Neutron activated ⁶⁴CuCl₂: a cost-effective probe for PET imaging of cancer

Copper-64 (t½ = 12.7 h., E.C. 45%, b- 37.1%, b⁺ 17.9%) is a promising radionuclide for positron emission tomography (PET) imaging which is generally produced by ⁶⁴Ni (p, n) ⁶⁴Cu reaction in a cyclotron. Despite excellent attributes of ⁶⁴Cu for PET imaging, the utility of this radioisotope is still limited to countries having good cyclotron facilities and excellent production logistics. We have explored the feasibility of using ⁶⁴Cu in the form of ⁶⁴CuCl₂, produced in medium flux research reactors by (n, γ) route, as a probe for tumor imaging by PET. The irradiation parameters (neutron flux and irradiation time) for production of ⁶⁴CuCl₂ with adequate specific activity and radionuclidic purity for use as a PET radiotracer were optimized by theoretical calculations using standard Bateman equations. The practicality of the approach was demonstrated by production of this radioisotope in several batches in the Dhruva reactor of our research centre. Exploring copper metabolism as an imaging biomarker, ⁶⁴CuCl₂ can directly be used as an effective probe for non-invasive visualization of tumors. The stability of ⁶⁴CuCl₂ under physiological conditions was assessed by detailed in vitro studies in mouse serum medium. The biological efficacy of ⁶⁴CuCl₂ was studied in C57BL/6 mice bearing melanoma tumors and Swiss mice bearing fibrosarcoma tumors. From theoretical calculations, it was demonstrated that it is essential to carry out the irradiation of ⁶³Cu at flux of ~1 × 1014 n.cm^-2.s^-1 for at least 2 days to produce ⁶⁴Cu with adequate specific activity and high radionuclidic purity. On irradiation of 13 - 22 mg of natural CuO target in the Dhruva reactor of our research centre, the activity of ⁶⁴Cu after radiochemical processing varied between 30 and 57 GBq (specific activity ~3 TBq/g), which is appreciably high for both preclinical as well as clinical studies. The results of the in vitro studies indicated that ⁶⁴CuCl₂ remained as ⁶⁴Cu2+ ion when incubated in mouse serum medium at 37 °C over a period of 24 h. The results of the biodistribution studies revealed significant tumor uptake (7.64 ± 1.71 %ID/g in melanoma, 6.54 ± 1.41 %ID/g in fibrosarcoma) within 4 h post-injection of ⁶⁴CuCl₂, with good tumor-to-background contrast. Owing to availability of several medium-flux nuclear reactors with good geographical distribution in different parts of the world, the promising results obtained in this study would set the stage for wide-scale utilization of neutron activated ⁶⁴CuCl₂ as a cost-effective probe for PET imaging. (author)