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Comparison of image quality with 62Cu and 64Cu-labeled radiotracers inpositron emission tomography whole-body phantom imaging
Article in Hellenic Journal of Nuclear Medicine · July 2015
DOI: 10.1967/s002449910203 · Source: PubMed

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SEE PROFILEOriginal Article

Comparison of image quality with 62Cu and64
Cu-labeled radiotracers in positron emission
tomography whole-body phantom imaging

Abstract
Masato Kobayashi1 PhD,
Tetsuya Mori2 PhD,
Tetsuya Tsujikawa2 MD, PhD,
Kazuhiro Ogai1 PhD,
Jyunko Sugama1 PhD,
Yasushi Kiyono2 PhD,
Keiichi Kawai2,3 PhD,
Hidehiko Okazawa2 MD, PhD

1. Wellness Promotion Science
Center, Institute of Medical,
Pharmaceutical and Health
Sciences, Kanazawa University,
Kanazawa, Japan
2. Biomedical Imaging ResearchCenter, University of Fukui, Fukui,Japan
3. School of Health Sciences,
College of Medical, Pharmaceutical and Health Sciences,
Kanazawa University,
Kanazawa, Japan

Objective: PET imaging is possible with copper (Cu) isotopes, 60Cu, 61Cu, 62Cu and 64Cu. Although 62Cuand 64Cu-labeled radiotracers are often used for preclinical and clinical PET studies, we do not know whichradiotracers have better image quality for tumor imaging. In this study, we compare image quality between 62Cu and 64Cu imaging with a diﬀerent acquisition mode and reconstruction algorithm using awhole-body phantom for tumor imaging. Methods: In a National Electrical Manufacturers Association(NEMA) 2001 whole-body phantom, the concentration of 62Cu-ATSM and 64Cu-ATSM was, respectively, approximately 2.7 and 1.8MBq/mL in all the spheres and approximately 0.9 and 0.6MBq/mL in the background. After adjustment for true coincidence events between 62Cu and 64Cu, two-dimensional (2D) andthree-dimensional (3D) PET scan data were acquired for 10min. The data were reconstructed using filtered
back projection (FBP) and the ordered subset expectation maximization (OSEM) algorithm. Image qualityof 62Cu and 64Cu was compared using recovery coeﬃcient (RC), sphere-to-background ratio (SBR) and coeﬃcient of variation (%COV). Results: There were little significant diﬀerences between 62Cu and 64Cu imaging, visually. Recovery coeﬃcients of 64Cu images were higher than those of 62Cu images. The RC of 64Cu
images with 3D acquisition mode and OSEM was the highest in all experiments. No SBR values were significantly diﬀerent from the true value of 3.0 in 37mm sphere diameters, but 3D acquisition and OSEMyielded slight overestimations compared with 2D acquisition and FBP, the gold standard forquantification in PET studies. Percentage COV values of 64Cu with OSEM were significantly lower thanthose of 62Cu. Conclusions: Copper-64 radiotracers provide higher image quality than 62Cu-radiotracers
in whole-body tumor imaging only when the 3D acquisition mode and OSEM algorithm are applied. However, the quantitative values for smaller tumors may be slightly overestimated.

Hell J Nucl Med 2015; 18(2): 103-107

Epub ahead of print: 19 July 2015

Published online: 5 August 2015

Introduction
64

Keywords: Cu - Acquisition
mode-Reconstruction algorithm-Image quality - 62Cu radiotracers

Correspondence address:
Masato Kobayashi PhD,
Wellness Promotion Science
Center Institute of Medical,
Pharmaceutical and Health
Science, Kanazawa University
5-11-80 Kodatsuno,
Kanazawa 920-0942, Japan
Tel: +81-76-265-2500;
Fax: +81-76-234-4366
kobayasi@mhs.mp.
kanazawa-u.ac.jp

