Automated production of copper radioisotopes and preparation of high specific activity [64Cu]Cu-ATSM for PET studies
Introduction
Molecular imaging is becoming an emerging technology for the assessment of tumour characterization, being potentially a very accurate method for assessing patient's prognosis and predicting treatment response. At present, a very important issue is to transfer such technology into a clinical environment, thus allowing the study of a significant population of patients and, at the end, establishing its usefulness and impact in oncology. One of the most promising molecular imaging methodology is positron emission tomography (PET) combined with copper labelled radiopharmaceuticals. Of particular interest are the copper radioisotopes 64Cu (t1/2=12.7 h; β− 40%; β+ 19%), 60Cu (t1/2=23.7 min; β+ 93%) and 61Cu (t1/2=3.32 h; β+ 60%). These radioisotopes may be used to label substrates potentially useful for hypoxia detection (Dehdashti et al., 2003a, Dehdashti et al., 2003b; Obata et al., 2003a). 64Cu, due to its relatively long physical half-life, may also be relevant for radiotherapy (Lewis et al., 2001; Obata et al., 2005; Dehdashti et al., 2008). Moreover, they have already been used to label peptides for the diagnosis of oncological (Weiner and Thakur, 2002) and non-oncological diseases (Sosabowsky et al., 2003). The production of copper radionuclides has been reported in the literature (Zweit et al., 1991; Szelecsenyi et al., 1993; Maziere et al., 1983; Zinn et al., 1994; Kozempel, 2007; Fukumura et al., 2004) using different cyclotrons, targets supports and enriched starting materials.
The demand of 64Cu in PET departments started to increase when it was clear that its production with high yield and with high specific activities using typical biomedical cyclotrons (with proton energy ranging from 11 to 18 MeV) was feasible in routine conditions. At present, the production method generally adopted for the production of the copper radioisotopes is the irradiation of gold disk foils, previously electroplated with enriched target isotopes (such as 60/61/64Ni) to generate the desired radionuclide through the general 60/61/64Ni(p,n)60/61/64Cu nuclear reaction using automated or semi-automated systems for their production and purification (McCarthy et al., 1997; McCarthy et al., 1999; Obata et al., 2003b; Avila-Rodriguez et al., 2007; Szajek et al., 2005). Although production yields and specific radioactivity of 64Cu have already demonstrated to be satisfactory for many applications, the critical point for a widespread diffusion of such a methodology is the actual lack of process automation, with special emphasis for target handling and radiopharmaceutical preparations. The target handling systems currently commercially available are manual as, the target mounting and, more important, the target recovery at the end of bombardment, always foreseeing one or more operations that have to be manually performed, thus implying a potentially very high irradiation doses to the operators, especially in view of a routine daily production. Our goal was to develop a new, dedicated and fully automated system for the production, the handling and the purification of radioactive metals which is flexible, easy to use, safe for the operators, reliable and reproducible and that can be applied to the production of copper as well as of other radionuclides.
The above automated system, called “Alceo”, was developed within a joint project of the radiochemistry group of the Hospital San Raffaele (Milan, Italy) and Comecer S.p.A. (Castelbolognese, Italy).
In this paper we report the preliminary results and experience on the production of copper radionuclides using a self-shielded cyclotron IBA Cyclone 18/9 MeV and the above mentioned Alceo system.
Section snippets
Materials and methods
High purity reagents were used for the preparation of the alkaline 60/64Ni bath used for electroplating. HCl (30%, Ultrapur) and HNO3 (60%, Ultrapur) were purchased from Merck S.p.A, Milano, Italy. NH4OH (28% ammonia in water, 99.99+%) was purchased from Sigma-Aldrich, Milano, Italy. NH4Cl (99.999%, Puratronic, Metals Basis) was obtained from Alfa Aesar GmbH, Germany. Isotopically enriched 64Ni (<0.00376% 58Ni; <0.00298% 60Ni; <0.0058% 61Ni; 0.135 62Ni and 99.858% 64Ni) and 60Ni (0.32% 58Ni;
Electrodeposition of target material
The proposed procedure for dynamic Ni electroplating was based on the hypothesis that it should be possible to obtain results comparable with those already described in the literature (McCarthy et al., 1997) for static electroplating by allowing the electrolytical solution to recirculate in a well defined volume of a cylindrical chamber. However, static tests were also performed. In Table 1 the results obtained with the static method using natural Ni are reported.
The data are quite comparable
Conclusions
With the use of the Alceo system it is possible to produce in an automated mode Cu radioisotopes and to apply them to the labelling of radiopharmaceuticals with high specific activities. Electroplating process, separation and radiosynthesis of [64Cu]Cu-ATSM have been well established. Further experiments to increase target yields and in particular to optimize the alignment of the beam on the target are in progress.
Acknowledgement
This work was supported by Research Grant MUR DM23455.
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