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Open access peer-reviewed chapter

Recent Advances of Copper-64 Based Radiopharmaceuticals in Nuclear Medicine

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Nasim Vahidfar, Mohsen Bakhshi Kashi, Saeed Afshar, Peyman Sheikhzadeh, Saeed Farzanefar, Yalda Salehi, Ebrahim Delpasand, Eóin N. Molloy, Siroos Mirzaei, Hojjat Ahmadzadehfar and Elisabeth Eppard

Submitted: 21 August 2023 Reviewed: 05 December 2023 Published: 05 January 2024

DOI: 10.5772/intechopen.1003993

Advances in Dosimetry and New Trends in Radiopharmaceuticals IntechOpen
Advances in Dosimetry and New Trends in Radiopharmaceuticals Edited by Otolorin Adelaja Osibote

From the Edited Volume

Advances in Dosimetry and New Trends in Radiopharmaceuticals

Otolorin Adelaja Osibote and Elisabeth Eppard

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Abstract

Copper radioisotopes including copper-60/61/62, and -64 exhibit a wide range of decay characteristics, making them appropriate choices for diagnostic/therapeutic (theranostic) applications in nuclear medicine. One notable feature of copper is the feasible coordination chemistry, which makes radiolabeling of a wide range of chemical structures including antibodies, proteins, peptides, and other biologically relevant small molecules possible. This chapter will summarize common radiopharmaceuticals of copper-64 and their radiation dosimetry in order to highlight recent improvements of positron emission tomography diagnostics.

Keywords

  • copper-64
  • radiopharmaceuticals
  • medical imaging
  • positron emission tomography
  • oncology

1. Introduction

Targeted nuclear imaging has significantly improved modern diagnostic methods and therapeutic procedures [1] by allowing for better imaging contrast, enhanced therapy effectivity, and reduction of radiation dose to the patients [2, 3]. Several classes of substances, including endogenous biomolecules, exogenous natural products, and synthetic molecules can be used practically as molecular probes for imaging or therapy [1]. Typically, molecular imaging is considered as a revolution in association with diagnosis and monitoring of disease [4]. Currently, positron emission tomography/computed tomography (PET/CT), alongside other diagnostic modalities, is well established, particularly given advances of PET/CT in terms of its superior resolution, sensitivity, and imaging quantification. These characteristics have made PET/CT a preferred method for molecular imaging [5, 6, 7]. In particular, copper radioisotopes have attracted much attention among PET radionuclides [8, 9]. Copper is an essential trace element in all living organisms [10, 11, 12, 13]. The available radioisotopes of copper, including copper-60 (60Cu), copper-61 (61Cu), copper-62 (62Cu), and copper-64 (64Cu), are appropriate for molecular imaging/or therapeutic applications (Table 1) [14].

RadioisotopeHalf-life (T1/2)Decay mode (abundance %)Energy (keV)SourceApplication
60Cu23.7 minβ+ (93)2940,3920CyclotronImaging
γ (7)511-467-826-1332
61Cu3.3 hβ+ (60)1220,1159CyclotronImaging
γ (40)511-283-589-656
62Cu9.7 minβ+ (98)2925CyclotronImaging
γ (2)511Generator
64Cu12.7 hβ+ (19)657CyclotronImaging/Therapy
γ (43)511-1346
β− (38.4)573
67Cu2.58 dβ− (100)575CyclotronTherapy

Table 1.

Physical characterization of copper radioisotopes [11]. β = Beta decay, γ = Gamma decay.

