha-emitting radionuclides are being more and more considered for their use in alpha-therapy because of their high LET (Linear Energy Transfer) which gives a high killing effect especially for small clusters of malignant cells. A few alpha-emitting radionuclides are available, including astatine-211, lead-212/bismuth-212 and actinium-225/bismuth-213. ARRONAX cyclotron will produce [*astatine-211*] (physical half-life: 7.2 hours) for preclinical and clinical alpha-therapy studies.

Radionuclides priduced byARRONAX
Radionuclide Target Nuclear reaction Cross section (mbarns) Needed Energy (MeV)
64Cu Ni 64Ni(p,n) ≈ 675 15
68Ge Ga 69Ga(p,2n) ≈ 550
124I Te 124Te(p,n) ≈ 590 15
82r RbCl natRb(p,4n) ≈ 98
67Cu ZnO 68Zn(p,2p) ≈ 10 70