Radiocobalt theranostic applications: current landscape, challenges, and future directions

Radiocobalt-based theranostics has emerged as a promising platform in nuclear medicine that offers dual capabilities for both diagnostic imaging and targeted radionuclide therapy. ⁵⁵Co (t_1/2 = 17.53 h, β⁺ = 77%, E_γ = 931.1 keV, I_γ = 75%) and ^58mCo (t_1/2 = 9.10 h, IC = 100%) serve as an elementally matched pair for positron emission tomography and targeted Auger electron therapy, respectively, that enable a more personalized approach to cancer management, where imaging with ⁵⁵Co can help to guide and predict therapeutic outcomes for ^58mCo therapy. The unique coordination chemistry of cobalt allows for stable complexation with various chelators, enhancing in vivo stability and targeting efficacy when conjugated to biomolecules such as peptides, antibodies, and small molecules. Recent developments in radiolabeling techniques, chelator design, and preclinical evaluations have significantly improved the pharmacokinetic profiles and tumor specificity of radiocobalt-based radiopharmaceuticals. The aim of this mini review is to provide an overview of the recent advancements and applications of radiocobalt isotopes with a particular focus on the production, chelation chemistry, and in vivo targeting of ⁵⁵Co- and ^58mCo-labelled radiopharmaceuticals over the last 5 years. While challenges still exist in production scalability, dosimetry optimization, and clinical translations, the current trajectory suggests a growing role for radiocobalt-based theranostics in precision oncology.

1 Introduction

Theranostics is an emerging medical approach that incorporates paired radiopharmaceuticals to selectively diagnose (“diagnostics”) and treat (“therapeutics”) various types of disease (1, 2). Theranostic radiopharmaceuticals consist of a radionuclide tethered to a vector (antibody, peptide, small molecule, etc.) that binds to a target (3). A positron or gamma-emitting radionuclide can be incorporated for diagnostic imaging with positron emission tomography (PET) or single-photon emitting computed tomography (SPECT) to provide a visual representation of the radiopharmaceutical distribution in vivo and help identify specific sites of disease. Diagnostic imaging provides information pertinent to disease staging, identifications of patients who express the specific target, and dosimetry for the radiopharmaceutical. Additionally, diagnostic radiopharmaceuticals can often identify disease before anatomical abnormalities have been determined. Targeted radiopharmaceutical therapy (TRT) incorporates alpha-particle, beta-particle, or Auger electron emitting radionuclides to deliver a therapeutic dose of ionizing radiation to the intended target. Leading treatment modalities including chemotherapy or radiation therapy often result in damage to healthy cells causing debilitating symptoms. TRT leads to radiopharmaceutical accumulation at the target where a cytotoxic radiation dose can be delivered, while minimizing the dose to healthy tissue. The clinical success of theranostics has continued to evolve with the recent U.S. Food and Drug Administration (FDA) approvals of therapeutic ¹⁷⁷Lu-based radiopharmaceuticals ($t_{1/2}$= 6.7 d, $E_{\beta -}$  = 134 keV) such as [¹⁷⁷Lu]Lu-DOTATATE (Lutathera) and [¹⁷⁷Lu]Lu-PSMA-617 (Pluvicto) for treatment of neuroendocrine tumors and prostate cancer, respectively (4–6). These radiopharmaceuticals are often paired with PET radionuclides such as ⁶⁸Ga ($t_{1/2}$= 68 min, ${\beta }^{+}$=89%, E_max = 1,899 keV) or ⁶⁴Cu ($t_{1/2}$= 12.7 h, ${\beta }^{+}$ = 17.9%, E_max = 660 keV) for staging and characterization of disease. One main challenge with radiopharmaceutical development arises in identifying matched pair radionuclides for diagnostic and therapeutic radiopharmaceuticals. Ideally, the chemistry of the diagnostic and therapeutic radionuclides should be identical to ensure that differences in radiopharmaceutical synthesis, binding affinities, off-target binding, biodistribution, etc. do not arise. Several theranostic pairs, including but not limited to, ⁶¹Cu/⁶⁴Cu/⁶⁷Cu, ⁴⁴Sc/⁴⁷Sc, and ¹⁴⁹Tb/¹⁵²Tb/¹⁵⁵Tb/¹⁶¹Tb, have garnered significant attention in the field of theranostics as a result of their identical chemistry and complementary nuclear characteristics, enabling both diagnostic imaging and TRT within a single element platform (7–9). Radiocobalt-based theranostics can bridge the gap of the aforementioned shortcomings and provide an additional elementally matched pair for diagnostic imaging (⁵⁵Co) and TRT (^58mCo). This mini review aims to provide an up-to-date overview of advances and challenges in radiocobalt radiopharmaceutical development in the new decade. Production and purification of radiocobalt for nuclear medicine applications prior to 2021 are omitted from this review as they were described in detail by Barrett et al. (10).