With a wide range of half-lives extending from 9.7 min to 12.7 h, copper provides a series of radioisotopes suited for diagnostic or therapeutic applications in nuclear medicine [13, 15]. Copper coordination chemistry has the ability to form complex compounds with many ligands including antibodies, peptides, proteins, and other relevant small molecules [14, 16]. The long half-life of 64/67Cu allows for sufficient accumulation of radiolabeled compounds in targeted organs, specific and proper uptake and, as a result, considerably higher contrast and image quality [14]. Each of the above-mentioned copper-based radioisotopes has variably preferable properties based on given applications. For example, the shorter half-life and higher positron decay fraction of copper-60 and -62 make them ideal radionuclides for imaging evaluation of radiotracers with faster pharmacokinetic procedures such as radiolabeled small molecules. In contrast, the longer half-life of 64Cu would be appropriate for radiolabeling of chemical structures, in order to formulate radiopharmaceuticals with slower pharmacokinetics, including radiolabeled peptides, nanoparticles, monoclonal antibodies (mAbs), antibodies, and higher molecular weight polypeptides [14]. While all copper radioisotopes are currently used in clinical applications, 64Cu has shown the most promising results in both preclinical and clinical studies [16]. In particular, the longer half-life of 64Cu (12.7 h) allows for the extension of the imaging period, which in turn compensates for lower sensitivity [9]. In a study assessing resolution, the “Derenzo” phantom application, demonstrated that PET imaging qualities with 64Cu are accurately comparable to fluorine-18 (18F) [17]. As 64Cu-radiopharmaceuticals for the evaluation of human morbidities are currently undergoing significant developments [18], this chapter will focus on 64Cu-radiopharmaceuticals that have been already approved for clinical trials or are close to being transferred to clinical settings (Table 2).

RadiopharmaceuticalsCondition or diseasePhaseLast update posted
60Cu————
61Cu————
62Cu[62Cu]Cu-ethylglyoxal bis (thiosemicarbazone)Renal failure2April, 2017 (Terminated)
64Cu[64Cu]Cu-ATSMRectal cancer2May, 2021
Cervical cancer2February, 2021
NSCLCN/AJuly, 2013
[64Cu]Cu-DOTA-TATENeuroendocrine tumors3July, 2019 (Approved for marketing)
[64Cu]Cu-DOTA-alendronateBreast carcinomaEarly 1November, 2021
[64Cu]Cu-DOTA-trastuzumabGastric cancerN/AMarch, 2021
Breast cancerN/AJanuary, 2021
[64Cu]Cu-RituximabNon-Hodgkin’s lymphomaN/AOctober, 2016
[64Cu]Cu-DOTA-ECL1iHead and neck cancer1December, 2021
[64Cu]Cu-LLP2AMultiple myelomaEarly 1August, 2021
[64Cu]Cu-SARTATENeuroendocrine tumors2May, 2021
[64Cu]Cu-SAR-bisPSMAProstatic neoplasms1August, 2021
[64Cu]Cu-DOTA-TLX592Metastatic prostate cancerEarly 1August, 2021
[64Cu]Cu-DOTA-pembrolizumabHematopoietic and lymphoid cell neoplasm1November, 2021
[64Cu]Cu-Macrin
[64Cu]Cu-NOTA-PSMAi-PEG-Cy5.5-C′ dotsSarcoid1September, 2021
[64Cu]Cu-FBP8Prostate cancer1September, 2021
Pulmonary embolism1July, 2019

Table 2.

64Cu radiopharmaceuticals list entered in clinical trials.

1.1 64Cu radiopharmaceuticals and their role in clinical studies

As it described above, 64Cu is a promising radionuclide that can be incorporated into many bio-conjugated chemical structures to further develop diagnostic and therapeutic agents with specific oncological indications [19]. The intermediate half-life of copper-64 (12.7 h) and its’ short positron range (comparable to fluorine-18) allow 64Cu to create high-resolution PET tracers [20, 21]. Hypoxia imaging agents based on bis(thiosemicarbazone) complexes radiolabeled with 64Cu have been used successfully for PET imaging of various types of tumors [22, 23, 24], blood flow [25], disease related to metabolism alterations [26, 27, 28, 29], and cell tracking [30]. Free [64Cu]CuCl2 can also been used as a valuable radiopharmaceutical for quantifying physiological biodistribution of Cu in associated disorders including Wilson’s and Menkes diseases in preclinical studies [29, 31], Alzheimer’s disease [32, 33], and cancer PET imaging (e.g., prostate cancer) [34]. Also, preclinical studies have shown the diagnostic efficiency of [64Cu]CuCl2 in a glioblastoma xenograft model [35]. Suitable visualization of the tumor by [64Cu]CuCl2 can provide a theory that supports the non-dependency of 64Cu complexes on ligands for tumor accumulations [35]. The following passages will discuss notable applications of 64Cu radiopharmaceuticals in accomplished clinical trials with the aim of clarifying new PET tracers’ roles in nuclear medicine.

