⁶¹Cu-Labeled Radiotracers: Alternative or Choice?

WHY ⁶¹CU VERSUS OTHER PET RADIONUCLIDES?

In Table 1, the physical properties of ⁶¹Cu are compared with other established PET radionuclides, and Figure 1 illustrates the PET image resolution using a phantom. ⁶¹Cu (half-life, 3.33 h; 61% β⁺-fraction; mean positron energy [E_β⁺], 500 keV; maximum E_β⁺, 1,216 keV) exhibits more favorable characteristics than ⁶⁴Cu. Even though ⁶⁴Cu has a lower positron energy (maximum E_β⁺, 655 keV) with intrinsically better spatial image resolution, ⁶¹Cu has a higher number of positrons (β⁺) emitted per decay (61% compared with 17.9%), leading to improved sensitivity, as already indicated by the pioneer work of McCarthy et al. (4). This provides the opportunity for a lower injected activity or a shorter scanning time to achieve adequate photon count statistics. Furthermore, the shorter half-life and absence of β⁻ particles (which account for 39% of decays in ⁶⁴Cu) result in a reduced radiation dose to the patient. In daily clinical practice, using ⁶¹Cu may offer greater convenience for patient management, especially in countries with stricter radioprotection regulations.

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FIGURE 1.

Visual comparison of spatial resolution of different PET radionuclides using Jaszczak phantom, 0.7–1.2 mm, filled with 6.5 MBq of [¹⁸F]FDG (¹⁸F), 13 MBq of [⁶⁴Cu]CuCl₂ (⁶⁴Cu), 5.9 MBq of [⁶¹Cu]CuCl₂ (⁶¹Cu), and 6 MBq of [⁶⁸Ga]GaCl₃ (⁶⁸Ga). PET images were obtained within 30 min on small-animal PET scanner (β-CUBE; Molecubes) and reconstructed using ordered-subsets maximization expectation (slice thickness, 0.4 mm).

Because of its intermediate half-life between ⁶⁸Ga (68 min) and ⁶⁴Cu (12.7 h), ⁶¹Cu enables PET scans to be conducted 3–6 h after injection, offering improved diagnostic performance due to higher image contrast and tumor-to-background ratios over time, compared with ⁶⁸Ga-labeled tracers. This can enhance sensitivity and accuracy while avoiding false-positive signals. In addition, multiple-time-point scans enable pretherapeutic dosimetry estimations. ⁶¹Cu-labeled tracers are less susceptible to delays that may occur after administration to a patient than are ⁶⁸Ga-labeled tracers. Certainly, in daily routine the 24-h availability of the generator-produced ⁶⁸Ga is convenient, and scans at early time points are preferable. Nevertheless, the limited production capacity of the ⁶⁸Ga tracers (2–3 patient doses) raises certain concerns, and multiple serial production is hampered by the waiting time between 2 consecutive elutions of the generator. ⁶¹Cu brings more flexibility in performing radiosynthesis, shipping from a central producer to satellite institutions, and scheduling patients, especially because of its longer half-life.

Although ⁶¹Cu does not possess better physical properties than ¹⁸F, it does offer advantageous chemical properties due to its ability to be labeled using chelators. As a result, radiosynthesis for ⁶¹Cu is simple, allowing for kit (shake-and-bake) formulation without requiring expensive infrastructure such as module-assisted radiosynthesis or purification systems commonly used for ¹⁸F radiotracers. These qualities make it well suited for daily routine use. Moreover, the notable structural differences between chelator-based therapeutics and ¹⁸F-based PET tracers bear a high risk of variations in biodistribution between the diagnostic and the therapeutic radiotracer. The increasing adoption of chelators, such as the NOTA chelator used in the Al¹⁸F strategy, in developing ¹⁸F-labeled tracers is a step toward solving this disparity. ⁶¹Cu offers the possibility of a chemically identical therapeutic companion (⁶⁷Cu-labeled tracer) or a similar one (e.g., [⁶⁴Cu]Cu/[¹⁷⁷Lu]Lu-DOTATATE, in analogy to [⁶⁸Ga]Ga/[¹⁷⁷Lu]Lu-DOTATATE).

Copper chemistry is widely understood and straightforward (2,3,5). However, the challenge in developing ^xCu-based radiotracers lies in the in vivo stability of the ^xCu-chelator complex (3). This challenge is due to the risk of ^xCu(II) decomplexation (e.g., transchelation or transmetallation) (5) and the bioreduction of ^xCu(II)/^xCu(I). ^xCu(I) may be released from the chelator and incorporated into endogenous copper-binding proteins, followed by accumulation in the liver and other off-target tissues. Thus, a range of chelators has been specifically designed for ^xCu-based radiotracers (5). In contrast to the widely used DOTA and its derivatives, which demonstrate the in vivo instability of the copper-DOTA complex, chelators such as sarcophagine and NODAGA have shown promise in circumventing this issue. Additionally, these ^xCu-tailored chelators offer the advantage of room temperature labeling within a few minutes (shake-no-bake approach), making the production of radiotracers even faster and simpler.