2 Properties of medically relevant radiocobalt isotopes

Cobalt is a transition element with atomic number 27 that plays an essential role in oncological medicine with applications including, but not limited to, radiotherapy and diagnostic imaging (11–14). While stable cobalt exists as ⁵⁹Co, 28 radioisotopes of cobalt have been characterized to date, and those radioisotopes that are most applicable for radiopharmaceutical development in nuclear medicine are tabulated in Table 1.

Table 1

Table 1. Decay characteristics, production methods, and applications of radiocobalt isotopes in nuclear medicine.

⁵⁵Co is a positron-emitting radiometal of interest for its application as a PET tracer. The high positron branching ratio and half-life compatible for radiolabeling macromolecules can be seen as advantageous over current tracers such as ¹⁸F ($t_{1/2}$= 110 min), ⁶⁴Cu ($t_{1/2}$= 12.7 h), ⁶⁸Ga ($t_{1/2}$= 68 min), or ⁸⁹Zr ($t_{1/2}$= 78.4 h). ⁵⁵Co is produced primarily through charged particle irradiation with the ⁵⁸Ni(p, $\alpha$)⁵⁵Co and ⁵⁴Fe(d,n)⁵⁵Co nuclear reactions being the most commonly employed (15–18). Although the ⁵⁶Fe(p,2n)⁵⁵Co reaction has been employed, the production method is limited by the coproduction of ⁵⁶Co and ⁵⁷Co that are chemically inseparable from ⁵⁵Co. The ⁵⁴Fe(d,n)⁵⁵Co reaction has a high cross section at low energies and has the advantage of producing radionuclidically pure ⁵⁵Co by minimizing the coinciding production of ⁵⁶Co and ⁵⁷Co; however, enriched iron targets are necessary for the production of radionuclidic and radioisotopically pure ⁵⁵Co (16, 19, 20). The ⁵⁸Ni(p, $\alpha$)⁵⁵Co reaction also coproduces ⁵⁶Co and ⁵⁷Co at higher energies (15, 18). Photoproton production via the ⁵⁸Ni($\gamma$,p2n)⁵⁵Co and ⁶⁰Ni($\gamma$,p4n)⁵⁵Co reactions have been attempted, but the radionuclide purity of ⁵⁵Co was deemed insufficient for use in PET as ^56,57,58Co contaminants were present (21).

⁵⁷Co decays primarily to stable ⁵⁷Fe by electron capture, emitting low energy gamma rays that are suitable for detection via SPECT. The long half-life of ⁵⁷Co (t_1/2 = 271.8 d) can be deemed discouraging for use in diagnostic imaging, although it has been incorporated into some SPECT radiopharmaceuticals (13, 20, 22). The current role of ⁵⁷Co in nuclear medicine is limited to tracer optimization, serving as a surrogate for ^55/58mCo in the radiopharmaceutical development stage. ⁵⁷Co can be produced by the ⁵⁸Ni(p,2p)⁵⁷Co reaction at energies above 15 MeV, although other production methods are listed in Table 1 (18).