1.2 Imaging tumor hypoxia

In circumstances under which cells are deprived of oxygen, hypoxia will occur and resistance to radiotherapy or chemotherapy and risk of invasion and metastases increases [11, 36, 37]. Hypoxia is a common condition in 50–60% of locally advanced solid tumors [11]. In addition to variable levels in different tumors, heterogeneity in a particular tumor tissue also can affect the reliable estimation of hypoxia [38]. Given a specific physiological state in hypoxia cells, they can be diagnosed with medical imaging modalities [39]. As a result, there are various PET tracers, which specifically detect hypoxia in humans [40, 41, 42]. In a series of ex-vivo studies, Fujibayashi et al. initially identified the critical role of the lipophilic radioactive copper (II) complex of the N2S2 ligand termed [62Cu]Cu-ATSM, specifically in relation to selective accumulation in hypoxia cells [43, 44]. Later, in-vivo studies demonstrated further that copper radiolabeled ATSMs have high specificity and selectivity as tracers for the detection of tumor hypoxia [45, 46, 47, 48, 49]. Despite the fact that the exact localization mechanism of Cu-ATSM is still not fully understood, theoretical evaluations suggest that Cu-ATSM can passively diffuse through cell membranes due to its high permeability. Moreover, due to the low redox potential of the tracer, it can be trapped constantly following the reduction process in hypoxic cells [14]. This reduction can only occur in hypoxic cells given that the abnormally reduced state of their mitochondria is not common in normoxic cells [43].

In a comparison study by Lewis et al., [64Cu]Cu-ATSM, [64Cu]Cu-PTSM, and [18F]F-MISO were identified as the most promising tumor hypoxia radiopharmaceuticals while also showing that the former ([64Cu]Cu-ATSM), exhibits heterogeneous oxygen concentration-dependent accumulation in different cells compared to the more stable uptake of the [64Cu]Cu-PTSM and [18F]F-MISO [50]. Also, [64Cu]Cu-ATSM presented faster clearance from normal tissues compared to the other tumor hypoxia tracers [51]. All in all, previous data show that PET/CT utilizing [64Cu]Cu-ATSM is a reliable and non-invasive imaging method that can accurately map hypoxic areas [52, 53]. In a clinical study of 10 cervical cancer patients, results showed that the signal-to-noise ratio was superior for [64Cu]Cu-ATSM was superior to [60Cu]Cu-ATSM. Consequently, [64Cu]Cu-ATSM has been proposed as a safe radiopharmaceutical that can be used to achieve high-quality imaging in tumor hypoxia cases [54]. Moreover, these data also showed that imaging reproducibility is feasible for up to 9 days. Accordingly, the authors concluded that [64Cu]Cu-ATSM is an ideal radiotracer for chronic tumor hypoxia rather than as an acute condition [55].

Furthermore, in a case report on a glioblastoma multiforme (GBM) patient, the authors observed accumulation of [64Cu]Cu-ATSM from early acquisition to late acquisition in hypoxia sites as well as high correlation between 64Cu-ATSM PET/CT results and HIF-1α expression as a hypoxia marker [56]. Feasibility of 64Cu-ATSM PET/CT in both cervical cancer and lung cancer has also been previously demonstrated [57, 58, 59], while in a comparative clinical study in 11 patients with head and neck cancer treated with chemoradiotherapy, the efficacy of [64Cu]Cu-ATSM and [18F]FDG was evaluated [60]. According to the findings of [64Cu]Cu-ATSM in seven patients, nodal metastases were detected and 22 cancer foci were identified in total calculated amounts for sensitivity and specificity of [64Cu]Cu-ATSM based on evaluated SUVmax were 100 and 50% and the same estimation considering the volume were 100 and 33%, respectively [60]. In conventional theories accumulation mechanism of [64Cu]Cu-ATSM was interpreted based on 64Cu(II) oxidation state [43, 61]. It was proposed that 64Cu(II) be reduced to 64Cu(I) by NADH/NADPH under the hypoxia circumstances. According to the lower stability of 64Cu(I) compared to 64Cu(II) dissociation of the [64Cu]Cu-ATSM results in H2-ATSM and free Cu ions [50]. However, the exact reduction process is under debate until now. Colombié et al. reported that the functional mechanism of [64Cu(II)]-Cu-ATSM is related to redox potential and formation of reactive oxygen species which can appear under the hypoxia cellular condition [53]. Further studies suggest that the accumulation of [64Cu(II)]-Cu-ATSM is not mediated depending on the oxygen pressure of the tumors [62]. In sum, these results show a comparable efficacy between [64Cu]Cu-ATSM and [18F]FDG PET/CT in the estimation of biological tumor volume (BTV), while clarifying that [64Cu]Cu-ATSM has higher sensitivity and lower specificity in predicting neoadjuvant chemoradiotherapy responses [60].

