Radiometals in Imaging and Therapy: Highlighting Two Decades of Research.

1. Introduction

External radiation therapy is a common and effective treatment for various cancers. Radiation therapy was first applied over 100 years ago, immediately after the discovery of the X-ray [ 1 ]. Clinicians used it for the treatment of skin diseases, lupus, and other lesions [ 2 , 3 , 4 , 5 ]. However, due to the collateral damage and resulting side effects, including hair loss, blurry vision, and dry and itchy skin, its application stalled and triggered the need for an alternative treatment option [ 6 ].

In the last two decades, nuclear medicine, including radionuclide therapy, has observed significant growth and development: newer radiopharmaceuticals have been introduced, and their applications in imaging and targeted radionuclide therapy have been diverse [ 7 ]. Targeted radionuclide therapy (TRT) has great potential to destroy even the smallest clusters of metastatic cancer cells present anywhere in the body, which is hard to achieve with either external beam radiation therapy or surgery. Therefore, TRT has been clinically used to treat numerous malignancies, such as neuroblastoma, along with breast, thyroid, and prostate cancer [ 7 , 8 , 9 ]. Treatments using TRT have been explored with and without additional treatment options, such as surgery and chemotherapy.

Typically, therapeutic radiopharmaceuticals consist of four components: (i) a therapeutic radioactive isotope (e.g., 177 Lu, 67 Cu, 90 Y, 212 Pb, 212 Bi, 225 Ac, 223 Ra, etc.), (ii) a chelator, (iii) a linker, and (iv) a targeting vector, which delivers the isotope to the affected organs/tissues for treatment. The targeting vector could be a monoclonal antibody (mAb), antibody (Ab) fragment (diabody, nanobody, or single chain variable fragment), protein, aptamer, peptide, extracellular vesicle, virus, or simply a small molecule, such as an inhibitor [ 7 ]. Radiometal-based imaging and diagnostic radiopharmaceuticals can be categorized as (i) positron emission tomography (PET) radiopharmaceuticals (bioactive molecules labeled with positron-emitting [β + ] isotopes) or (ii) single photon emission computed tomography (SPECT) radiopharmaceuticals (bioactive molecules labeled with gamma-emitting [γ] isotopes). Depending on the type of radiation-emitting isotopes, the therapeutic radiopharmaceuticals can be subdivided into (i) alpha (α) particle-emitting targeted radiopharmaceuticals, (ii) beta minus (β − ) particle-emitting targeted radiopharmaceuticals, and (iii) Meitner−Auger electron (MAE)-emitting radiopharmaceuticals [ 10 ]. Additionally, when radiopharmaceuticals are radiolabeled with both the diagnostic (imaging) and therapeutic isotopes, which could use the same element ( 64 Cu/ 67 Cu, 86 Y/ 90 Y, 44/43 Sc/ 47 Sc) or different elements ( 64 Cu/ 212 Pb, 68 Ga/ 177 Lu, 68 Ga/ 223 Ra), they are called “theranostic radiopharmaceuticals.” Depending on the plasma half-life of the targeting vector and the application (imaging/therapy), an appropriate radionuclide should be selected for radiolabeling. This article covers advancements made in radiometal-based diagnostic and therapeutic radiopharmaceuticals in the last two decades.

2. Diagnostic Radionuclides

PET and SPECT are radionuclide-based imaging modalities used routinely in nuclear medicine practice that fall under the category of “molecular imaging” because their radiotracers provide information about particular biological processes at the cellular and molecular levels.

PET measures the energy produced by the two gamma photons (511 keV) that result from annihilation of the positron emitted from the PET radionuclide with atomic electron [ 11 ]. The emitted gamma photons are detected with γ-cameras, also called scintillation detectors, which produce reconstructed three-dimensional images depicting the spatial distribution of radiotracers [ 11 ]. The common examples of PET probes includes [ 18 F]FDG, [ 13 N]NH 3 , [ 68 Ga]Ga-PSMA, and [ 18 F]NaF. Preclinical animal PET and clinical PET scanners offer spatial resolution of 1–2 mm and 6–10 mm, respectively, with high sensitivity of 10 −11 –10 −12 mol/L. This level of sensitivity is sufficient to detect biological changes in an organ or tissue to identify the onset of a disease before anatomical changes occur [ 12 ].

SPECT measures the single gamma photons emitted directly from γ-emitting radionuclides called SPECT radiopharmaceuticals. The conventional clinical SPECT scanners have lower sensitivity (10 −10 –10 −11 mol/L) and lower spatial resolution (7–15 mm) compared to PET scanners due to the limited performance of collimators [ 12 , 13 , 14 ] . Despite this, SPECT is the most routinely used nuclear imaging procedure in the clinic and is less expensive compared to PET. The most common SPECT isotopes are 111 In, 99m Tc, 123/131/125 I, and 67 Ga.

Recent advances in SPECT γ-cameras, collimators, and reconstruction algorithms have enhanced the spatial resolution and sensitivity of SPECT scanners, allowing for the imaging of a wide range of isotope energy (20–300 keV) [ 15 , 16 ]. Nevertheless, both PET and SPECT need either computed tomography (CT) or magnetic resonance imaging (MRI) for accurate anatomical information. Interestingly, PET cannot distinguish between two different PET probes when injected simultaneously because it measures two γ-rays with the same energy (511 keV); meanwhile, SPECT does have multiplexing capabilities because each radionuclide produces different γ-rays, enabling it to image different targets simultaneously [ 17 ].

3. Therapeutic Radionuclides

As stated previously, therapeutic radionuclides emit α particles, β − particles, and/or low-energy MAEs (non-energetic particles).

Beta minus emitters can be either of a high energy ( 90 Y, E β − max = 2.28 MeV,) or a low energy ( 177 Lu, E β − max = 496 keV), with tissue penetration ranges between 12 mm and 1.5 mm, respectively [ 18 ]. Given the long penetration depth of 0.2–12 mm and the moderate linear energy transfer (LET) radiation of ~0.2 keV/µm, β − emitters are more suited to treating large-sized tumors (>0.5 cm), and they are considered the current gold standard in targeted radionuclide therapy [ 19 , 20 ].

Alpha emitters emit α particles with high LET energies of 50–230 keV/µm and shorter penetration depths of 50–100 µm (i.e., 5–10 cell diameters) [ 21 ]. Alpha radionuclide-based targeted therapy is called targeted alpha therapy (TAT), and it is well suited for the treatment of hematological disease, small tumors, metastasis, and isolated cancer cells. Alpha emitters are perceived as a better therapeutic alternative to beta emitters due to their high LET and short tissue penetration range.

Meitner−Auger electrons are low-energy electrons that can penetrate up to the subcellular nanometer range (<0.5 µm), resulting in a high LET of 4–26 keV/µm [ 22 ]. Given the low tissue penetration range and high LET in an extremely small area, MAE emitters could be highly valuable for treating metastatic cancers if delivered selectively within the nucleus of the cancer cells [ 22 ]. Figure 1 explains the difference between LET, pathlength (penetration range), and the usefulness of α and β − radionuclide therapies.

4. Positron Emitters

4.1. Radioisotopes of Copper

4.1.1. General Information

Among the long list of radioisotopes of copper (Cu), 60 Cu, 61 Cu, 62 Cu, and 64 Cu are used for diagnostic imaging, while 64 Cu and 67 Cu are applied in radionuclide therapy [ 23 ]. 64 Cu decays by both β + (~17%) and β − (~38%), making it applicable for PET imaging and targeted radionuclide therapy; therefore, it is considered a theranostic radionuclide [ 24 ]. In addition, 64 Cu also decays by electron capture (EC), which results in a cascade of Auger electrons [ 22 , 24 ]. The decay characteristics of Cu radioisotopes are mentioned in Table 1 .

4.1.2. Growth and Advancement of Radiopharmaceuticals Labeled with Copper-Radioisotopes in Clinical Practice

In 1997, [ 62 Cu]Cu-diacetylbis(4-methylthiosemicarbazone), also known as [ 62 Cu]Cu-ATSM, was first discovered as a hypoxia imaging agent in a rat model of cardiac ischemia [ 26 ]. Later, other Cu isotopes, including 60/61/64 Cu, were used to radiolabel ATSM and employed for imaging of hypoxic solid tumors, with a similar uptake and clearance profile in patients [ 27 , 28 , 29 , 30 , 31 ].