^58mCo is a promising therapeutic radionuclide with potential applications in Auger electron therapy (23–25). ^58mCo decays to ^58gCo via internal conversion and releases 3 low energy Auger electrons, when internalized by a cancerous cell, can directly damage DNA. The decay product, ^58gCo, is a positron emitter that can potentially be utilized for PET imaging but does emit a prominent 811 keV gamma ray (99.5%) that would deposit unintended dose to normal tissue. ^58mCo is produced in highest yields by either proton or deuteron bombardment of enriched iron targets, although success using nickel and manganese targets have been demonstrated (24, 26, 27). Since deuterons have a higher stopping power, the targets require a smaller amount of isotopically enriched target material, although significant costs are noted with the target materials. While other radioisotopic impurities can be reduced with modification to charged particle energies and target enrichment, the co-production of ^58gCo is unavoidable. Valdovinos et al. evaluated the activity yields for the production of ^58mCo and ^58gCo via the ⁵⁷Fe(d,n)^58gCo reaction. Using deuteron currents between 90 and 124 $\mu$ Ah, they reported ^58mCo yields ranging from 11 to 17.8 MBq/$\mu$ Ah and ^58gCo co-contaminant yields between 115 and 158 MBq/$\mu$ Ah at the end of bombardment (16).

3 Chelation chemistry

Recent advances in chelation chemistry for radiocobalt, while limited, have concentrated on optimizing coordination stability and redox compatibility to support its use in theranostic applications. The intermediate ionic radius and accessible oxidation states of cobalt including Co²⁺ and Co³⁺ have directed research toward macrocyclic chelators including DOTA and NOTA, along with tailored derivatives like NO2A and NO3A (28). Recent work by Lin et al. has emphasized the importance of controlling cobalt redox chemistry to minimize in vivo transchelation and off-target distribution. This study demonstrated that the oxidation state of ^nat/55Co can be readily modulated and is highly sensitive to the chelator environment. Using the chelator-tryptophan conjugates [⁵⁵Co][Co(NO2A)]-W, [⁵⁵Co][Co(NOTA)]-W and [⁵⁵Co][Co(DO3A)]-W, the authors discovered that the conjugates all readily formed stable Co²⁺ species. However, the NOTA and NO2A conjugates could be readily oxidized to the Co³⁺ state upon exposure to hydrogen peroxide, illustrating the ligand-specific redox behavior pertinent to the radiocobalt complex design (28). Another study by Lin et al. investigated the labeling conditions of ⁵⁵Co with sarcophagine-based chelators. The authors demonstrated that the [⁵⁵Co]Co-DiAmSar complexes could be efficiently formed under mild conditions with purity and stability suitable for pre-clinical in vivo radiopharmaceutical applications (29). These results highlight the potential of sarcophagine frameworks for radiocobalt theranostic applications, offering an alternative to traditional macrocyclic chelators with favorable stability profiles. Ge et al. explored the use of a [(triazol-4-yl)methyl]-N1,N2,N2-tris(pyridin-2-ylmethyl)ethane-1,2-diamine (TZTPEN) conjugate for binding Co²⁺ and Co³⁺. While the TZTPEN complex demonstrated promising coordination properties, in vivo evaluation revealed bone uptake, indicating potential dissociation and incomplete kinetic stability under physiological conditions. This effort was the first application of a polydentate polypyridyl-amine chelator in radiochemistry (30). The results of these studies will be further discussed in the next section.

4 Radiopharmaceutical development

The discovery of molecular targets and the development of suitable chelators for targeted imaging and therapy remain active areas of preclinical research. This section offers a concise overview of molecular targets explored using ⁵⁵Co- and ^58mCo-labeled radiopharmaceuticals for theranostic applications since 2021.