Received:
22 April, 2015
Accepted revised:
20 May, 2015

www.nuclmed.gr

Copper (Cu)-labeled radiotracers have been used in some basic science research
and for clinical PET. In particular, Cu-pyruvaldehyde-bis(N4-methylthiosemicarbazone) (Cu-PTSM) [1] and Cu-diacetyl-bis(N4-methylthiosemicarbazone) (CuATSM) [2] have been applied as potential markers of hypoxia and perfusion,respectively. Most clinical Cu-PTSM/ATSM studies have used the short-lived positronemitting radionuclide of 60Cu [3] or 62Cu [4-7] (Table 1). Copper-64 is potentially usefulfor not only tumor imaging [8] but also tumor therapeutics [9]. In these radiotracers,
the amount of annihilation γ- rays following to β+-decay yields higher image quality
in Cu PET imaging unless saturation of the detector occurs. Lewis et al. (2008) reported
64
Cu-ATSM appeared to have a higher image quality than 60Cu-ATSM in cancer of theuterine cervix [10]. However, the high-energy positron and gamma emissions of 60Cu,
compared to 64Cu, are the greatest disadvantages of using 60Cu as a PET imaging
agent[10]. In addition, they did not consider that true coincidence events between
60
Cu- and 64Cu-ATSM imaging should be adjusted, although the radiation doses of thetwo radiotracers were the similar in whole body imaging.
Instead of 60Cu, 62Cu-ATSM has been utilized because 62Cu-ATSM generates 62Zn/62Cu[11-13] and it is less expensive. Moreover, a clinical study showed that the radiation exposure from 62Cu is lower than that from 60Cu [14].
However, we do not know which radiotracers of 62Cu and 64Cu have better image
quality for tumor imaging. In this study, we compare image quality between 62Cu and64
Cu imaging with diﬀerent acquisition modes and reconstruction algorithms using a
National Electrical Manufacturers Association (NEMA) 2001 whole-body phantom.
Hellenic Journal of Nuclear Medicine • May - August 2015103

Original Article

Materials and methods
Preparation of 62Cu- and 64Cu-ATSM
The 62Cu-glycine (no-carrier-added 62Cu) solution was obtained from a 62Zn/62Cu generator system [15]. Copper-62 ATSM was prepared with a simple mixture of 62Cu solution(5mL) and 0.2mL of ATSM solution (0.5mM in dimethyl sulfoxide) in a sterilized vial [2, 16]. The radiochemical purityof 62Cu-ATSM was confirmed with high-performance liquid
chromatography using authentic unlabeled Cu-ATSM before the phantom study. The radiochemical purity of 62CuATSM was greater than 95%.
64
Cu was produced as reported previously [17]. The purification of 64Cu and the preparation of 64Cu-ATSM were
performed according to previously reported procedures[17, 18]. The radiochemical purity of the resulting 64CuATSM was greater than 95%, as assessed by silica gel thinlayer chromatography (TLC; silica gel 60; Merck, Whitehouse
Station, NJ, USA) with ethyl acetate as the mobile phase[19]. Radioactivity levels on the TLC plates were analyzed
with a bioimaging analyzer (FLA-7000; Fujifilm, Tokyo,
Japan). Elemental 62/64Cu could not be used for this phantom study because the 62/64Cu attached to the sidewalls of
the whole-body phantom. Consequently, we have used
62/64
Cu-ATSM, a type of 62Cu or 64Cu-labeled radiotracer.
Phantoms
A NEMA 2001 whole-body phantom [20], an elliptical phantom with six individually fillable spheres whose diametersare 10, 13, 17, 22, 28, and 37mm, was prepared. The concentration of 64Cu-ATSM in all spheres was approximately
1.8MBq/mL, which is as dense as that seen in a tumor in aclinical scan [10]. The background was approximately
0.6MBq/mL for 64Cu-ATSM. However, the concentration of
62
Cu-ATSM was approximately 2.7MBq/mL in all spheres,with a background of approximately 0.9MBq/mL because
we prepared the phantoms to have the same radioactive
counts between 62Cu and 64Cu, considering the half-life of62
Cu (23.7min) and 64Cu (12.7h) because their image quality
can be compared when their radioactive counts are almost
the same. Before starting the acquisition, we regulated andadjusted the true coincidence counts between 62Cu-ATSM
and 64Cu-ATSM.
PET scanThe study was approved by the Ethics Committee of the University of Fukui, Faculty of Medical Sciences. A whole-body
PET scanner (Advance; GE Healthcare, Milwaukee, Wisconsin,
USA) capable of simultaneous acquisition of 35 image slices,with an interslice spacing of 4.25mm, was used for data acquisition [21]. This scanner has 12,096 bismuth germanate
crystals with transaxial, axial and radial dimensions of 4.0,
8.1 and 30mm, respectively. The phantom was positioned
at the center in the scanner. Two-dimensional (2D) andthree-dimensional (3D) dynamic PET scans with 1 frame/min
were acquired for 10 min. A 10-min post-injection transmission scan was acquired after the emission scan with a68
Ge/68Ga rod source for attenuation correction.

