*3.3. Clinical Studies*

As early as in 1972, the absorption of copper was determined by the simultaneous administration of <sup>64</sup>Cu orally and <sup>67</sup>Cu intravenously to patients with Wilson's disease. The disease results in excess accumulation of copper in tissues, such as the liver and brain. However, in this study, copper radionuclides were administered in a simple cationic form [100]. Two decades later, following the promising pre-clinical results, the radioimmunoconjugate <sup>67</sup>Cu-2IT-BAT-Lym-1 was introduced to the clinics [101]. Then the phase I/II clinical trial of <sup>67</sup>Cu-2IT-BAT-Lym-1 was conducted, in an effort to further improve the therapeutic index of Lym-1-based radioimmunotherapy patients with B-cell non-Hodgkin's lymphoma (NHL). <sup>67</sup>Cu-2IT-BAT-Lym-1 provided good imaging of NHL and favorable radiation dosimetry. The mean radiation ratios of tumor to body and tumor to marrow were 28:1 and 15:1, respectively. Tumor-to-lung, -kidney, and -liver radiation dose ratios

were 7.4:1, 5.3:1, and 2.6:1, respectively. This <sup>67</sup>Cu-2IT-BAT-Lym-1 trial for patients with chemotherapy-resistant NHL had a response rate of 58% (7/12). No significant nonhematologic toxicity was observed. Hematologic toxicity, especially thrombocytopenia, was dose limiting [102]. Recently, there have been several new completed and ongoing clinical trials with <sup>67</sup>Cu radiolabeled compounds. These included the theranostic trial for pre-treatment dosimetry of somatostatin analog 64/67Cu-SarTATE [103] and peptide receptor radionuclide therapy using <sup>67</sup>Cu-SarTATE in pediatric patients [104,105].

The decay properties of <sup>67</sup>Cu were also explored in order to improve the patient management in the hospital, going into two critical steps further: demonstrating the therapeutic efficacy of <sup>67</sup>Cu-PRIT (pre-targeted radioimmunotherapy) and illustrating the usefulness of pre-targeted <sup>64</sup>Cu-PET as a predictive indicator of response to <sup>67</sup>Cu-PRIT [106]. The use of γ-emissions of <sup>67</sup>Cu at 184.6 keV (48.7%) and rarely 93.3 keV (16.1%) for SPECT imaging, assuming that the branching ratios of <sup>67</sup>Cu's γ-emissions are much higher than those of <sup>177</sup>Lu, is expected to provide higher imaging sensitivity [107,108]. It is relevant to underline the recent work on SPECT imaging with Derenzo phantom, to study SPECT image quality using <sup>67</sup>Cu [10]. The use of a medium energy (ME) collimator is typically recommended for <sup>177</sup>Lu, since its γ-ray has an energy of 208 keV, while for the 140 keV γ-ray emitted by 99mTc, the gold-standard radionuclide for SPECT imaging, the low-energy high-resolution (LEHR) collimator is recommended. As the γ-emission energy of <sup>67</sup>Cu (185 keV, Table 1) falls between these two aforementioned energies, the appropriate collimator for SPECT imaging with <sup>67</sup>Cu was found to be the ME collimator. Although there is a reduced image quality for <sup>67</sup>Cu and <sup>177</sup>Lu, these radionuclides are still considered adequate for tumor identification, suggesting that the post-treatment dosimetry is possible for <sup>67</sup>Cu-labeled radiopharmaceuticals as it is for <sup>177</sup>Lu [10].