4.1 Neurotensin receptors

Neurotensin receptors (NTSRs) are a family of transmembrane G-protein-coupled receptors (GPCR) that bind the peptide neurotensin (NTS), which acts as a neurotransmitter or neuromodulator in the central nervous system and as a hormone in the peripheral nervous system. NTS promotes the growth of tissue, suggesting that NTS could contribute to the growth of cancers (31–33). Three subtypes of NTSRs have been identified and are overexpressed in varying levels in different types of cancers including pancreatic, prostate, breast, colon, and non-small cell lung cancers, indicating that it may be a suitable molecular target (34–38). A theranostic study using novel [^55/58mCo]Co-NOTA-NT-20.3 tracers investigated the targeting properties and cytotoxicity in HT29 human colorectal adenocarcinoma cells. in vitro experiments using [^55/58mCo]Co-NOTA-NT-20.3 suggested that the tracer behaves similarly to natural neurotensin with reduced binding affinity. in vivo imaging with [⁵⁵Co]Co-NOTA-NT-20.3 showed uptake in the HT29 tumor, indicating radiotracer selectivity (25, 39). While therapy studies demonstrated enhanced cytotoxicity of [^58mCo]Co-NOTA-NT-20.3 in comparison to [^58mCo]CoCl₂ (>15x), only modest therapeutic response was identified in vivo, and the tumor receiving an absorbed dose of 0.6 Gy from a 110 MBq treatment. Due to the low absorbed dose to the tumor, the authors suggested that uptake could be enhanced by utilizing alternative neurotensin analogues with improved binding affinities or by employing neurotensin antagonists (25). However, it is crucial that any selected alternative retains internalizing capability, particularly to the nucleus, as it is essential for Auger therapy.

Another study investigated the in vivo feasibility of a ⁵⁵Co-labeled NTS complex conjugated with a functionalized sarcophagine chelator and found that [⁵⁵Co]Co-NT-sarcage demonstrated prominent tumor uptake in HT29 xenografted nude mice and achieved a high tumor-to-background ratio (29). Fonseca Cabrera et al. synthesized ⁶⁴Cu-, ⁵⁵Co-, and ⁶⁸Ga-labeled radiopharmaceuticals targeting different tumor models expressing NTSR-1 and investigated the effect of macrocycles on in vivo distribution. [⁵⁵Co]Co-NT-CB-NOTA revealed high tumor uptake, high tumor-to-background contrast, and sustained tumor uptake in HT29 tumor models leading the authors to conclude that NT-Sarcage labeled with ⁵⁵Co/^58mCo may be an excellent theranostic pair targeting NTSR-1 positive cancers (40).

4.2 Prostate-Specific membrane antigen

Prostate-specific membrane antigen (PSMA) is a type II membrane glycoprotein that is overexpressed in prostate cancer and has been deemed the most promising target for prostate cancer imaging and therapy, to date, as highlighted via the FDA approval of [¹⁷⁷Lu]Lu-PSMA-617 (41). A preclinical study by Baun et al. evaluated the theranostic pair [^55/58mCo]Co-DOTA-PSMA-617 for PET imaging and Auger therapy of prostate cancer using PC3-PIP (PSMA+), LNCaP (PSMA+), and PC3-flu (PSMA-) cell lines. in vitro binding assays showed PSMA-specific uptake in PC3-PIP and LNCaP cells with high cell-associated activity in the nucleus. in vivo studies in tumor-bearing mice showed high specific tumor uptake and a significantly increased median survival for mice treated with [^58mCo]Co-DOTA-PSMA-617 compared to control mice (Figure 1). The authors concluded that [^55/58mCo]Co-DOTA-PSMA-617 exhibited excellent in vitro and in vivo properties with no observed toxicities (23). A deep dive into the synthesis of single redox species employed the PSMA-targeted radiopharmaceuticals [⁵⁵Co]Co-NO2A-PSMA-617, [⁵⁵Co]Co-NOTA-PSMA-617, and [⁵⁵Co]Co-DO3A-PSMA-617 to stabilize ⁵⁵Co²⁺ or ⁵⁵Co³⁺ species for PET imaging in a mouse model. Results of the PET region of interest quantification and the biodistribution profiles at 24 h post-injection of the three tracers identified [⁵⁵Co]Co-DO3A-PSMA-617 as achieving the highest tumor uptake and suggested that it may be due to the anionic charge of the complex. They determined that once the ⁵⁵Co²⁺ and ⁵⁵Co³⁺ species are formed and isolated as thermodynamically favored, the oxidation state is retained in vivo and suitable for radiopharmaceutical development (28).