Considering the longer half-life of 64 Cu, [ 64 Cu]Cu-ATSM was applied as a hypoxia imaging radiotracer in rectal cancer (National Clinical Trial (NCT) 03951337) [ 32 ]. However, several debatable preclinical studies highlighted its lower uptake in hypoxic tumors [ 28 ]. The therapeutic potential of [ 64 Cu]Cu-ATSM was first studied in 2001, where it resulted in a six-fold increase in the survival of 50% of hamsters bearing human GW39 colon cancer [ 33 ]. Later, several additional preclinical studies supported the theranostic potential of [ 64 Cu]Cu-ATSM to treat various colon carcinoma xenografts (Colon-26, HT-29). In addition to preclinical studies, clinical studies are needed to prove its true theranostic value [ 34 , 35 , 36 ].

During the last two decades, various 64 Cu-labeled Abs have been developed for immuno-PET imaging [ 37 , 38 , 39 ]. Among them, [ 64 Cu]Cu-DOTA-trastuzumab showed promising clinical utility in identifying HER2+ tumors with high sensitivity (~89%) in breast cancer patients [ 40 , 41 ].

Currently, commonly used somatostatin radiotracers for neuroendocrine tumor (NET) diagnosis are [ 111 In]In-DTPA-octreotide [ 42 ], [ 99m Tc]Tc-EDDA/HYNIC-TOC [ 43 ], and [ 68 Ga]Ga-DOTATOC [ 44 ], with first-in-human studies reported in the years 1993, 2005, and 2001, respectively. During 2012–2017, Pfeifer and Johnbeck’s team conducted two separate clinical studies using newly developed [ 64 Cu]Cu-DOTA-TATE on NET patients. Their findings revealed the outperformance of [ 64 Cu]Cu-DOTA-TATE over [ 111 In]In-DTPA-octreotide [ 45 ] and [ 68 Ga]Ga-DOTATOC [ 46 ] in terms of spatial resolution, lesion detection rate, and, most importantly, the ability to identify additional lesions.

A recent clinical study of [ 64 Cu]Cu-DOTA-TATE (200 MBq dose) demonstrated that [ 64 Cu]Cu-DOTA-TATE is excellent for lesion detection in neuroendocrine neoplasm patients [ 47 ]. In 2020, the Food and Drug Administration (FDA) approved the first 64 Cu-labeled PET radiopharmaceuticals, [ 64 Cu]-DOTA-TATE (Detectnet TM ), for the localization of somatostatin-targeting receptor (SSTR)-positive NETs in adult patients [ 48 ]. Additionally, the radiotracer [ 67/64 Cu]Cu-Sar-TATE was recently entered into multiple clinical trials to diagnose and treat SSTR-positive tumors [ 49 ].

In addition to radiolabeled somatostatin-targeting peptides, a series of PSMA ligands have been identified and radiolabeled with Cu radioisotopes for clinical diagnosis and radionuclide therapy applications in PCa [ 50 , 51 , 52 ]. In 2016, 64 Cu-labeled PSMA-617 became the first 64 Cu-labeled ligand for PET imaging of PCa patients and was investigated at two nuclear medicine centers (Vienna, Austria, and Bed Berka, Germany) [ 53 ]. Even though [ 68 Ga]Ga-PSMA is an excellent tracer to detect PCa and metastatic lesions in the lymph node or bone at low PSA levels [ 54 ], the advantage of the lower positron energy of 64 Cu (E β + avg = 278 keV) vs. 68 Ga (E β + avg = 829 keV) and the longer half-life (12.7 h) of 64 Cu allow its distribution and use as [ 64 Cu]Cu-PSMA-617 at various clinical PET centers with no sophisticated onsite radiotracer production facility [ 53 ].

67 Cu is one of the most promising radionuclides for radioimmunotherapy (RIT), as its 61.8 h isotopic half-life is well matched with the residence time of a typical Ab on the tumor site. In 1998, DeNardo reported a pilot study of [ 67 Cu]Cu-2IT-BAT-Lym-1 to image and treat chemo-resistive B-cell in non-Hodgkin’s lymphoma while employing favorable SPECT imaging and the remarkable radiotherapeutic effects of 67 Cu-labeled 2IT-BAT-Lym-1 [ 55 ]. The clinical investigation of Cu radiopharmaceuticals is outlined in Table 2 .

4.1.3. Production and Availability

At present, the most common method to produce 64 Cu is proton irradiation of enriched 64 Ni via a 64 Ni(p,n) 64 Cu nuclear reaction in a small−medium-energy biomedical cyclotron [ 66 ]. The main route to produce 67 Cu for decades had been via a 68 Zn(p,2p) 67 Cu nuclear reaction that utilizes enriched 68 Zn and high-energy proton irradiation (up to 40 MeV), which also coproduces 64 Cu [ 67 ]. Recently, Mou et al. developed and patented the fabrication of multi-layer targets composed of enriched 70 Zn and 68 Zn that could maximize 67 Cu production yield [ 68 ].

4.2. Radioisotopes of Gallium

4.2.1. General Information

Among the many radioisotopes of Gallium (Ga), 66 Ga, 67 Ga, and 68 Ga are predominantly used in medical applications for the radiolabeling of various biomolecules [ 69 ]. 67 Ga and 68 Ga are predominantly used in nuclear medicine for SPECT and PET imaging, respectively. 66 Ga ((t 1/2 = 9.49 h) is an attractive PET radionuclide with a relatively longer half-life than 68 Ga (t 1/2 = 67.71 min). Due to its high positron emission energy (E β+avg = 1750 keV), though, along with the co-emission of higher gamma rays than 68 Ga, 66 Ga suffers from poor image resolution and high radiation exposure to workers, limiting its medical application [ 70 ].

67 Ga is one of the longer-lived Ga radioisotopes, and it decays by EC (100%) with multiple gamma emissions, with the most common gamma energies emitted as 93 keV (39%), 184 keV (21%), and 300 keV (17%) for the SPECT imaging [ 71 ]. [ 67 Ga]Ga-citrate is the most popular radiopharmaceutical of 67 Ga. For several decades, it has been used in the diagnosis of osteomyelitis and other bone infections [ 72 , 73 ]. To date, [ 67 Ga]Ga-citrate scintigraphy is used worldwide for the diagnosis of lymphomas [ 74 ], lung cancer [ 75 , 76 ], and inflammation of the kidneys [ 77 ]. The nuclear decay properties of Ga radionuclides are displayed in Table 3 .

4.2.2. Clinical Practice

Gallium-68 is one of the earliest radionuclides applied in the early days of PET scans (early 1960s), long before the discovery of [ 18 F]fluorodeoxyglucose (FDG) in 1978 [ 79 ]. However, the growth of 68 Ga-labeled radiopharmaceuticals in clinical applications began after the commercial launch of next-generation 68 Ge/ 68 Ga generators in the early 21st century (mid-2000s) [ 80 , 81 ]. During 2000–2010, various Ga-68-labeled peptide-based radiopharmaceuticals, such as [ 68 Ga]Ga-DOTA-TATE [ 82 ], [ 68 Ga]Ga-DOTA-TOC [ 44 , 82 ], and [ 68 Ga]Ga-DOTA-NOC [ 83 ], were clinically evaluated in peptide receptor radionuclide therapy (PRRT) to visualize NET-expressing SSTR2. Later, [ 68 Ga]Ga-PSMA-11 (also known as PSMA-HBED, HBED-CC) was investigated for the diagnosis of recurrent PCa, and it received FDA approval in 2020 [ 84 ]. Several clinical studies involving 68 Ga were recently conducted with its “theranostic twin”, 177 Lu, for diagnosis and radionuclide therapy of NETs and PCa. A tremendous growth in the application of [ 68 Ga]Ga-PSMA-11 has occurred for imaging metastatic castration-resistant PCa over other radiotracers. Additionally, there is high demand for its theranostic pair of PSMA, labeled with either beta emitter 177 Lu or alpha emitter 225 Ac [ 85 , 86 , 87 , 88 ]. The clinical investigation of 68 Ga radiopharmaceuticals is noted in Table 4 .

4.2.3. Production and Availability

Currently, the most convenient method to produce 68 Ga is from germanium (Ge) 68 (t 1/2 ~271 d) using 68 Ge/ 68 Ga generators [ 89 ]. However, the shortage of these generators and on-demand supply of 68 Ga have led to the generation of alternative methods of production using, as an example, cyclotrons (12–17 MeV) via the 68 Zn(p,n) 68 Ga nuclear reaction [ 90 ]. During 2014–2019, Pandey et al. pioneered cyclotron-mediated 68 Ga production using a liquid target to overcome the global shortage of 68 Ga [ 91 , 92 , 93 ]. Besides liquid target-based production, several high-yielding solid target-based production methods, also using cyclotron, have been developed and commercialized to meet the upcoming demands of 68 Ga [ 94 , 95 , 96 ]. On the other hand, the common production of 67 Ga through the irradiation of nat Zn or isotopically enriched 68 Zn targets via 68 Zn (p,2n) 67 Ga or 67 Zn(p,n) 67 Ga on cyclotron have been reported [ 97 ].

