Choice Is Good at Times: The Emergence of [⁶⁴Cu]Cu-DOTATATE–Based Somatostatin Receptor Imaging in the Era of [⁶⁸Ga]Ga-DOTATATE

Somatostatin receptor (SSTR) imaging has brought about impactful changes in clinical management of neuroendocrine tumors (NETs), including pheochromocytoma and paraganglioma (PPGL) (1,2). It allows tumor detection and disease characterization and is mandatory for selecting patients who are likely to benefit from peptide receptor radionuclide therapy (commonly referred to as theranostics). In 2016, [⁶⁸Ga]Ga-DOTATATE (Netspot; Advanced Accelerator Applications) received Food and Drug Administration approval. Recently in 2020, the Food and Drug Administration approved the radiopharmaceutical [⁶⁴Cu]Cu-DOTATATE (Detectnet; Curium) as an SSTR imaging option.

[⁶⁸Ga]Ga-SSTR PET/CT has been increasingly evaluated in PPGLs of various genetic backgrounds (3,4). A recent metaanalysis showed the pooled PPGL detection rate of [⁶⁸Ga]Ga-SSTR PET/CT in patients with unknown genetic status to be 93%, which was significantly higher than that of [¹⁸F]-fluorodihydroxyphenylalanine ([¹⁸F]-FDOPA) PET/CT (80%), [¹⁸F]-FDG PET/CT (74%), and [^123/131I]-metaiodobenzylguanidine scintigraphy [(38%), P < 0.001 for all] (5). These studies reflect the clinical utility of [⁶⁸Ga]Ga-SSTR in PPGL imaging. However, [¹⁸F]-FDOPA is the preferred radiopharmaceutical of choice in cluster 1B (pseudohypoxia-related: VHL/HIF2A/PHD1/2) or cluster 2 (kinase signaling–related: RET/NF1/TMEM127/MAX) mutated PPGLs (3,4).

Recently, DOTATATE was radiolabeled with Copper-64, which should be inspected from a clinical perspective. In a prospective head-to-head comparison between [⁶⁴Cu]Cu-DOTATATE and [⁶⁸Ga]Ga-DOTATOC PET/CT in 59 NET patients, Johnbeck et al. reported a slightly higher detection rate for the former (99.1% vs. 95.6%), with 701 concordant lesions on both scans (6). Of 40 additional true-positive lesions detected on either scan, significantly more true-positive lesions were detected by [⁶⁴Cu]Cu-DOTATATE (n = 33) than by [⁶⁸Ga]Ga-DOTATOC (82.5% vs. 17.5%, P < 0.0001). Although the authors attributed the better detection rate to the shorter positron range of Copper-64 (6), one must consider that the study used different peptides (DOTATATE vs. DOTATOC) linked to Copper-64 versus Gallium-68, respectively. In a prospective phase III clinical trial from the United States on 42 NET patients and 21 healthy volunteers, Delpassand et al. determined that PET/CT images of diagnostic quality can be acquired with a dose of 148 MBq of [⁶⁴Cu]Cu-DOTATATE, achieving a sensitivity of 100.0% with 96.8% specificity by masked readers (7). In another study, on 112 NET patients, when [⁶⁴Cu]Cu-DOTATATE was compared with [¹¹¹In]In-diethylenetriamine pentaacetate-octreotide the former detected more lesions (1,213 vs. 603) and more organ involvement (in 36% of patients) (8). These 2 studies led to approval of [⁶⁴Cu]Cu-DOTATATE by the Food and Drug Administration in September 2020 for the localization of NETs (8).

Tumor detectability also depends on the radionuclide’s physical properties, which can have a significant impact on diagnostic performance (6). Gallium-68 has a lower positron energy than Copper-64 (0.65 vs. 1.90 MeV), resulting in a lower positron range (0.56 vs. 3.5 mm) that provides superior spatial resolution, improved imaging quality, and enhanced detection of small lesions (7). Since Copper-64 suffers from a lower positron yield than Gallium-68 (17% vs. 88%), Copper-64 would theoretically require a higher injected activity to achieve the same positron count as Gallium-68 (6). However, PET/CT images of diagnostic quality were acquired with a dose of 148 MBq of [⁶⁴Cu]Cu-DOTATATE (7). Nevertheless, the radiation exposure associated with 200 MBq of [⁶⁸Ga]Ga-DOTATATE (4.3 mSv) is lower than that associated with 148 MBq of [⁶⁴Cu]Cu-DOTATATE (4.7 mSv), per the package inserts. Furthermore, the long half-life of Copper-64 (12.7 h) has potential advantages over Gallium-68 (1.1 h). This longer half-life allows a scanning window of at least 1–3 h after injection, potentiating a better tumor-to-background ratio and offering logistic benefits in coordinating radiochemical production and patient arrival (6). Additionally, serial multiple-time-point imaging is possible with a longer half-life, enabling dosimetric calculations. Lastly, this longer half-life along with centralized production of Copper-64 allows for easier distribution of Copper-64 to remote geographic areas. The physical properties, including other characteristics of both [⁶⁸Ga]Ga-DOTATATE and [⁶⁴Cu]Cu-DOTATATE, are summarized in Supplemental Table 1 (supplemental materials are available at http://jnm.snmjournals.org).