Figure 1

Figure 1. Coronal maximum intensity projection PET/CT images showing uptake and distribution of [⁵⁵Co]Co-DOTA-PSMA-617 in PC3-PIP tumor-bearing NOD-SCID mice at (a) 1 h, (b) 4 h, and (c) 24 h pi. The intensity of the PET data is displayed from zero to maximum tumor uptake. Arrows indicate the subcutaneous PC3-PIP tumor. [Figure adapted from Baun et al. (23) Creative Commons Attribution 4.0 International License].

4.3 Gastrin-releasing peptide receptors

Gastrin-releasing peptide receptors (GRPRs) are compelling molecular targets for imaging and therapy due to their overexpression in a variety of malignancies, including prostate, gastrointestinal, and breast cancers (42–44). Targeting GRPRs with PET imaging agents has demonstrated the potential to enhance imaging sensitivity and facilitate the early detection of lymph node involvement. Notably, GRPR has emerged as a promising target for estrogen-receptor positive (ER+) breast cancer in a preclinical study using [⁵⁵Co]Co- and [¹⁷⁷Lu]Lu-DOTA-RM26. in vitro studies using the ER + T47D cell line demonstrated high binding that significantly increased from 1 h to 4 h and was effectively blocked by a 1,000× excess of unlabeled DOTA-RM26, confirming binding specificity. in vivo biodistribution studies revealed that the tumor exhibited the highest radioligand uptake at 4 h post-injection, followed by the kidneys. Although tumor uptake decreased over time, it remained the highest uptake among all tissues. The authors concluded PET/CT imaging with [⁵⁵Co]Co-DOTA-RM26 demonstrated GRPR-specific tumor visualization and enabled next day imaging (44).

4.4 Human epidermal growth factor receptors

The human epidermal growth factor receptors (HER) are a family of transmembrane proteins involved in regulating proliferation, motility, and apoptosis (45). Overexpression of the epidermal growth factor receptor (EGFR/HER1) is implicated in several cancers, including non-small-cell lung cancer and head and neck squamous cell carcinoma, making EGFR a well-established target for anti-cancer therapies (46–48). [⁵⁷Co]Co-GE11-TZTPEN is a novel construct that was investigated for its EGFR-targeting capabilities by Ge et al. in vitro studies confirmed a high radiochemical yield (99%) and radionuclidic purity (99%), along with specific uptake in EGFR-positive cell lines. However, in vivo imaging revealed negligible tumor uptake and predominant accumulation in non-target organs, including the liver, gall bladder, kidneys, and spleen. Based on these findings, [⁵⁷Co]Co-GE11-TZTPEN was deemed unsuitable as an EGFR-targeted radiopharmaceutical for in vivo applications (30).

5 Challenges and future directions

While radiocobalt-based theranostics offer unique advantages for PET imaging and targeted Auger electron therapy, particularly due to the favorable half-lives of ⁵⁵Co ($t_{1/2}$ = 17.5 h) and ^58mCo ($t_{1/2}$ = 9.1 h), and their strong coordination chemistry, several key challenges remain that hinder clinical translation. One of the major limitations is the coproduction of long-lived radionuclidic contaminants during cyclotron irradiation including ⁵⁶Co ($t_{1/2}$ = 77.2 d) and ^58gCo ($t_{1/2}$ = 70.9 d). These impurities are particularly problematic for therapeutic applications, where small contributions can substantially increase patient dose and compromise safety.