4.3. Radioisotopes of Zirconium

4.3.1. General Information

Zirconium-89 ( 89 Zr) is a promising radionuclide for the PET imaging of Abs due to its longer physical half-life (78.4 h), which matches with the blood half-life of most full-length Abs (days to weeks) [ 104 ]. 89 Zr has a relatively short penetration range by emitting low-energy positrons (E β + avg = 396 keV), which facilitate high-resolution PET images [ 104 ]. However, 89 Zr emits an abundance of high-energy γ-rays of 909 keV, adding radiation exposure to medical staff and patients [ 104 ]. Table 5 summarizes the decay characteristics of Zr-89.

4.3.2. Clinical Practice

In 2006, the first clinical study of [ 89 Zr]Zr-immuno PET was reported, where 89 Zr-labeled chimeric mAb U36 localized in all primary tumors and lymph node metastasis of head and neck cancer patients with an accuracy as high as 93% [ 106 ]. Presently, the FDA has approved hundreds of mAbs against various biological targets, such as HER2, CD20, epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF), and PSMA, resulting in several [ 89 Zr]Zr-Immuno PET-based clinical oncology trials [ 107 , 108 ]. Currently, [ 89 Zr]Zr-trastuzumab and [ 89 Zr]Zr-pertuzumab are the two common choices for immuno-PET-targeting HER2+ breast cancer. The first-in-human studies using [ 89 Zr]Zr-trastuzumab (37 MBq) and [ 89 Zr]Zr-pertuzumab (74 MBq) on metastatic breast cancer patients were reported in the years 2010 and 2018, respectively [ 109 , 110 ]. Currently, both radiopharmaceuticals are registered in clinical trials.

Additional clinical pilot studies have been published using [ 89 Zr]Zr-immuno-PET probes, such as [ 89 Zr]Zr-bevacizumab targeting VEGF-A expression [ 111 ], [ 89 Zr]Zr-rituximab targeting B-lymphocyte antigen (CD20) expression [ 112 ], and [ 89 Zr]Zr-cetuximab-targeting EGFR [ 113 ], in various tumors. These [ 89 Zr]Zr-immuno-PET probes have been shown to be useful for imaging and/or radionuclide therapy applications. Currently, [ 89 Zr]Zr-bevacizumab is registered in an ongoing clinical trial (National Clinical Trial (NCT) 01894451) [ 114 ]. Considering the long blood circulation time of monoclonal Abs (mAbs), alternative Abs and their fragments were developed in the last five years to significantly shorten their retention time in blood and to rapidly clear the unbound fragments from the body [ 115 ]. Early examples of Ab fragment application are minibody-based radiopharmaceuticals, such as [ 89 Zr]Zr-Df-IAB2M, which were used to detect PSMA-positive PCa and recurrent cerebral high-grade gliomas [ 116 , 117 ]. In addition to minibody-based radiopharmaceuticals, several preclinical studies reported 89 Zr-labeled affibodies, such as [ 89 Zr]Zr-Df-ZEGFR:03115 and [ 89 Zr]Zr-DFO-MAL-Cys-MZ, as targeting EGFR and HER2, respectively [ 118 , 119 ]. To fully evaluate the clinical value of affibodies and Ab fragments, additional clinical studies demonstrating their usefulness are paramount.

Besides Abs, cell labeling with 89 Zr has been explored for the imaging of white blood cells and CAR-T cells. Several preclinical studies using [ 89 Zr]Zr-oxine and [ 89 Zr]Zr-Df-aTCRmu-F(ab’) 2 were reported to track T cells in glioblastoma and acute myeloid sarcoma, respectively [ 120 , 121 ]. Covalent tethering of [ 89 Zr]Zr-DBN to cells is another highly studied methodology to noninvasively track various cell types with PET. Published reports of this method demonstrate that it offers a robust and reliable approach that could be translated in humans for monitoring cell-based therapies [ 122 , 123 , 124 , 125 ]. Table 6 summarizes the clinical applications of 89 Zr-based radiopharmaceuticals.

4.3.3. Production and Availability

The production and availability of 89 Zr have been improved significantly in the last two decades. Various methods of 89 Zr production on solid and liquid targets using cyclotron have evolved over the years, resulting in better and simplified methods of purification and radiolabeling [ 91 , 93 , 126 , 127 , 128 , 129 , 130 , 131 , 132 ]. The main route of production is proton irradiation of yttrium (Y) via a 89 Y(p, n) 89 Zr nuclear reaction [ 126 ]. At present, 89 Zr is routinely produced at various academic institutions for their own use, including Mayo Clinic Rochester, and for supplying other institutions, including the University of Wisconsin, the University of Alabama, and commercial vendors within the United States. Some European and Asian academic institutions also manufacture 89 Zr routinely and use it predominantly in preclinical studies. In the last 10 years, several groups have come up with alternative solutions that facilitate the GMP-grade production and formulation of 89 Zr. For example, Wooten et al. designed an automated system for routine 89 Zr production and purification at high radioactivity quantities, with >99.9% of radionuclidic purity [ 133 ]. In terms of purification, Pandey et al. developed a simplified synthesis of hydroxamate resin for trapping of Zr-89 with a trapping efficiency of 93% and its subsequent elution either as oxalate or phosphate in a high elution efficiency (>90%) [ 134 ]. Recently, the same group designed a new solid target insert and optimized the thickness of 89 Y foil and proton beam energy to improve the production yield of 89 Zr (~129 mCi or 4.77GBq) using medium energy cyclotrons [ 126 ]. Others in the field have also significantly contributed towards the advancement of Zr-89 production and purification [ 135 , 136 ].

4.4. Radioisotopes of Scandium

4.4.1. General Information

Scandium (Sc) has 25 different radioisotopes, but 43 Sc, 44 Sc, and 47 Sc are the commonly explored radionuclides for PET imaging and targeted radionuclide therapy applications [ 150 ]. 44 Sc and 43 Sc are promising PET radionuclides, and they are superior alternatives to 68 Ga because of their lower positron energy and almost 3.5-fold longer half-life [ 150 , 151 ]. However, 44 Sc also decays via high gamma ray (E γ = 1157 keV; 99.9% abundance) emission and could give a high radiation exposure dose compared to other competing PET radionuclides [ 152 ]. The decay properties of Sc radionuclides are given in Table 7 .

4.4.2. Current Clinical Application of Scandium-44

In 2017, the first clinical study of generator-derived 44 Sc with [ 44 Sc]Sc-DOTATOC was reported for the imaging of a metastatic neuroendocrine neoplasm at Bed Berka [ 153 ]. Recently, [ 44 Sc]-PSMA-617 was also applied for the imaging of PCa patients [ 154 ], and it showed performance comparable to [ 68 Ga]Ga-PSMA-617 in terms of tumor uptake and image quality [ 154 ]. Given the availability of both imaging ( 43/44 Sc) and therapeutic ( 47 Sc) radionuclides, Sc radiopharmaceuticals are gaining significant interest as an alternative theranostic pair [ 155 ].

43 Sc is another PET isotope of the Sc family with similar physical characteristics to 44 Sc, but it is devoid of high-energy gamma emission and lower positron energy (E β + avg = 476 keV), making it a more favorable imaging isotope than 44 Sc [ 150 ]. However, no preclinical or clinical studies are yet reported with 43 Sc-labeled radiopharmaceuticals.

47 Sc is a radio theragnostic isotope that emits low-energy β − particles (E β − avg = 162 keV) and low-energy γ-radiations (E γ = 159 keV) [ 150 ]. The decay characteristics of 47 Sc are like 67 Cu (E β-avg = 141 keV, E γ = 184 keV) and 177 Lu (E β − avg = 134 keV, E γ = 113, 208 keV). Recently, a comparative preclinical study with [ 47 Sc]Sc-folate (12.5 MBq), [ 177 Lu]Lu-folate (10 MBq), and [ 90 Y]Y-folate (5 MBq) showed a similar therapeutic response in an ovarian xenograft model [ 156 ]. Due to the challenging production routes of 47 Sc, though, clinical studies involving 47 Sc have yet to evolve [ 156 ].