WHICH LIGANDS MAY BENEFIT FROM ⁶¹CU?

The favorable properties of ⁶¹Cu make it suitable for delayed imaging with ligands that exhibit peak tumor uptake 1–2 h after injection and have fast body clearance. This is especially relevant for small molecules or peptides. Indicative ligands in combination with ⁶¹Cu are somatostatin analogs (SSA), which have a peak tumor uptake of between 4 and 24 h. Currently, ⁶⁸Ga-SSA PET/CT imaging is acquired 45–90 min after injection, which might be suboptimal. Thus, delayed imaging using ⁶¹Cu could better exploit the pharmacokinetic properties of SSA and further enhance image contrast and sensitivity. However, the benefit of delayed imaging with [⁶⁴Cu]Cu-DOTATATE compared with ⁶⁸Ga-SSA PET or ¹⁸F-SSA PET scans at 1 h after injection is still uncertain (6,7).

In PSMA scans using ⁶⁸Ga-PSMA ligands, an uptake time of approximately 60 min is recommended. Yet, PET/CT imaging at 3 h after injection has demonstrated improved detection of tumor lesions with higher uptake and contrast (8). For unclear findings, particularly for lesions near the bladder or ureter, or in bone scans using [¹⁸F]PSMA-1007, scanning at a later time point may be considered (9).

Using ⁶¹Cu in exendin-4 PET imaging would be beneficial because of difficulties associated with module-assisted radiolabeling and elevated temperatures. Fast radiolabeling at room temperature may resolve these issues, whereas late scanning (>2.5 h after injection) enables washout of exendin-4 from the duodenum, pancreas, and kidneys. This may lead to more conclusive findings and may reveal small insulinomas in the tail of the pancreas that were obscured on earlier scans because of the high renal uptake of the radiotracer (10,11).

WHERE DO ⁶¹CU PRODUCTION, DISTRIBUTION, AND AVAILABILITY STAND?

Despite its favorable physical properties, the development of ⁶¹Cu has been limited by availability constraints. Recently, 2 methods for large-scale production of ⁶¹Cu using liquid (12) and solid (13) targets have been developed for commercial production on a standard medical cyclotron (16.5- or 18-MeV proton capability). The main routes of production involve proton bombardment of inexpensive natural zinc, or enriched ⁶⁴Zn or ⁶¹Ni and deuteron bombardment of natural nickel or enriched ⁶⁰Ni. Although liquid targets offer easy processing, their lower production yields and longer irradiation times may restrict widespread use, especially in view of interference with the routine ¹⁸F production. Yet, simultaneous production of ⁶¹Cu and ¹⁸F is possible using a dual-proton-beam setup. On the other hand, solid target production through an 8.4-MeV deuteron bombardment of ^natNi or ⁶⁰Ni or a 12- to 14-MeV proton bombardment of ⁶¹Ni required shorter times and can be scaled from 4 to 60 GBq by increasing the enrichment levels of the ^xNi. However, solid targets require additional steps such as target material dissolution but provide higher production yields at shorter irradiation times and scalability based on material enrichment. The choice between liquid and solid targets depends on production requirements, material availability, and commercial demand. A comparison of the production routes is listed in Table 2.

There are several major factors contributing to the cost and sustainability of ⁶¹Cu production. The first is the cost of the target material, especially when enriched isotopes are used. Although upscaling production is possible only with enriched isotopes, their higher cost and limited supply require target material recycling to minimize expenses.

A second factor is the operation and maintenance costs of the cyclotron. These costs directly impact the cost per hour of irradiation. Limiting the irradiation time and complexity of the production can be beneficial in contract manufacturing to minimize costs.

A third factor are the separation and purification costs, as specialized processes are required to isolate the desired ⁶¹Cu from the target material and other by-products. These processes require expensive trace-metal–free chemicals and consumables.

A final factor is radiopharmaceutical production and distribution: additional costs are involved in the final product’s formulation, manufacturing, and distribution. With its relatively long half-life, ⁶¹Cu provides a distribution range of over 400 km and the advantages of centralized manufacturing and longer shelf-life than for ⁶⁸Ga or ¹⁸F radiopharmaceuticals.

DISCLOSURE

Melpomeni Fani is a scientific advisor of Nuclidium AG and coinventor on 2 patent applications filed by Nuclidium AG and the University of Basel, Switzerland. No other potential conflict of interest relevant to this article was reported.