A significant barrier to radiocobalt production is the need for medium or high energy cyclotrons and enriched target materials, such as ⁵⁸Ni and ⁵⁴Fe, which are expensive and not widely available. One solution involves implementation of target recovery and recycling methods as demonstrated by Valdovinos et al., which could reduce the cost of production (16). Additionally, alternative target designs could improve manufacturability. Siikanen et al. designed a target consisting of a ⁵⁸Ni/Mg matrix that enabled faster target fabrication, higher thermal conductivity, and a more efficient dissolution to streamline the production of ⁵⁵Co (49). Another study investigated the employment of a siphon style liquid target system to produce ^58mCo on a 13 MeV medical cyclotron (50). Improved target design and reprocessing could support routine clinical production leading to more widespread use.

Despite growing interest in the field of theranostics, there are currently no FDA-approved radiopharmaceuticals incorporating radiocobalt. While preclinical studies have demonstrated that ^55/58mCo-labeled analogues can offer superior imaging and therapeutic capabilities compared to some FDA-approved agents incorporating ⁶⁸Ga and ⁶⁴Cu, further research is needed to identify predictive biomarkers that support clinical efficacy (51). To highlight an example of such, radiocobalt-labeled NTS analogues have demonstrated excellent in vitro cytotoxicity, but only modest therapeutic effects were observed in vivo, highlighting the need for biomarkers that better correlate with therapeutic outcomes (25). In contrast, PSMA-targeted imaging and therapy with ^55/58mCo-labeled analogues have demonstrated excellent internalization and tumor uptake, indicating the potential for clinical translation (23). Additionally, ⁵⁵Co-labeled compounds targeting GRPRs and EGFRs have allowed for successful visualization of tumors in mouse models, though therapeutic data utilizing ^58mCo remains limited and should be the priority for future work.

To advance clinical potential, improvements in in vivo performance should focus on improving the stability and minimizing off-target uptake. This highlights the need for novel chelators that exhibit fast complexation kinetics and maintain high in vivo stability. Expanding the range of molecular targets and designing radiopharmaceuticals with high binding affinities is critical for broadening the scope of radiocobalt-based theranostics. However, clinical translation may face considerable challenges when considering the need for dosimetric validations and toxicity profiling.

6 Conclusion

The radiocobalt isotopes ⁵⁵Co and ^58mCo offer a promising elementally matched pair for theranostic applications due to their excellent nuclear properties and identical coordination chemistry. This theranostic pair supports the development of novel radiopharmaceuticals for PET imaging (⁵⁵Co) and Auger electron therapy (^58mCo), with the capability targeting a wide variety of malignancies. To date approximately 67 papers have been published on ⁵⁵Co and 12 on ^58mCo, with 12 and 8 of those, respectively, having been published in the last five years. This indicates a trending increase in the excitement towards the production, radiochemistry, and translation of radiocobalt. Successful clinical translation relies on robust isotope production methods and the formulation of stable radiopharmaceuticals with a high affinity and specificity for molecular targets of interest. Although numerous production methods have been identified, proton and deuteron irradiation of enriched targets remain the most commonly implemented and have demonstrated the ability to generate high purity ⁵⁵Co and ^58mCo suitable for radiopharmaceutical use. These production methods are mostly limited by the limited supply and expense of enriched target materials and access to cyclotrons. Future efforts should prioritize on enhancing production efficiency while maintaining high radionuclidic purity and cost-effectiveness. Advancements in chelation chemistry and the development of novel targeting vectors have led to promising preclinical results in prostate, breast, and other cancers, however, challenges still persist in achieving high in vivo stability, reducing off-target accumulation, and validating therapeutic efficacy in preclinical studies. Radiocobalt theranostics provides a compelling platform in precision medicine. Continued progress in isotope production and radiopharmaceutical design are essential in bridging the gap between preclinical studies and clinical translation.

Author contributions

AS: Writing – original draft, Writing – review & editing. IC: Writing – review & editing.

Funding

The author(s) declare that financial support was received for the research and/or publication of this article. Financial support from the University of Tennessee Department of Nuclear Engineering was received to publish this work.

Acknowledgments

We would like to thank the Department of Nuclear Engineering at the University of Tennessee, Knoxville.

Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Generative AI statement

The author(s) declare that no Generative AI was used in the creation of this manuscript.

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