4.4.3. Production and Availability

In 2010, Frank Rosch et al. reported the production of 44 Sc (approx.185 MBq) using a 44 Ti/ 44 Sc generator for the first time at Bed Berka, Germany [ 157 ]. However, the production of the parent radionuclide, 44 Ti, and the accessibility of these generators were challenging. Later, in 2015, Van der Meulen et al. reported a cyclotron-based production of 44 Sc via proton irradiation (11 MeV) of an enriched 44 Ca target, which allowed elution of approximately 2 GBq of 44 Sc at the Paul Scherrer Institute (PSI) in Switzerland [ 158 ]. Later, Szkliniarz et al. reported several cyclotron-based production routes for emerging 43 Sc using either α particles or deuteron beams because the limited availability of high-energy multi-particle cyclotrons restricted the utility of these production routes [ 159 ]. Van der Meulen et al. demonstrated the production of 480 MBq of 43 Sc using enriched 43 CaCO 3 and targets via a 43 Ca(p,n) 43 Sc reaction; limited purity of 43 Sc was obtained due to the co-produced mixture of 43 Sc (66.2%) and 44 Sc (33.3%) [ 160 ]. 47 Sc can be produced using a cyclotron [ 161 ], neutron flux reactor [ 162 ], or electron linear accelerator [ 163 , 164 ].

4.5. Radioisotopes of Terbium

4.5.1. General Information

Among the various radioisotopes of Terbium (Tb), four ( 149/152/155/161 Tb) are of great interest in nuclear medicine and are commonly referred as a “Swiss army knife” of nuclear medicine [ 165 ]. 149 Tb has both positron and α-emission properties for both PET and targeted therapy applications [ 166 ]. 152 Tb is another positron emitter with a relatively longer half-life of 17.5 h that could be utilized for radiolabeling of large biomolecules [ 166 ]. The decay characteristics of Tb radionuclides are listed in Table 8 .

In 2012, Muller et al. performed the first radiolabeling of albumin-binding folate conjugates (cm09) with 149/152/155/161 Tb in an FR-positive tumor xenograft mouse model [ 167 ]. The findings demonstrated excellent tumor visualization through PET/CT using [ 152 Tb]Tb-cm09 and SPECT/CT, using both [ 155 Tb]Tb-cm09 and [ 161 Tb]Tb-cm09 probes at 24 h post administration. On the other hand, α therapy version [ 149 Tb]Tb-cm09 and β − therapy version [ 161 Tb]Tb-cm09 resulted in significantly delayed tumor growth by 33% and 80%, respectively.

4.5.2. Preclinical and Clinical Applications

149 Terbium: 149 Tb represents one of the powerful candidates for TAT, which emits short penetrating (~25 µm range) α particles (Eα = 3.97 MeV; I α = 16.7%) compared to currently employed α emitters [ 168 ]. Because 149 Tb also decays by positrons (β + ) and γ-radiations, 149 Tb-labeled radiopharmaceuticals could also be useful for PET and SPECT imaging [ 168 ].

In 2004, Beyer et al. demonstrated the first preclinical RIT with [ 149 Tb]Tb-rituximab in a leukemia xenograft mouse model, which resulted in tumor-free survival >120 days among 89% of the [ 149 Tb]Tb-rituximab-treated mice [ 169 ]. However, nearly 28% of the residual radioactivity of longer-lived daughter nuclides, 149 Eu (t 1/2 = 93 d), 145 Sm (t 1/2 = 340 d), and others were retained mainly in the mice bone marrow. Baum et al. demonstrated the first in-man PET/CT study of SSTR-targeted [ 149 Tb]Tb-DOTANOC on a male patient diagnosed with neuroendocrine ileum. The result was an excellent localization of [ 149 Tb]Tb-DOTANOC in this neuroendocrine neoplasm, in addition to multiple lymph nodes, skeletal metastasis, and SSTR-expressing organs [ 170 ].

Currently, 149 Tb is predominantly produced by ISOLDE/CERN (Switzerland), TRIUMF (Vancouver, Canada), and PNPI (Gatchina, Russia) [ 171 ]. More recently, preclinical studies with [ 149 Tb]Tb-DOTANOC and [ 149 Tb]Tb-PSMA-617 were reported in tumor xenograft mouse models of AR42J pancreatic and prostate cancers, respectively [ 168 , 172 ]. Thus far, no clinical study has been reported with 149 Tb [ 168 ].

152 Terbium: 152 Tb is a diagnostic radionuclide that decays via positron emission (E β + avg = 1142 keV) and multiple gamma radiations, which could lead to high radiation exposure [ 170 ]. The relatively long half-life of 152 Tb (t 1/2 = 17.5 h) allows it to be useful in dosimetry estimation. In fact, 152 Tb is an exact diagnostic match for 149 Tb and 161 Tb, as well as other clinically useful therapeutic radionuclides, like 177 Lu, due to their similarities in coordination chemistry and pharmacokinetics.

155 Terbium: 155 Tb is a suitable SPECT isotope, a promising alternative to the 111 In isotope, and it could be useful for dosimetry estimation of β − emitters, like 177 Lu, 90 Y, and 166 Ho [ 173 ].

161 Terbium: 161 Tb decays by low-energy (E β − avg = 154 keV) (β − ) emission, having a short tissue penetration (0.29 mm) range and a long half-life (t 1/2 ) of 6.8 d [ 174 ]. The decay characteristics and half-life of 161 Tb are like 177 Lu (E β − avg = 134 keV, t 1/2 = 6.7d) [ 174 ], although 161 Tb also emits a substantial number of auger electrons, which could be advantageous for therapeutic applications. However, the clinical superiority of 161 Tb over 77 Lu is yet to be established [ 175 , 176 , 177 ]. In addition to radionuclide therapy, 161 Tb also emits gamma photons enabling SPECT imaging [ 174 ]. Recently, Baum et al. demonstrated the first-in-human SPECT imaging using [ 161 Tb]Tb-DOTATOC in patients with paraganglioma and NETs and showed high-quality images and visualization of hepatic metastasis as well as multiple osteoblastic skeletal metastasis in patients [ 178 ].

The main constraint to the wider application of Tb isotopes is their availability: there are insufficient production quantities. The production of Tb isotopes requires expensive enriched targets and accelerator-based isotope separation on-line technology (ISOLDE), which is not widely available [ 166 ]. Table 9 summarizes the clinical investigation of Tb radionuclides.

4.5.3. Production and Availability

In 2012, Muller et al. reported on the production of 149/152/155 Tb in a range of ~6–15 MBq activity through a high-energy proton-induced spallation of tantalum foil targets, followed by dissolution and isotope separation [ 167 ]. Such a high-energy proton accelerator facility and mass separation technology (ISOLDE) are limited to a few centers worldwide, including CERN, Switzerland. Lately, CERN-MEDICIS (Medical isotopes collected from ISOLDE) technology was developed, which allowed for the production of 38 GBq of 149 Tb, 37 GBq of 152 Tb, and 5.3 GBq of 155 Tb [ 166 ]. 161 Tb (up to 15 GBq) can be produced in a neutron flux reactor using 160 Gd targets, as proposed by Lehenberger et al. at PSI, Switzerland [ 181 ]. Interestingly, the production concept and the cost of 161 Tb is like a non-carrier added 177 Lu [ 181 ].

4.6. Radioisotopes of Zinc

4.6.1. General Information

Zinc (Zn) exists in three positron-emitting isotopes ( 62/63/65 Zn) that have the potential to be used as PET biomarkers of zinc trafficking in various pathological conditions [ 182 ]. Among them, 62 Zn has limited use because it decays to another positron-emitting isotope, 62 Cu (β + = 98%; t 1/2 = 9.7 min), which could confound the image interpretation of PET scans [ 182 ]. Nevertheless, 62 Zn has been used preclinically to image zinc transport in pancreatic exocrine function [ 183 ].

Among the Zn PET isotopes, 65 Zn has the longest half-life (t 1/2 = 243.9 d), making it unsuitable for diagnostic imaging because it will cause high radiation exposure to patients over time [ 182 ]. 63 Zn has a favorable decay characteristic (β + = 93%; t 1/2 = 38.47 min) for diagnostic imaging and pharmacokinetic studies [ 184 , 185 ]. The decay properties of Zn radionuclides are given in Table 10 .

4.6.2. Clinical Applications

In 2016, DeGrado et al. conducted the first-in-human PET imaging study of [ 63 Zn]Zn-citrate on Alzheimer’s disease patients [ 185 ]. Although low uptake of [ 63 Zn]Zn-citrate was seen in the brain (SUV ~0.4) compared to other organs, like the liver, pancreas, kidney, and gastrointestinal tract, it was sufficient to study 63 Zn clearance kinetics on a regional basis in those patients. The regions with slower 63 Zn clearance corresponded to the regions of known amyloid-β pathology on [ 11 C]C-PiB PET scans and also the regions of lower uptake on [ 18 F]FDG-PET scans [ 185 ]. Further imaging studies are warranted, though, to study zinc homeostasis in persons with Alzheimer’s disease.