Five patients (4 new, 1 follow-up) who had undergone [⁶⁴Cu]Cu-DOTATATE at outside institutions presented to us and underwent [⁶⁸Ga]Ga-DOTATATE scans prospectively at the National Institutes of Health. The institutional review board of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (clinical trial number NCT00004847) approved this study, and all subjects gave written informed consent. Four of these 5 patients (2 women, 2 men; mean age, 52.3 ± 21.0 y; range, 32–75 y; 1 SDHB, 1 SDHD, and 2 sporadic) did not receive any new antitumor intervention between the 2 scans. The median interval between the [⁶⁴Cu]Cu-DOTATATE scan (mean activity, 148 ± 11.1 MBq; mean uptake time, 71.8 ± 10.9 min) and the [⁶⁸Ga]Ga-DOTATATE scan (mean activity, 199.8 ± 7.4 MBq; mean uptake time, 60.3 ± 1.3 min) was 2 mo (range, 1–4 mo). Details on the PET/CT imaging techniques, scanner, and protocol are summarized in Supplemental Tables 2 and 3. All 4 patients were positive on both scans (Fig. 1). In patient 1, who was undergoing cold somatostatin analog therapy with lanreotide, [⁶⁸Ga]Ga-DOTATATE seemed to detect more lesions than [⁶⁴Cu]Cu-DOTATATE, and one might conclude that there had been progression of disease despite therapy. However, this observation could also be attributable to a difference in spatial resolution between scanners, differences in image acquisition and reconstruction methods, or a combination of these factors. Therefore, it is also important to optimize [⁶⁴Cu]Cu-DOTATATE image acquisition and reconstruction methods, using protocols optimized for the physical properties of Copper-64.

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FIGURE 1.

SSTR imaging with [⁶⁴Cu]Cu-DOTATATE and [⁶⁸Ga]Ga-DOTATATE in PPGL. Figure shows maximum-intensity projection images in 4 patients who underwent imaging with both [⁶⁴Cu]Cu-DOTATATE (top panel) and [⁶⁸Ga]Ga-DOTATATE (bottom panel). Leveling of all maximum-intensity projection images is at same SUV_max, ranging from 0 to 14.

Intraindividual head-to-head comparison between [⁶⁴Cu]Cu-DOTATATE and [⁶⁸Ga]Ga-DOTATATE is lacking in PPGLs. It is too early to answer the question of whether Copper-64 or Gallium-68 should be used for PPGL imaging, especially in the widespread landscape of functional imaging options available ([¹⁸F]-FDOPA, [¹⁸F]-FDG, and [¹²³I]-metaiodobenzylguanidine) (4,9). Until we gather more evidence, both [⁶⁸Ga]Ga-DOTATATE and [⁶⁴Cu]Cu-DOTATATE should be considered interchangeable; however, we do suggest remaining consistent with the SSTR imaging choice for follow-up imaging. This is vital in those patients who are in a watch-and-wait scheme (stable for a considerable time because of their slow progression), and the incorrect determination could lead to an unwarranted change in management. Seamless availability and distribution of SSTR imaging to the users is necessary to adequately meet an increasing and broader geographic demand.

In conclusion, despite the theoretic advantages of each radiopharmaceutical over the other, currently available comparison data are not conclusive about the superiority of one over the other. Therefore, until definitive data emerge, both [⁶⁸Ga]Ga-DOTATATE and [⁶⁴Cu]Cu-DOTATATE can be used interchangeably, if one remains consistent with the SSTR imaging choice for follow-up imaging. The future looks bright for SSTR theranostics with the advent of novel promising radionuclides that will substantially expand their use in NETs, including PPGLs.

• © 2022 by the Society of Nuclear Medicine and Molecular Imaging.

• Received for publication March 27, 2022.
• Revision received May 16, 2022.