104

Hellenic Journal of Nuclear Medicine • May - August 2015

Reconstruction
The data were reconstructed using a filtered back projection(FBP) algorithm with 0.4 cycle/pixel Hanning filter. For 2D PET,an ordered subset expectation maximization (OSEM) algorithm was applied using four iterations and 28 subsets, a
128×128 matrix, and post-smoothing with a 2.8mm full-widthat half maximum (FWHM) post-filter. The 3D data were converted into sets of contiguous transaxial 2D sinograms using
Fourier rebinning (FORE). Images 3D were reconstructedusing FORE with FBP and FORE with OSEM followed by aweighted least-squares algorithm using three iterations and
32 subsets. 3D Gaussian post-smoothing was applied using
2mm FWHM. The parameters used for the reconstruction algorithms of both 2D and 3D datasets have been optimized inprevious studies [22, 23] and by matching of noise on background areas between 2D and 3D images. The scatter correction method was used with the convolution subtraction
method [24, 25]. In addition, normalize correction, delayedcoincidence correction, dead time correction, and decayedcorrection were incorporated in the reconstruction algorithm.
After reconstruction, the data was used to generate summed
images of 10min from dynamic data of 1 frame/min.
Image analysis
Circular volumes of interest (VOI) were placed over visible
and invisible hot sphere locations on the images using thecorresponding transmission images. VOI (10cm) were also
located in the background area.
The recovery coeﬃcient (RC) was calculated using the following formula:
RC (%)=A/B×100,where A is the mean pixel counts of eachhot sphere, and B is the known radioactive counts obtainedusing the gamma counter. Image noise of RC was definedas the coeﬃcient of variation (%COV), standard deviation /mean×100 %) of pixel values within the VOI on sphere diameter areas and background areas.
The sphere-to-background ratio (SBR) of approximately
3:1 was regulated corresponding to an injected patient activity of 370MBq(10mCi) of 62Cu-ATSM, assuming a typicalpatient weight of 70kg [5-7]. SBRs were calculated using
mean pixel counts of each diameter sphere divided by thoseof background.
Statistical analysis
A statistical software package (JMP® version 9 SAS InstituteInc., Cary, NC, USA) was used for statistical analysis. We applied a Wilcoxon test for comparison of 62Cu and 64Cu or analysis of RC, SBR and %COV for 2D and 3D acquisition mode withFBP and OSEM algorithms, which were used as a multiplex
analysis with a population mean value. Statistically significant
diﬀerences were defined as P< 0.05.

Results
Figure 1 shows images of the whole-body phantom. There
were little significant diﬀerences between 62Cu and 64Cu imaging, visually. We could not identify the smallest sphere region (10mm diameter) in all cases.
www.nuclmed.gr

Original Article

Figure 1. Images of the whole-body phantom at a ratio of sphere activity to background activity of 3.0.