4.6.3. Production and Availability

In 2014, DeGrado et al. developed a cyclotron-based production of 63 Zn via a 63 Cu(p,n) 63 Zn nuclear reaction using a liquid target by irradiating an isotopically enriched solution of [ 63 Cu]Cu-nitrate [ 184 ]. 63 Zn was produced with a specific activity of 41.2 + 18.1 MBq/µg (uncorrected) and radionuclidic purity of 99.9% using 1.23 M of [ 63 Cu]-copper nitrate.

5. SPECT Probes

5.1. Technetium-99m

5.1.1. General Information

Technetium-99m ( 99m Tc) is the most widely used medical isotope in nuclear medicine, accounting for more than 80% of all nuclear medicine procedures, including myocardial perfusion imaging, cancer, and infection imaging [ 186 ]. 99m Tc-based agents are a favored choice for cardiac imaging in the U.S [ 187 ]. 99m Tc mainly disintegrates into its other isomeric 99 Tc (which is radioactive) with the release of low-energy monochromatic gamma rays (140.5 keV, 98.6%) that can be detected by any sensitive gamma cameras [ 188 ]. Despite the advent of superior PET technology and the prevalence of CT or MRI over nuclear medicine, 99m Tc-based radiopharmaceuticals have been continuously supplied in hospitals during routine clinical examinations [ 188 ]. The advantages behind them are (i) a short/sufficient half-life of 6 h, which offers minimum radiation exposure to patients, (ii) instant kit-based labeling and formulations due to rich coordination chemistry of Tc (multiple oxidation states), (iii) availability of transportable generators ( 99 Mo/ 99m Tc) for production, and (iv) cost-effective SPECT gamma cameras compared to expensive PET technology. These points have solidified the continuous application of 99m Tc-labeled radiopharmaceuticals [ 188 , 189 ]. The nuclear decay characteristics of 99m Tc are given in Table 11 .

5.1.2. Clinical Applications

Among the various clinical applications of 99m Tc-labeled radiopharmaceuticals, [ 99m Tc]Tc-HYNIC-TOC (Tektrotyd) is commercially available for the imaging of metastatic NETs [ 190 ]. A recent comparative study of [ 68 Ga]Ga-DOATATE and [ 99m Tc]Tc-HYNIC-TOC ( 99m Tc-octreotide) on NET patients showed the superiority of [ 68 Ga]Ga-DOATATE over [ 99m Tc]Tc-HYNIC-TOC in terms of sensitivity and specificity [ 191 ]. However, it is reasonable to re-evaluate the performance of 99m Tc-radiopharmaceuticals using ultra-fast SPECT scanners that may increase the image resolution up to twofold [ 192 ]. Additionally, [ 99m Tc]Tc-MIP1404 and [ 99m Tc]Tc-MIP-1405 are the first [ 99m Tc]Tc-labeled PSMA ligands applied in humans [ 193 ]. Although both agents can visualize PSMA tumors and metastatic lymph node/bone lesions, [ 99m Tc]Tc-MIP1404 (also known as Tc-Trofolastat) is advantageous over [ 99m Tc]Tc-MIP-1405 to detect PCa at early stages of the disease, and it is currently registered in a phase 3 clinical trial ( NCT02615067 ) [ 194 ]. In 2016, another promising PSMA-based SPECT agent [ 99m Tc]Tc-PSMA-Investigation & Surgery was applied for first-in-human radio-guided surgery (RSG) [ 195 ]. The clinical applications of 99m Tc radiopharmaceuticals are summarized in Table 12 .

5.1.3. Production and Availability

99m Tc is a radioactive decay product of 99 Mo (t 1/2 = 66h), which is traditionally made in a large nuclear reactor via fission of high-enriched uranium targets ( 235 U) [ 189 ]. The production of 99m Tc in the form of pertechnetate [ 99m Tc]TcO 4 − from the parent 99 Mo was achieved using the commercially available and transportable 99 Mo/ 99m Tc generators in nuclear medicine for the preparation of almost all of the 99m Tc-based radiopharmaceuticals. Until 2011, the global requirement for 99 Mo was fulfilled by seven nuclear research reactors. The mandatory shutdowns of these reactors for maintenance or due to breakdowns stopped the global supply in 2009, 2012, and 2013 [ 189 ]. To overcome such an unavoidable global crunch in the supply of 99 Mo, several research efforts were initiated, including the use of linear accelerators and cyclotrons, which utilize electron beam and proton irradiation of solid 100 Mo targets, respectively [ 205 , 206 ].

5.2. Indium-111

5.2.1. General Information

Indium-111 ( 111 In; t 1/2 = 2.8 d) is a SPECT isotope that decays by EC (100%) and low- energy γ-emission (171 keV, 245 keV) [ 207 ]. The decay characteristics are summarized in Table 13 . Over the decades, 111 In has been used as the reference standard for SPECT-immuno imaging of Abs [ 207 ]. 110m In is a PET radioisotope of In with a short half-life (69 min), and it is suitable for tracking short peptides (e.g., octreotide) having faster kinetics [ 208 ].

5.2.2. Clinical Practice

In mid-1978, McAffee and Thakur introduced a radiotracer, [ 111 In]In-oxine, which could be used to radiolabel leukocytes (white blood cells (WBC)) for the scintigraphic detection of focal infections [ 209 ]. In 1985, the FDA approved [ 111 In]In-oxine-tagged WBC scans for clinical imaging of inflammatory disease [ 210 ]. The reported sensitivity and specificity of these [ 111 In]In-WBC scans ranged from 60–100% to 69–92%, respectively, in detecting osteomyelitis, vascular grafts infection, bone infections, etc. [ 211 ]. Other than cell labeling, 111 In was also used in radiolabeling of various peptides, proteins, Abs, and drugs. For example, [ 111 In]In-capromab pendetide (ProstaScint ® ) was FDA-approved for immuno-SPECT imaging of PCa [ 212 ]; however, the poor tumor-to-background signals limited its routine clinical use [ 212 ]. Later, another promising PSMA immuno-SPECT tracer, [ 111 In]In-J591 (PSMA-Ab), was developed, and the first clinical trial was reported in 2005 [ 213 ]. Clinical trials of [ 111 In]In-J591 are underway and associated with the dosimetric projections of RIT with [ 90 Y]Y-J591 [ 214 ]. Furthermore, in 2018, Heckman et al. demonstrated the first-in-man study using the novel SPECT tracer [ 111 In]In-DOTA-girentuximab for intraoperative guidance of renal cell carcinoma resection in patients [ 215 ]. Table 14 summarizes the clinical application of 111 In-labeled radiopharmaceuticals.

5.2.3. Production and Availability

The most common production route of 111 In in a high yield (222 ± 5 MBq/µA.h) is proton irradiation (21 MeV) of enriched 112 Cd target via a 112 Cd (p,2n) 111 In nuclear reaction using a cyclotron [ 216 ].

6. Beta Minus Emitter

6.1. Yttrium-90

6.1.1. General Information

Yttrium-90 ( 90 Y) is a pure high-energy β − emitter (E β − max = 2284 keV, E β − avg = 933 keV), which decays to stable Zr-90 with no accompanying gamma emissions [ 223 ] ( Table 15 ). Y-90 has a longer tissue penetration depth of up to 11.8 mm [ 223 ]. To date, Y-90 has been radiolabeled with tumor-targeting Abs [ 224 ], SSTR-targeting peptides [ 225 ], and resins/glass microspheres to treat a variety of tumors [ 226 ].

6.1.2. Clinical Application of 90 Y

The FDA has approved two types of 90 Y microspheres, TheraSphere TM (glass microspheres) and SIR-spheres ® (resin microspheres), to treat unresectable hepatocellular carcinoma and colorectal metastasis, respectively [ 227 , 228 ].

These 90 Y-microspheres have been used in therapies based on the concept of “radioembolization” (also known as selective internal radiation therapy); it is a promising catheter-based liver-directed therapy approved by the FDA for patients with primary/metastatic liver tumors. It was found that the antitumor effect of 90 Y-microspheres (glass microspheres, also known as Thersphere TM ) are related to beta radiations rather than embolization and therefore proven safer/successful for advanced-stage liver cancer [ 227 ]. The recent phase III trials of radioembolization of 90 Y-resin microspheres in patients with HCC demonstrated significantly higher tumor response with respect to standard first-line treatment with Sorafenib. However, these results did not meet the primary endpoint, such as overall survival or the patient’s quality of life. Several Asian guidelines recommend 90 Y-resin microspheres for HCC treatment based on certain considerations, such as patient selection, treatment planning using accurate dosimetry pre/post-radioembolization, and technical aspects [ 229 , 230 , 231 , 232 ].