1.3 Tumor targeting by radiolabeled antibodies

1.3.1 [64Cu]Cu-trastuzumab

Epidermal growth factor receptor (ErbB) is composed of four closely related members including ErbB-1 (HER1 or epidermal growth factor receptor, EGFR), ErbB-2 (HER2), ErbB-3 (HER3), and ErbB-4 (HER4). HER1, HER3, and HER4 bind to approximately a dozen of different ligands while HER2 has no specific ligand [63, 64]. Previously, it has been demonstrated that HER2 is activated through dimerization with other HER derivatives. This complex will subsequently activate intracellular signaling pathways of MAPK (mitogen-activated protein kinase) and PI3K (phosphoinositide 3-kinase) [65]. These pathways are responsible for tumor growth, invasion, migration, and survival while gene coding associated with breast cancer can amplify 15–20% of them [66, 67]. Gene amplification or protein overexpression are notable criteria for the candidacy of breast cancer patients from primary to metastatic stages for HER2-directed therapy [63]. Trastuzumab is confirmed as the first-line of a therapeutic plan for HER2-positive in advanced breast cancer [68]. Trastuzumab is a humanized antibody that binds to the extracellular domain of HER2 and inhibits the proliferation progress [69]. It was demonstrated as a remarkable point that [64Cu]Cu-trastuzumab can be used for pretreatment assessment of breast cancer. Since measurements of [64Cu]Cu-trastuzumab uptake in lesions is a very promising criterion of patient selection for treatment procedures [63]. In a clinical trial performed of five HER2-positive breast cancer patients, results indicated that [64Cu]Cu-trastuzumab PET/CT scan is a safe and feasible for non-invasive and serial detection of HER2 status in metastatic brain tumors [70]. Based on clinical trials, [64Cu]Cu-trastuzumab can be efficient for the diagnosis of metastases related to other malignancies [71]. For instance, radiolabeled trastuzumab can be mentioned as a standard tracer for HER2-positive gastric or gastro-esophageal junction cancer patients [72]. Moreover, a recent clinical trial compared [64Cu]Cu-NOTA-trastuzumab in a HER2-positive primary gastric cancer patient with liver metastases, to [18F]FDG [73] with results showing comparable outcomes. Specifically, six liver metastases >1 cm were identified by both detection radiopharmaceuticals. Two metastases <0.5 cm were detected only with [18F]FDG and were not easily identified with [64Cu]Cu-NOTA-trastuzumab [73]. However, SUVmax of [64Cu]Cu-NOTA-trastuzumab in the primary lesion was estimated 28.6 ± 0.50 versus 13.5 ± 0.30 for [18F]FDG [73]. Based on comparable clinical results between [18F]FDG and [64Cu]Cu-trastuzumab attained by these data, it can be argued that further clinical evaluations of [64Cu]Cu-trastuzumab are needed.

1.3.2 [64Cu]Cu-rituximab

Rituximab (RTX) is a chimeric human/murine mAb that targets CD20 positive B-cell malignancies and has been used for immunotherapy of patients with non-Hodgkin’s lymphoma (NHL) [74, 75]. Radiolabeling of RTX with (β−/β+) emitters could augment the antibodies’ theranostic activity. In this regard, 64Cu-labeled RTX ([64Cu]Cu-DOTA-rituximab) as a PET imaging agent could be used to track the progress of NHL treatment [75]. The ongoing pre-clinical trial using [64Cu]Cu-DOTA-rituximab PET/CT was established to determine the tracers’ pharmacokinetics, biodistribution, stability, uptake, and radiation dosimetry in CD20-positive B-cell NHL patients compared to the [18F]FDG PET/CT [76]. Following this study, Natarjan et al. reported validated production of [64Cu]Cu-rituximab under good manufacturing practices (GMP) in order to clinical indication for the diagnosis of CD20 positive B-cell non-Hodgkin lymphoma [75]. Finally based on strong evidences efficacy of [64Cu]Cu-rituximab in detecting of B-cells in a murine model of MS was confirmed [77]. This achievement can be very hopeful in detection or even early diagnosis of MS in patients who respond to anti-B-cell therapies.

