Table 1 Clinical studies using *copper(II)-diacetyl-bis(N4-methylthiosemicarbazone) ([^*Cu][Cu(ATSM)]) or *Cu-dichloride ([^*Cu]CuCl₂) as radioactive tracer in PET

[*Cu][Cu(ATSM)]

Lung cancer

6

⁶²Cu-ATSM rapidly accumulated in tumors of patients with lung cancer but not in the lung of healthy volunteers. The level of radiocopper reached abnormally intense plateau levels within a few minutes after intravenous administration in tumors with different distribution from [¹⁸F]-FDG.

[39]

Lung cancer (NSCLC)

19

PET imaging with ⁶⁰Cu-ATSM in patients with NCSLC is feasible. At a tumor (T)/muscle (M) threshold of 3.0 clear distinct prediction can be made between patients that respond to therapy (mean T/M = 1.5 ± 0.4) and the non-responders (mean T/M = 3.4 ± 0.8). No significant difference in tumor SUV was observed with [¹⁸F]-FDG.

[31]

Cervical cancer

14

Tumor uptake of ⁶⁰Cu-ATSM inversely correlate with progression-free and overall survival. Uptake of [¹⁸F]-FDG did not correlate with ⁶⁰Cu-ATSM and no significant [¹⁸F]-FDG distribution difference between hypoxic and normoxic tumors.

[40]

Cervical cancer

15

Patients with hypoxic cancer as determined by ⁶⁰Cu-ATSM correlates with overexpressed VEGF, EGFR, COX-2, CA-9, as well as high apoptotic and worse prognosis.

[110]

Cervical cancer

38

Patients were monitored through a period from 3 to 79 months. With a threshold of T/M = 3.5 the 3-year progression free and cause-specific survival rate of patients with normoxic tumors (T/M < 3.5, 71%) is significantly higher than that of hypoxic tumor (T/M > 3.5, 28%). Advantages of ⁶⁰Cu-ATSM over ¹⁸F-FMISO include much faster pharmacokinetics which results in better target-to-background ratio, and no interference due to urinary bladder uptake.

[32]

Rectal

19

⁶⁰Cu-ATSM PET may be predictive of survival and possible tumor response to neoadjuvant chemoradiotherapy in rectal cancer.

[34]

Cervical cancer

10

PET images from [⁶⁴Cu][Cu(ATSM)] have better image quality (lower noise) than images from [⁶⁰Cu][Cu(ATSM)]. Patterns and magnitude of the tumors were similar between the two tracers with different copper isotopes.

[111]

Lung cancer

13

SUV of ⁶²Cu-ATSM is higher than [¹⁸F]-FDG at the peripheral region of tumor while [¹⁸F]-FDG is higher at the center of the tumor. This difference of intratumor distribution indicates the difference of high glucose metabolism regions and hypoxia region inside various histopathologic types of lung cancer.

[41]

Head and neck

17

Increased uptake of [⁶²Cu][Cu(ATSM)] predicted tumor resistance to chemo- and radiotherapy as well as recurrence.

[35]

Head and neck

30

Among 27 patients with squamous cell carcinoma, [⁶²Cu][Cu(ATSM)] showed higher accumulation in the peripheral regions than in the center of the tumor mass, opposite to the accumulation pattern of [¹⁸F]-FDG. In 3 patients with adenocarcinoma, the accumulation of both ⁶²Cu-ATSM and [¹⁸F]-FDG were homogeneous.

[33]

Glioma

22

Uptake (SUV_max) and T/B ratio of [⁶²Cu][Cu(ATSM)] were much higher in grade IV than grade III/II gliomas, correlated with MRI findings of necrosis. At T/B=1.8 threshold, [⁶²Cu][Cu(ATSM)] is predictive of HIF-1a expression, with 92.3% sensitivity and 88.9% specificity.

[112]

Head and neck

25

At T/M = 3.2 [⁶²Cu][Cu(ATSM)] uptake threshold, patients with hypoxic tumors have significant worse 2-year progression free survival (20%) and cause-specific survival (33%), compares to patients with lower [⁶²Cu][Cu(ATSM)] uptake (73% and 80%, respectively).

[113]

Head and neck

11

[⁶⁴Cu][Cu(ATSM)] has very high sensitivity (100%) of predicting radiotherapy response, but relatively low specificity for the prediction of neoadjuvant chemoradiotherapy response.

[114]

Head and neck

30

With a cut-off TMR of 3.2, patients with hypoxic tumors have significantly worse progression-free survival and cause-specific survival. ⁶²Cu-ATSM is predictive of treatment resistance and poor prognosis for head and neck cancers.

[115]

Lung /H&N

7/11

Moderate to high uptake of [⁶⁴Cu][Cu(ATSM)] were found in all patients. No statistic significant difference in SUV between the two tumor types.

[116]

Ionic copper (II)

Prostate cancer

7

Due to the absence of urinary excretion lesions in the pelvic area can be easily imaged with [⁶⁴Cu]CuCl₂-PET. No adverse or clinical detectable pharmacologic effects were observed in any of the patients at mean activity of 339 MBq (4 MBq/kg).

[36]

Brain cancer

19

Using [⁶⁴Cu]CuCl₂ the brain cancerous lesions can be clearly visualized at 1 h after the injection and have stable retention between 3-24 hours. Accumulation of the tracer in consistent agreement with MRI images. The brain lesions were also clearly visualized in patients simultaneously affected by other types of cancer.

[38]

Healthy volunteer

6

Healthy volunteers were injected with [⁶⁴Cu]CuCl₂ at a dose of 4.0 MBq/kg. No observable adverse effects, clinically detectable pharmacologic effects, and change in standard vital signs were observed. Uptake of copper-64 was observed predominantly in liver, followed by bowel and kidneys.

[101]

Prostate cancer

50

Among the 50 patients, 41 were detected (82%) positive via [⁶⁴Cu]Cu-PET, compared to 56% using [¹⁸F]F-choline PET and 74% using multiparametric MRI. Unlike [¹⁸F]F-choline, [⁶⁴Cu]CuCl₂ allows thorough pelvic exploration due to lack of excreted or accumulated urinary tract.

[37]

Prostate cancer

50

The maximum tumor-to-background ratio was reached 1 hour after injection. Mean SUV_max in lymph nodes and bone metastases were significantly higher than local relapse. Discounting the Auger electrons, the mean absorbed dose for PCa lesions per administration was ~0.06 mGy/MBq. The therapeutic effect of [⁶⁴Cu]CuCl₂ is mainly dependent on the Auger electron emission instead of beta radiation.

[58]