In 2002, the FDA approved the first anti-CD20 radioimmunoconjugate [ 90 Y]Y-Ibritumomab tiuxetan (Zevalin TM ) for the treatment of advanced B-cell lymphoma as a first line of treatment for rituximab-relapsed or refractory low-grade lymphomas; the overall response rate has ranged from 74% to 82% [ 233 ]. Despite the demonstrated immunotherapy efficacy of Zevalin TM , it failed commercially due to the underutilized practice by hematologist–oncologists for logistic and economic reasons [ 234 ]. In addition, other competitive RIT drugs, such as rituximab (anti-CD20) and second-generation mAbs, undoubtedly contributed to the limited sale of Zevalin TM [ 235 , 236 ].

The development of second-generation mAbs, particularly bispecific Abs (e.g., biotin, IgG-single chain variable fragment), have been utilized in an alternative approach called multi-step pre-targeted RIT to enhance the therapeutic efficacy and to diminish its toxicities [ 237 ]. Based on PRIT technology, [ 90 Y]Y-DOTA-biotin was developed, which makes a strong conjugate with Abs (streptavidin, avidin) present on the tumor. In 1999, Paganelli et al. published the first clinical preliminary results of [ 90 Y]Y-DOTA-biotin for the treatment of high-grade gliomas ( n = 48) based on biotin–streptavidin chemistry and showed tumor reduction (>25–100%) in 25% of patients; in 16% of these, the response lasted for at least a year [ 238 ]. In 2000, a phase II clinical trial of [ 90 Y]Y-DOTA-biotin was reported in patients with metastatic colon cancer [ 239 ]. Despite evaluating the feasibility, safety, and efficacy of [ 90 Y]Y-DOTA-biotin, the immunogenicity of these types of pre-targeting agents have not been addressed, which in turn caused the clinical trials to end in 2005 [ 240 ].

Paganelli et al. developed an innovative therapeutic approach called “Intra-operative avidination for radionuclide therapy” (IART ® ) that relies on a biotin–avidin binding system [ 241 ]. A phase II study of IART ® in 2010 using [ 90 Y]Y-DOTA-biotin on breast cancer patients demonstrated its potential use immediately after breast resection, thereby shortening the time course of external beam radiotherapy [ 241 ]. In the past decade, several peptide-based 90 Y-tracers were developed for PRRT, and they are currently under clinical trial. Table 16 summarizes the clinical application of 90 Y radiopharmaceuticals.

6.1.3. Production and Availability

90 Y can be produced from the 90 Sr/ 90 Y generator, where the parent isotope is 90 Sr (t 1/2 = 29 y), and it can be generated as a by-product in large quantities in U-based nuclear reactions [ 242 ]. Commercial availability and the steady supply of Y-90 are advantageous in conducting Y-90-based clinical trials.

6.2. Radioisotopes of Rhenium

6.2.1. General Information

Among several radioisotopes of rhenium (Re), 186 Re and 188 Re are recognized for their therapeutic potential, and they were used to develop various therapeutic radiopharmaceuticals. In addition to beta emission, 186 Re and 188 Re also emit low-abundant γ-rays of 137 keV and 155 keV, respectively ( Table 17 ), that permit scintigraphic monitoring and dosimetry calculations via SPECT imaging [ 251 ].

Given the two distinct tissue penetration ranges of 188 Re (11 mm) and 186 Re (4.5 mm), they can be selectively applied for treating large-sized tumors and small- or mid-sized tumors, respectively [ 251 ]. Moreover, to better understand the biodistribution, 99m Tc represents a diagnostic match for 186/188 Re radioisotopes, as both Re and Tc exhibit similar chemical properties [ 251 ]. However, 99m Tc- and 188 Re-labeled radiotracers do not always show the same in vivo biodistribution [ 251 ].

6.2.2. Clinical Applications of Rhenium Radioisotopes

188 Re-labeled therapeutic radiopharmaceuticals have been investigated in multiple clinical trials involving primary tumors, bone metastasis, rheumatoid arthritis, and intracoronary β-brachytherapy [ 252 ]. In 1998, Maxon et al. evaluated phosphonate-based radiotracer [ 188 Re]Re-HEDP for bone pain palliation [ 253 ]. Bone pain is a major issue in ~50% of women with breast cancer and 80% of men with PCa. A phase III trial comparing [ 188 Re]Re-HEDP with a well-known bone-targeting agent [ 223 Ra]RaCl 2 is ongoing ( NCT03458559 ). The primary objective of this study is to compare the overall survival in patients with PCa metastatic to bone after treatment with [ 188 Re]Re-HEDP and [ 223 Ra]RaCl 2 . Several Ab fragments have been radiolabeled with 186/188 Re for RIT. These include alemtuzumab (anti-CD66) in leukemia [ 254 ], rituximab (anti-CD20) in lymphoma [ 255 ], MN-14 (ant-CEA) in gastrointestinal cancer [ 256 ], and bivatuzumab in head and neck cancers [ 257 ]. Among them, the evaluation of [ 186 Re]Re-bivatuzumab in a variety of diseases ( NCT02204033 ) as a phase I clinical trial has been completed. However, the results are not yet published. Recently, 188 Re-colloids-based brachytherapy kit (Rhenium-SCT ® ) became commercially available to treat basal cell carcinoma or squamous cell carcinoma, particularly to the face and neck, where surgery and radiotherapy are either not possible or refused by patients ( NCT05135052 ) [ 258 ]. Several preliminary clinical reports have demonstrated that this innovative epidermal therapy is effective in 98% of melanoma patients even after a single application [ 259 ]. The clinical investigations of Re radiopharmaceuticals are summarized in Table 18 .

6.2.3. Production and Availability

188 Re is routinely produced in high specific activity by a 188 W/ 188 Re generator, like the 99m Tc generator [ 260 ]. On other hand, 186 Re is most commonly produced in apparent specific activity of 111–148 GBq/mg at the Missouri Research Nuclear Reactor [ 261 ].

6.3. Holomium-166

166 Ho is not only a β − emitter but also a gamma emitter; it is one of the lanthanide radionuclides that can be imaged using SPECT and MRI [ 267 , 268 ]. 166 Ho is a theranostic radionuclide with favorable physical decay characteristics, including a sufficient half-life of 26.6 h, an average emission energy of (E βav ) of 670 keV, a soft tissue penetration range of 8.7 mm, and a low-energy γ-emission (80.5 keV, 6%) for SPECT imaging [ 267 , 268 ]. Being a lanthanide with its paramagnetic properties, 166 Ho-labeled drugs enable the visualization and quantification of the biodistribution of drugs in the tumor tissues by means of SPECT and MRI [ 268 ]. In 1991, Murphy et al. first investigated the potential possibility of 166 Ho microspheres for the internal radiation therapy of hepatic tumors in rabbits [ 269 ]. In 2010, Smith et al. investigated the first 166 Ho-based liver radioembolization, which was followed by growing interest in this treatment possibility, as evidenced by the increasing number of publications in the last few years [ 268 ]. In terms of clinical applications, 166 Ho-microspheres serve as an alternative to existing 90 Y microspheres to treat liver tumors, with potential advantages of the shorter half-life of 166 Ho (t 1/2 = 26.6 h) compared to 90 Y (t 1/2 = 64 h) along with its quantification by MRI [ 268 ]. Additional information on 166 Ho- radiopharmaceuticals have been discussed in a recent review by Klaassen et al. [ 270 ]; therefore, we have kept the discussion extremely short.

6.4. Lutetium-177

6.4.1. General Information

177 Lu is currently the most important and highly valuable theranostic β − /γ-emitting radionuclide in nuclear medicine across the globe [ 271 ]. 177 Lu has a long half-life (t 1/2 = 6.7d) and decays to 177 Hf by emitting medium-energy cytotoxic β − particles, with the most abundant β − particles (78%) having a maximum energy of 0.497 MeV ( Table 19 ) [ 271 ]. Furthermore, the co-emission of γ-photons (112.9 keV, 208.5 keV) enables the visualization and quantification (dosimetry) of the biodistribution of 177 Lu- radiopharmaceuticals using SPECT [ 271 ].