1.4 Tumor targeting by radiolabeled somatostatin derivatives: [64Cu]Cu-DOTA-TATE, and [64Cu]Cu-DOTA-TOC

Somatostatin receptors (SSTR) have been reported as qualified targets for the evaluation of neuroendocrine tumors (NETs) [78]. After [68Ga]Ga-DOTA-TATE, which was introduced as a gold standard for diagnosis purposes of NETs, it was hypothesized that 64Cu would be superior for radiolabeling of somatostatin derivatives [78]. The physical properties of 64Cu compared to 68Ga, including longer half-life (12.7 h versus 67.7 min for 68Ga), and shorter positron range (1 mm versus 4 mm), makes 64Cu more accessible radionuclide with higher spatial resolution for clinical studies [79]. Various comparative studies have been performed to clarify the emphasis of radiolabeled somatostatin derivatives with 64Cu. In a clinical trial study of 59 NET patients carried out by Johnbeck and colleagues, the authors compared diagnostic results derived from [68Ga]Ga-DOTA-TOC and [64Cu]Cu-DOTA-TATE PET/CT radiopharmaceuticals [78]. Results showed that 701 lesions were concordantly recognized with both radiopharmaceuticals. However, in detection of 68 lesions, there were no correlation between the [68Ga]Ga-DOTA-TOC and [64Cu]Cu-DOTA-TATE. Forty-two lesions were detected only by [64Cu]Cu-DOTA-TATE, of which 33 were found to be true positives. Moreover, only 26 lesions were found with [68Ga]Ga-DOTA-TOC, of which seven were true positive [78]. These results demonstrated that [64Cu]Cu-DOTA-TATE exhibits higher specificity and sensitivity compared to [68Ga]Ga-DOTA-TOC [78].

Further studies have confirmed that [64Cu]Cu-DOTA-TATE’s role as a safe imaging protocol in providing of accurate and high-quality images for diagnosis, treatment, and follow-up of NETs [80, 81, 82, 83]. In accomplished comparative clinical studies for [64Cu]Cu-DOTA-TATE, [99mTc]Tc-HYNIC-octreotide, and [111In]In-DTPA-OC, superiority of [64Cu]Cu-DOTA-TATE in the diagnosis of NETs was demonstrated [82, 84]. [64Cu]Cu-DOTA-TATE is the most appropriate choice for the diagnosis of NETs due to robust manufacturing with no need for regional generators, and a longer half-life allowing a wide geographical range for commercial distribution. This drug was approved in September 2020 by FDA and is now commercially available in the USA. Figures 1–3 display detection rate of [64Cu]Cu-DOTA-TATE in NETs. In a clinical trial [64Cu]Cu-MeCOSar-Tyr3-octreotate ([64Cu]Cu-SARTATE) was applied in [68Ga]Ga-DOTA-TATE positive NET patients [85]. A significant advantage of this radiopharmaceutical compared to [68Ga]Ga-DOTA-TATE is the higher stability of sarcophagine (Sar) linker versus DOTA. The concluded results showed comparable diagnosis visualization in 9 of 10 patients in 1 h imaging. In one patient a liver lesion was missed by [64Cu]Cu-SARTATE. However, the imaging obtained in 24 h, demonstrated the diagnostic superiority of [64Cu]Cu-SARTATE compared to [68Ga]Ga-DOTA-TATE [85].

Figure 1.

Physiologic uptake is seen in the pituitary, salivary, and lacrimal glands, liver, spleen, GI tract, adrenals, kidneys, and urinary bladder. Mild & diffuse bone marrow uptake or focal activity in the pancreas might occur as normal physiologic variants (e.g., uncinate process of the pancreas). (Courtesy of Courtesy Ebrahim Delpassand, MD RadioMedix, Inc. Houston, TX, USA).

Figure 2.

53-year-old female with newly diagnosed neuroendocrine tumor in the terminal ileum. The red arrow points to the primary tumor. The blue arrow points to the uncinate process uptake, which is a normal physiological variant. (Courtesy Ebrahim Delpassand, MD, RadioMedix, Inc. Houston, TX, USA).