We could not identify the smallest sphere region (10mm
diameter, arrow) with either the FBP or OSEM algorithm.
There were no significant diﬀerences between 62Cu and 64Cu
imaging, visually.
In Figure 2, RCs of 64Cu images were higher than those of62
Cu images. Especially, 3D acquisition and OSEM produced
the highest RC on 64Cu images. percent COV of 64Cu images
were lower than those of 62Cu images. 3D acquisition
yielded lower %COV than 2D acquisition, and OSEM reduced
percent COV compared with FBP.
No SBR values were significantly diﬀerent from the true
value of 3.0 in 37mm sphere diameters (Table 2). In 64Cu imaging, 3D acquisition and OSEM significantly elevated SBR
in comparison with 2D acquisition and FBP in 13, 17 and22mm sphere diameters. In background areas, %COV valuesof 64Cu with OSEM were significantly lower than those of 62Cu
with OSEM (Table 3).

Discussion
A

B

PET imaging of 64Cu had higher image quality than that of
Cu in the whole-body phantom only when the 3D acquisition mode and OSEM algorithm were applied, althoughthese diﬀerences were little apparent visually in the phantom images. RCs of 64Cu images were also greater than thoseof 62Cu images (Fig. 2a, b) because 62Cu has a higher maximum energy of β+ (Table 1), and consequently has a longer
positron range than 64Cu [26]. The 3D acquisition mode and
OSEM algorithm yielded the highest RC on 64Cu images.
Fakhri et al. (2007) reported that 3D acquisition produced
greater image quality in normal-sized patients [27]. Lartizien
et al. (2004) also reported that the full 3D mode and Fourier
rebinning OSEM oﬀered better or equivalent detection performance than the 2D mode and OSEM for the same injected
dose typically used in clinical practice [28]. As shown in Fi62

C

D

Figure 2. RC and %COV with 2D and 3D acquisition mode and FBP (A, C) and OSEM
(B, D) algorithms. RCs of 64Cu images were higher than those of 62Cu images. 3D
acquisition and OSEM algorithm provided the highest RC on 64Cu images. %COV
of 64Cu images were lower than those of 62Cu images. 3D acquisition yielded lower
percentCOV than 2D acquisition, and OSEM reduced %COV compared with FBP.
* P< 0.05 vs. 64Cu images with 2D acquisition mode for RC.
Table 1. Decay properties of Cu radioisotopes.

IsotopeEC (%)

Half-life

β- (MeV)β+(MeV)β+ intensity (%)

0.93
1.22
(1.16)

5.5
51

36

-

1.91
1.98
2.95
3.77
(2.94)

11.6
49
15
5

7.2

60

Cu

23.7min

61

Cu

3.3h

-

62

Cu

9.67min

-

2.93

97.2

2

64

Cu

12.7h

0.579

0.65

17.6

40

β : electron; β : positron; EC: electron capture; γ: gamma emission; ( ): average of end-point-energies-+

www.nuclmed.grγ (MeV)γ intensity (%)

0.283
0.373
0.511
0.656
1.19

12.2
2.1
123
10.8
3.7

0.511
0.826
1.33
1.79
3.12

0.511
0.511
1.35

185
21.7
88
45.4
4.8

195
35.2

0.5

Hellenic Journal of Nuclear Medicine • May - August 2015

105

Original Article

Table 2. Average SBR values with 2D and 3D acquisition mode and FBP and OSEM algorithms without RC in all sphere sizes.
IsotopeAcquisition mode

Sphere size (mm)
10
13
17
22
28
37

FBP
0.95
1.39
1.87
2.03
2.84
3.00

62

2D

OSEM
0.97
1.40
1.88
2.05
2.85
3.05

Cu

FBP
0.95
1.41
1.90
2.05
2.86
3.02

3D

OSEM
0.97
1.40
1.88
2.05
2.85
3.05

FBP
0.97
1.46
1.84
2.05
2.84
3.03

2D

OSEM
0.97
1.51b
1.90b
2.07
2.86
3.04

64

Cu

FBP
0.96
1.48
1.89
2.06
2.86
3.05

3D

OSE
1.01
1.61a
1.99a
2.11b
2.87
3.06

2D: two-dimensional scan; 3D: three-dimensional scan; FBP: filtered back projection; OSEM: ordered subset expectation maximization;aP< 0.01 and bP< 0.05 vs. 2D acquisition and FBP of 62Cu or 64Cu.