6.4.2. Clinical Applications

Since 2000, 177 Lu-labeled somatostatin analogues have been utilized in PRRT for the treatment of inoperable or metastatic NETs [ 272 ]. 177 Lu-labeled somatostatin has six- to seven-fold higher affinity for SSTR2 compared with its 90 Y-loaded counterpart [ 272 ]. Several preclinical and clinical studies have been conducted on the therapeutic effectiveness of 177 Lu-based radiopharmaceuticals in last two decades [ 273 ]. In 2005, the first-in-human proof-of-concept study was published on endoradiotherapy with [ 177 Lu]Lu-PSMA-I & T, which was found to be promising in patients with castration-resistant and metastatic prostate cancers [ 274 ].

In 2017, the results of a clinical phase 3 trial (NETTER-1) involving 229 patients randomized to either PRRT using [ 177 Lu]Lu-DOTATATE (7.4 GBq every 8 weeks) or a long-acting release (LAR) formulation of octreotide (control groups) to treat patients with midgut NET were released [ 275 , 276 ]. The groups receiving [ 177 Lu]Lu-DOTATATE had a significantly higher response rate (18%) and longer progression-free survival (65.2%) at 20 months compared to the controls, with 10.8 and 3%, respectively. [ 177 Lu]Lu-DOTATATE treatment yielded a clinically significant improvement in progression-free survival as a primary end point as well as an improvement in the median survival of 11.7 months [ 276 ]. Overall, the treatment was well tolerated with grade 3 or 4 adverse events, which were similar in both the groups. No evidence of renal toxicities was observed among patients in the [ 177 Lu]Lu-DOTATATE groups [ 275 , 276 ]. In 2018, the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) approved [ 177 Lu]Lu-DOTATATE (Lutathera ® ; Novartis company) for mid gut NET. In the same year, [ 177 Lu]Lu-PSMA-617 was proposed for the treatment of metastatic castration-resistant prostate cancer (mCRPC). The results of a phase 2 trial (TheraP) demonstrated a significant decline (>50%) in PSA in the groups treated with [ 177 Lu]Lu-PSMA-617 compared to the standard treatment using Carbazitaxel, which eventually led to FDA and EMA approvals under the name of Pluvicto ® (Novartis). The clinical use of 177 Lu-radiopharmaceuticals has been increased in the past few years, including [ 177 Lu]Lu-FAPI-46 [ 277 , 278 ] and combination therapy with 90 Y-labeled peptides and chemotherapy. Several clinical trials of 177 Lu-based radio theranostics are underway, as listed in Table 20 .

6.4.3. Production and Availability

There are two common independent ways to produce large-scale 177 Lu in nuclear reactors. The first is a direct production route (also known as carrier added or c.a.) based on neutron irradiation of 176 Lu via 176 Lu (n, γ) 177 Lu nuclear reaction in medium–high-energy reactors [ 271 , 288 ]. The second approach is an indirect production route (also known as non-carrier added or n.c.a) based on neutron irradiation of 176 Yb target via 176 Yb (n, γ) 177 Yb → 177 Lu in high-energy flux reactors [ 288 ]. The advantage of the direct production route is that it can create large quantities of 177 Lu (740–1110 GBq) using 176 Lu; however, the major concern is the co-emission of small amounts of long-lived radioactive impurity of 177m Lu along with “useful” 177 Lu. Additionally, only a part of the target matrix (or carrier) of 176 Lu is converted into the desired 177 Lu, which cannot be chemically isolated as they are the isotopes of the same element; this therefore decreases its specific activity [ 288 ].

On the other hand, the indirect approach using highly enriched 176 Yb (>98%) produces high specific activity (>2.96 TBq/mg) non-carrier-added 177 Lu; however, this process requires a suitable method for the radiochemical separation of 177 Lu from 176 Yb, which is quite challenging, especially in large-scale or industrial settings, to meet the surging demand [ 271 , 288 ]. 177 Lu can also be produced in cyclotron using deuteron beams (<6 MeV); however, this is less explored due to the low production yield [ 288 ].

7. Alpha-Particle-Emitting Radiopharmaceuticals

Alpha radiations are better suited for the treatment of small metastasis due to their short tissue penetration range and high LET per micrometer of tissue compared to β − -emitting radionuclide via double strand DNA breaks in cancerous cells, while sparing nearby healthy tissues [ 21 ]. However, due to the early stages of development of alpha-targeted radionuclide therapy, most clinical trials continue to use beta-emitting radionuclide therapy rather than alpha-emitting radionuclide therapy.

7.1. Radioisotopes of Bismuth

7.1.1. General Information

Two promising medically relevant isotopes of bismuth (Bi) with mixed α/β − emission properties are 212 Bi and 213 Bi [ 289 ]. 212 Bi undergoes β − decay (64%) to 212 Po (α-emitter) and α-decay (36%) to 208 Tl (β − emitter). Both daughters of 212 Bi ( 212 Po and 208 Tl) further decay to the stable 208 Pb [ 289 ]. Moreover, the emission of high-energy γ-rays through the decay of 208 Tl (2.6 MeV) necessitates appropriate shielding to avoid radiation exposure, making it a less favorable choice over 213 Bi [ 289 ].

213 Bi is considered a magic bullet in targeted radionuclide therapy. The isotope predominantly undergoes β − decay (97.8%) to the pure α-emitter 213 Po, whereas the remaining 213 Bi (2.2%) undergoes α- decay to beta-emitter 209 Tl [ 289 ]. Both of these daughter nuclei ( 213 Po, 209 Tl) decay to 209 Pb, which further decays to long-lived 209 Bi (essentially stable) [ 289 ]. In addition, 213 Bi also emits γ-radiation (440 keV) that can be employed for SPECT imaging [ 289 ]. Overall, each 213 Bi decay delivers only one α particle (5.9–8.4 MeV) [ 289 ]. The nuclear decay properties of Bi radionuclides are given in Table 21 .

7.1.2. Clinical Applications of 213 Bismuth

In 2002, Joseph et al. reported the first proof-of-concept phase I study demonstrating the anti-leukemic effect of 213 Bi conjugated with anti-leukemia Ab HuM195 (Lintuzumab) to treat leukemia patients [ 290 ]. In a subsequent clinical study (phase I/II) in 2010, complete remission was seen in acute myeloid leukemia patients with sequential administration of [ 213 Bi]Bi-HuM195 (37 MBq/Kg) and the chemotherapy drug cytarabine ( Table 22 ) [ 291 ]. The promising clinical results with [ 212 Bi]Bi-mAb-TAT initiated its use to treat other cancers, including melanoma, NETs, and glioma [ 292 , 293 ].

In the last two decades, research efforts have facilitated the development of 213 Bi-based peptide conjugates for PRRT study. In 2014, Kratochwil et al. reported the first and only radiopeptide therapy with [ 213 Bi]Bi-DOTATOC on NET patients, which was refractory to β − therapy with 90 Y/ 177 Lu-DOTATOC [ 294 ]. The results indicated that TAT could induce considerable and long-lasting remission in both the primary tumor and liver metastases [ 294 ]. Another tracer, [ 213 Bi]Bi-PSMA-617, was reported in metastatic castration-resistant PCa patients [ 295 ]. The remarkable drop in prostate-specific antigen levels from 237 µg/L to 43 µg/L after [ 213 Bi]Bi-PSMA-617 treatment showed the great potential of TAT using [ 213 Bi]Bi-PSMA-617 over conventional β − radionuclide therapy. In addition, TAT may be able to break the radioresistant effect of β − emitters [ 295 ]. In the past few years, different clinical trials have used 213 Bi-carrying radiopharmaceuticals for the treatment of various diseases. Although the outcomes were encouraging, further investigations are needed to ensure its safety and efficacy in the clinic.

7.1.3. Production and Availability

Many α-emitter radionuclides are produced from naturally occurring heavy α radionuclides, including U, radium (Ra), and actinium (Ac). The clinical amount of 213 Bi is obtained from its parent radionuclide 225 Ac (t 1/2 = 9.9 d) as a 225 Ac/ 213 Bi generator [ 298 ]. The parent isotope 225 Ac is obtained from the decay of 229 Th (t 1/2 = 7317 y), which in turn originates from a decay chain of fissile materials of 233 U [ 298 ]. The relatively long half-life of the parent radionuclide 225 Ac allows shipment of the 225 Ac/ 213 Bi generator to any radiopharmaceutical facility located even long distances away and permits in-house generation of 213 Bi for radiolabeling purposes over weeks to months. However, the limited global production of 229 Th and the concern for the non-proliferation of the fissile product of 233 U restricted the commercial supply of 225 Ac stocks to produce 213 Bi-labeled radiopharmaceuticals [ 293 ]. An alternate route to producing 225 Ac is using proton irradiation of 226 Ra targets via 226 Ra (p,2n) 225 Ac in a cyclotron; still, the presence of hazardous 222 Rn poses serious limitations in clinical translation and waste disposal [ 293 ].