Figure 3.

49-year-old male with pancreatic neuroendocrine tumor. On the fused [64Cu]Cu-DOTA-TATE PET/CT images a [64Cu]Cu-DOTA-TATE avid lesion is noted in the pancreatic tail. Also, multiple hypodense [64Cu]Cu-DOTA-TATE avid lesions are noted in both liver lobes suggesting metastatic involvement. (Courtesy Courtesy Ebrahim Delpassand, MD RadioMedix, Inc. Houston, TX, USA).

Several somatostatins analogs radiolabeled with SPECT and PET radionuclides have been evaluated in clinical trials to ascertain a possible gold standard for the diagnosis and treatment of NETs [86]. To date, 68Ga radiolabeled somatostatin derivatives including DOTA-TOC, DOTA-TATE, and DOTA-NOC (Figure 4) have shown promising results as diagnostic radiopharmaceuticals for NETs [78]. Recently, it was also demonstrated that 64Cu radiolabeled somatostatin analogs have advantages compared to former radiopharmaceuticals, some of which are discussed previously. In a retrospective study, 33 patients with NETs who had surgically removed primary lesions, underwent [64Cu]Cu-DOTA-TOC PET/CT scan [87]. Five patients exhibited no detectable pathological lesion in PET/CT scan, while eight showed enhanced uptake at the skull base, and 20 presented at least one pathological lesion [87]. Based on this clinical trial, it was concluded that [64Cu]Cu-DOTA-TOC PET/CT scan can differentiate NET lesions with a feature of high target-to-background contrast [87]. Interestingly, these findings also correlated with [177Lu]Lu-DOTA-TATE results obtained from a follow-up assessment in another patient’s group [87]. Further studies on larger populations are needed to identify the most appropriate somatostatin derivative for NETs diagnosis in radiolabeling with 64Cu. As an example, (Figure 5) displays the detection rate of [64Cu]Cu-DOTA-TOC in NET of the bladder.

Figure 4.

Chemical structures of DOTA-TOC (top), DOTA-TATE (middle), and DOTA-NOC (bottom).

Figure 5.

68-year-old male patient with a neuroendocrine tumor of the bladder (G3) with multiple pelvic LN and bone metastases. Additionally, we see the primary tumor in the bladder with infiltration into the surrounding tissue. [64Cu]Cu-DOTA-TOC (179 MBq) PET/CT. (Courtesy of Clinic Ottakring, Institute of Nuclear Medicine with PET-Center, Vienna, Austria).

1.5 Tumor targeting by radiolabeled PSMA ligands

1.5.1 [64Cu]Cu-PSMA-617

Previous studies have been demonstrated that prostate-specific membrane antigen (PSMA) is over expressed in prostate cancer (PCa) [88], suggesting that PSMA can be used as a potent tumor marker for PCa, as well as a vital target for imaging and therapy [88]. Among the recognized radiolabeled PSMA inhibitors, it has been shown that [68Ga]Ga-PSMA-11 is highly effective as a PET tracer for the detection of PCa [88]. Furthermore, PSMA can also be radiolabeled with 64Cu, offering a longer half-life and higher spatial resolution [89]. In a comparative clinical trial, the biodistribution of [64Cu]Cu-PSMA-617 and [68Ga]Ga-PSMA-11 were assessed in PCa patients [89]. Diagnostic results showed that both radiopharmaceuticals show similar biodistribution, except the excretion route, in which [64Cu]Cu-PSMA-617 excreting takes place through the gastrointestinal tract rather than the renal excretion of [68Ga]Ga-PSMA-11 [89]. The low metabolic rate of PCa cells leads to negligible uptake of [18F]FDG in PCa. [18F]FDG accumulates based on glucose consumption and as a consequence of the mentioned fact unacceptable specificity of [18F]FDG for the detection of PCa is raised [90, 91, 92]. However, it has also been demonstrated that [18F]FDG is useful for selected PCa patients with hormone-resistant poorly differentiated cell types [93, 94, 95].