Table 3. Average % COV with 2D and 3D acquisition modeand FBP and OSEM algorithms on background areas.
Cu
64
Cu
62

FBP
19.7
18.4

2D

OSEM
15.1
13.7a

FBP
18.9
17.5

3D

OSEM
14.4
11.3a

2D: two-dimensional scan; 3D: three-dimensional scan; FBP: filtered back projection; OSEM: ordered subset expectation maximization; aP< 0.05 vs. 62Cu.

gure 2 and Table 3, 3D acquisition decreased image noisecompared with 2D acquisition. Lodge et al. (2006) reported
that 3D PET acquisition reduced image noise on 2-[18F]fluoro-2-deoxy-D-glucose (18F-FDG) PET [29]. In addition,
OSEM decreased the noise compared with FBP (Figure 2c,d). Therefore, we estimate a combination of 3D acquisitionmode and OSEM algorithm produces better RC and %COV
for tumor imaging with Cu radioisotopes.
SBR values were not diﬀerent from the true value of approximately 3.0 in 37mm sphere diameters (Table 2). 2D acquisition and OSEM showed similar SBR values with 2D
acquisition and FBP, the gold standard for quantification in
PET studies using both Cu isotopes. Chen et al. (2007) also
reported that the quantification of 13NH3 PET using 2D acquisition and OSEM was similar to that using 2D acquisition
and FBP [30]. Our results show that 64Cu imaging with OSEM
gave slight overestimations compared with FBP because
OSEM reduced the positive bias from the non-negativity
constraint and the inaccuracy of Poisson statistics, (Table 2).
Despite the overestimation, the combination of 3D acquisition and OSEM provides better image quality for wholebody tumor imaging with both Cu radiotracers. %COV
values of 64Cu with OSEM were significantly lower than thoseof 62Cu (Table 3). Especially, 3D acquisition and OSEM significantly yielded the lowest %COV in all cases because the
combination had the lowest standard deviation.
Although the shorter half-lives and higher positron decay
fractions of 60Cu and 62Cu make them suitable for characterizing the faster kinetics of blood flow, etc., the higher sensitivity of 60Cu and 62Cu has been used for slower kinetic tumor
imaging because 61Cu and 64Cu need enriched targets andincrease overall costs [31, 32]. The longer half-lives of 61Cu
and 64Cu are basically better suited to studying tumor imag-

106

Hellenic Journal of Nuclear Medicine • May - August 2015

ing; however, they result in higher radiation doses. In particular, 64Cu provides the highest radiation doses to humans
among the Cu radioisotopes [14]. Although each Curadioisotope has unique advantages and disadvantages for tumor
imaging, in previous literature on image quality, 64Cu-ATSM
had higher image quality than 60Cu-ATSM in cancer of theuterine cervix [10]. We surmise that 62Cu-ATSM can produce
a better image quality than 60Cu-ATSM because 60Cu exhibitshigh radioactivity from γ rays compared with 62Cu, whichemits just single γ rays (0.511MeV). With 62Cu imaging, it may
be possible to acquire emission data for up to 30min because of the shorter half-life; however, 62Cu images acquired
over 10min will be similar to those acquired over 30min andcan be compared with 64Cu images acquired over 10min.
Therefore, including our results, 64Cu imaging produces thehighest image quality in clinical Cu PET imaging when the
3D acquisition mode and OSEM algorithm are applied. However, specific Cu radioisotopes may need to be selected foreach examination because of the potential radiation dose topatients. We must also be wary of potentially overestimatedresults when combining 3D acquisition and the OSEM algorithm in Cu imaging.
In conclusion, 64Cu radiotracers provide higher image quality than 62Cu radiotracers in whole-body tumor imaging. Although 64Cu imaging has better image quality when using a
combination of a 3D acquisition mode and OSEM algorithm,
the quantitative values for small tumors may be slightly overestimated.
Acknowledgements
The author thanks the staﬀ members at the Biological Imaging
Research Center, University of Fukui for their technical support.

The authors declare that they have no conflicts of interest.

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