Choline is an essential precursor for phospholipid synthesis of membranes in normal cells and based on the proliferation rate, uptake of choline increases mainly in cancerous cells [96, 97]. [18F]F-choline ([18F]FCH) PET/CT has been used for the detection of PCa widely during the last decade and optimistic results have been achieved [90]. It assessed that [18F]FCH PET/CT is useful for detection of local and distant nodal recurrence and bone metastases [90, 98, 99, 100]. In another cohort study, the efficacy of [64Cu]Cu-PSMA-617 and [18F]FCH PET/CT was compared [101]. This study, conducted on 43 patients, assessed restaging after biochemical recurrence [101]. In terms of detection rate, results indicated no statistically significant differences. However, [64Cu]Cu-PSMA-617 showed better performance with overall positivity at 74.4% compared to 44.2% for [18F]FCH [101]. This retrospective study demonstrated that [64Cu]Cu-PSMA-617 is promising in the prediction and assessment of recurrent sites relative to other PET tracers [101].

In another clinical trial performed by Grubmuller et al., it was shown that [64Cu]Cu-PSMA-617 has high potential as a PET tracer in detection of recurrent cases or progressive local lesions in primary staging of PCa patients [102]. In comparison to [68Ga]Ga-PSMA-11, higher image quality resulting from higher image contrast and superior uptake for [64Cu]Cu-PSMA-617 was shown, suggests the latter as an appropriate radiopharmaceutical compared to conventional PCa radiotracers [102]. Subsequently, [64Cu]CuCl2 has also been reported as an applicable diagnostic tracer for PCa [34, 103]. Cu is an essential requirement for normal cells in signaling transduction pathways of proliferation processes [104]. So increased uptake of Cu in aggressive uncontrolled cancerous prostate cells with a high proliferation rate would be inevitable [103]. In a previous study 50 patients with biochemical relapse PCa after surgery or external beam radiation therapy went through [64Cu]CuCl2 and [18F]F-choline PET/CT scans [34], results indicated that biodistribution of [64Cu]CuCl2 is more appropriate for exploring the prostate and pelvic bed. Finally, it was shown that in patients with relapsed PCa and low levels of PSA, [64Cu]CuCl2 has a higher detection rate compared to [18F]F-choline [34]. In sum, it can be argued that [64Cu]CuCl2 is a suitable tracer for the primary staging of PCa and regional lymph nodes [103]. However, based on high diagnostic accuracy, [64Cu]Cu-PSMA-617 has been suggested in both primary staging in patients with progressive local disease and recurrent cases [102, 105, 106].

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2. Pre-clinical and clinical dosimetry results of 64Cu-radiopharmaceuticals

Table 3 shows the results of the injected dose level and the estimated absorbed doses and organs at risk in 64Cu radiopharmaceuticals. Based on previous studies on 64Cu-radiopharmaceuticals, injected dose levels for patients were between 105 and 192 MBq which is about half of [18F]FDG dose and provided acceptable image quality. The calculated effective absorbed dose for the total body with 64Cu-radiopharmaceuticals in human studies or in animal studies indicated a range of 0.01–0.06 mSv/MBq. In the case of radiation potential hazards, these ranges are within an acceptable level and lower than other similar radiopharmaceuticals.

PharmaceuticalDose (MBq)Average effective dose (mSv/MBq)Study typeOrgans with highest absorbed dose (mGy/MBq)Ref.
[64Cu]Cu-DOTA-trastuzumab115–1360.036 ± 0.009
(mean: 4.5 mSv)		PatientHeart: 0.340[71]
Liver: 0.237
Spleen: 0.142
[64Cu]Cu-NOTA-trastuzumab3.7—Animal/Monte Carlo simulationHeart: 0.048[107]
Liver: 0.079
Spleen: 0.047
[64Cu]Cu-PSMA-61718.7* 119–160#0.0292Animal/patientGallbladder wall: 2.04[108]
Liver: 0.014
Kidney: 0.009
[64Cu]Cu-DOTA-TATE193–2320.0315PatientPituitary gland: 0.19[109]
Liver: 0.16
Kidneys: 0.14
[64Cu]Cu-DOTA-pembrolizumab7.40.004AnimalaLiver: 0.032[110]
Red marrow: 0.018
Lungs: 0.010
[64Cu]Cu-TETA-OC107–130#0.013Animal/patientBladder wall: 0.25[111]
Liver: 0.092
Kidneys: 0.078
[64Cu]Cu-DOTA-AE105197–2130.0276HumanLiver: 0.175[112]
Kidney: 0.0562
[64Cu]Cu-DOTA-alendronate37–740.0418AnimalbLLI wall: 0.159[113]
ULI wall: 0.113
Kidneys: 0.108
[64Cu]Cu-Cl24.0 MBq/kg0.051 (m)HumanLiver: 0.310 (m)[114]
Liver: 0.421 (f)
0.061 (f)LLI wall: 0.153 (m)
LLI wall: 0.161 (f)
[60/61/62/64Cu]Cu-ATSM48010.0111Animal/patientscLiver: 0.0641[115]
0.0292Liver: 0.2752
0.0033Liver: 0.0173
0.0364Liver: 0.3904
[64Cu]Cu-SARTATE1920.0454HumanSpleen: 0.361[85]
Kidneys: 0.202
Adernals: 0.169
[64Cu]Cu-DOTA-Rituximab7.40.024AnimalbSpleen: 0.098[76]
Liver: 0.051
Osteogenic cells: 0.042

Table 3.

Injected dose level, estimated absorbed doses, and organs at risk in [64Cu]Cu-radiopharmaceuticals.

LLI wall: lower large intestine wall.


ULI wall: upper large intestine wall.


m: men.


f: women.


mice.


patient.


copper-60.


copper-61.


copper-62.


copper-64.


based on ex-vivo biodistribution and PET/CT images.


estimation for humans.


dose estimation for human based on copper-60.


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3. Conclusion

The number of developing 64Cu labeled radiopharmaceuticals is growing. The most considerable characteristics of 64Cu include a longer half-life and superior image quality, resulting in high image contrasts, robust centralized manufacturing, and wider geographical range of distribution and ease of use by the end user. These characteristics have led to the introduction of novel and promising 64Cu radiopharmaceuticals in both pre-clinical and clinical trials. [64Cu]Cu- DOTATATE (Detectnet™) is the first 64Cu labeled radiopharmaceutical approved by the FDA and is commercially available in the USA. 64Cu/67Cu pair has great and true theranostic applications. Impressive numbers of clinical trials using 64Cu labeled compounds suggest that the menu of approved radiopharmaceuticals in this field will increase in the near future.

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Abbreviations

ATSM:

diacetyl-bis(N4-methylthiosemicarbazone)

BTV:

biological tumor volume

CD20:

cluster of differentiate 20

CT:

computed tomography

Cu:

copper

DOTA:

2,2′,2”,2”'-(1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrayl)tetraacetic acid

FCH:

fluorocholine

FDG:

fludeoxyglucose

FDA:

food and drug administration

Ga:

gallium

GBM:

glioblastoma multiform

GI:

gastro intestinal

HER:

human epidermal growth factor receptor

MAb:

monoclonal antibody

MAPK:

mitogen-activated protein kinases

MBq:

mega becquerel

MISO:

misonidazole

NADH:

nicotinamide adenine dinucleotide (NAD) + hydrogen (H)

NADPH:

nicotinamide adenine dinucleotide phosphate

NET:

neuroendocrine tumors

NHL:

non-Hodgkin lymphoma

NOC:

[Nal3]-octreotide

NOTA:

2,2′-(7-(2-((2,5-dioxopyrrolidin-1-yl)oxy)-2-oxoethyl)-1,4,7-triazonane-1,4-diyl)diacetic acid

PCa:

prostate cancer

PET:

positron emission tomography

PTSM:

pyruvaldehyde-bis(N4-methylthiosemicarbazone)

PSA:

prostate specific antigen

PSMA:

prostate specific membrane antigen

RTX:

Rituximab

SAR:

sarcophagine

SPECT:

single-photon emission computed tomography

SSTR:

somatostatin receptor

TATE:

[Tyr3]-octreotate

TOC:

[Tyr3]-octreotide

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Written By

Nasim Vahidfar, Mohsen Bakhshi Kashi, Saeed Afshar, Peyman Sheikhzadeh, Saeed Farzanefar, Yalda Salehi, Ebrahim Delpasand, Eóin N. Molloy, Siroos Mirzaei, Hojjat Ahmadzadehfar and Elisabeth Eppard

Submitted: 21 August 2023 Reviewed: 05 December 2023 Published: 05 January 2024

© The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution 3.0 License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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