7.2. Actinium-225

7.2.1. General Information

225 Ac is one of the promising therapeutic isotopes for α-RIT of cancer. It decays to six principal intermediate radionuclide progenies ( 221 Fr, 217 At, 213 Bi, 213 Po, 209 Tl, 209 Pb) before reaching the stable 209 Bi [ 300 ]. Overall, 225 Ac decay (t 1/2 = 9.9 d) contributes to the emission of four α-, three β − , and two principal γ-emissions (218 keV; 221 Fr, 440 keV; 213 Bi), from which recognizable 225 Ac results as a “nanogenerator.” 225 Ac is also considered an in vivo generator of 213 Bi and an alternative to 213 Bi-based TAT, presumably because of the four α- emissions and its longer half-life compared to 213 Bi (t 1/2 = 45.6 min) [ 300 ]. The decay characteristics of Bi radionuclides are given in Table 23 .

225 Ac-based radiopharmaceuticals are prone to the redistribution of daughter progenies, particularly 213 Bi, which can induce renal toxicity and dose-limiting toxicity to other organs [ 300 ]. Moreover, dosimetry is essential using an isotope with a similar half-life and chelation chemistry to 225 Ac (e.g., Ln 3+ ) to track the biodistribution of 225 Ac accurately. A handful of clinical trials of 225 Ac are underway.

7.2.2. Clinical Applications of Actinium-225

In 2011, the first clinical study of α therapy was reported showing the anti-leukemic effect of [ 225 Ac]-lintuzumab in acute myeloid leukemia patients (>60 y) [ 301 ]. Motivated by the initial findings, several clinical trials (phase I/II), including a dose-escalation study of [ 225 Ac]Ac-lintuzumab combined with low-dose chemotherapeutic drugs (e.g., mitoxantrone, cladribine), have been initiated ( NCT03867682 [ 258 ]).

By 2018, a multicenter phase I study using [ 225 Ac]Ac-FPI-1434 ( NCT03746431 ) was designed to treat solid tumors from non-cell lung, prostate, and breast carcinomas [ 302 ]. Recently, a clinical study reported by Kratochwil et al. demonstrated the remarkable anti-tumor effect of [ 225 Ac]Ac-PSMA-617 (100 kBq/kg) in 81% of metastatic castration-resistant PCa patients [ 303 ]. Additional clinical trials are warranted to further investigate the anti-tumor potential of [ 225 Ac]Ac-PSMA-617 TAT in men with prostate cancer ( NCT04597411 ). The clinical investigation of 225 Ac radiopharmaceuticals is summarized in Table 24 .

7.2.3. Production and Availability

Currently, the clinical supply of 225 Ac is produced from 229 Th generators (t 1/2 = 7340 y), which are obtained from the parent 233 U (t 1/2 = 160,000y) [ 300 ]. 229 Th generators are available at the Oak Ridge National Laboratory USA, the Institute of Transuranium Elements, Germany, and the Institute of Physics and Power, Russia [ 300 ]. However, as of 2008, the approximate total worldwide production of 225 Ac accounts for only 68 GBq/year, which can support only several hundred patients per year. Therefore, large-scale production of 225 Ac is needed. Alternative production routes are being explored, including proton irradiation of 226 Ra targets, which could produce sufficient quantities of 225 Ac due to the relatively high reaction cross-section; however, the handling of 226 Ra (t 1/2 = 1600 y) is challenging [ 300 ].

To date, the accelerator-based production route involves high-energy proton irradiation (>100 MeV) of natural thorium ( 232 Th), and it could serve as another potential path for the future production of 225 Ac. This method may yield twenty times greater quantities of 225 Ac than the current annual production worldwide [ 310 ].

7.3. Radioisotopes of Lead

7.3.1. General Information

Lead ( 212 Pb; t 1/2 = 10.6 h) is a β − -emitting radionuclide that decays to 212 Bi (t 1/2 = 61 min), which decays by mixed α/β- particle emission [ 311 ]. Importantly, 212 Pb also emits imageable γ-radiation (238.6 keV) that has the potential to image 212 Pb-labeled radiopharmaceuticals directly via SPECT imaging ( Table 25 ). Moreover, 203 Pb is a γ-emitting analogue of 212 Pb, and it is considered an ideal SPECT imaging isotope for the estimation of an accurate dosimetry for 212 Pb-labeled therapeutic radiopharmaceuticals [ 311 ].

7.3.2. Clinical Practice

During 2014–2018, Meredith et al. performed several clinical studies using therapeutic [ 212 Pb]Pb-TCMC-trastuzumab in HER2 expressing malignancy, with promising outcomes, including improved safety, tolerability, and therapeutic efficacy [ 313 , 314 , 315 ]. Delpassand et al. investigated [ 212 Pb]Pb-DOTAMTATE (Alpha Medix TM ) for the treatment of inoperable SSTR-NETs, which could be superior to the gold standard β − -emitting [ 177 Lu]Lu-DOTATATE radiopharmaceutical [ 316 ]. The clinical investigation of Pb radiopharmaceuticals has been detailed in Table 26 .

7.3.3. Production and Availability

212 Pb is commonly produced from the decay chain of a 228 Th (t 1/2 = 1.9 y) generator, followed by its elution in 2M HCl using a cation exchange column with a maximum yield of 85% [ 319 ]. At high radioactivity (>37 MBq), however, the radiolytic damage of the cation exchange resin in the 228 Th generator increases the back pressure and decreases the yield [ 319 ]. To circumvent this, an alternative generator using 224 Ra (t 1/2 = 3.7 d) was designed, which serves as a source of either 212 Bi or its parent nuclide 212 Pb [ 319 ]. The 224 Ra/ 212 Pb generator could elute 212 Pb with a radioactivity up to ~600 MBq (16 mCi) [ 319 ]. Currently, 212 Pb is mainly supplied by OranoMed and Oak Ridge National Laboratory [ 319 ]. McNeil et al. established a production protocol of 203 Pb via proton irradiation of either natural thallium (Tl) or enriched 203 Tl in a TR13 (13 MeV) cyclotron to create a 228Th / 212 Pb generator for 212 Pb [ 312 ].

7.4. Radioisotopes of Radium

7.4.1. General Information

Ra has several radioisotopes, of which 223 Ra and 224 Ra are of considerable interest to the medical field as bone-seeking α-emitters for TAT [ 320 ]. 223 Ra (t 1/2 = 11.4 d) is an α-emitter that decays to 207 Pb via six intermediate progenies ( 219 Rn, 215 Po, 211 Pb, 211 Bi, 211 Po, 207 Tl) and delivers four α particles and two beta particles ( Table 27 ) [ 320 ]. However, 223 Ra faces challenges in quantitative imaging because of the limited abundance of short-range gamma photons (<2%) [ 321 ]. Several research studies are ongoing to investigate its dosimetry approach [ 322 , 323 , 324 ].

224 Ra is a pure α-emitter that decays via a series of six daughter nuclides ( 220 Rn, 216 Po, 212 Pb, 212 Bi, 212 Po, 208 Tl) and emit overall four alpha particles and two beta particles before stabilizing to 208 Pb [ 325 ]. 224 Ra emits abundant gamma emissions at 241 keV that can be employed for SPECT imaging [ 325 ]. 224 Ra (3.6d) has a shorter half-life than 223 Ra (11.4d), but its decay profile and biokinetics are like 223 Ra [ 307 ].

7.4.2. Clinical Practice

From mid-1940 to 1990, [ 224 Ra]RaCl 2 of high doses (up to 140 MBq) was used to treat different bone and joint diseases, mainly in Germany, but this practice was abandoned for technical and commercial reasons [ 329 ]. During 2000–2005, the use of [ 224 Ra]RaCl 2 (low dose up to 10 MBq) was revived to treat ankylosing spondylitis patients, but this was discontinued in 2005 due to the enhanced risk of malignant disease following injection [ 330 , 331 ]. One of the potential drawbacks of 224 Ra is the release of progeny β − -emitting 212 Pb with a significant half-life of 10.6 h, which could cause unwanted non-target exposure [ 330 ]. Therefore, alternative delivery strategies are of considerable interest, which could promote the retention of the daughter nuclides or mitigate their recoiling spread.

During 2007–2015, several preclinical studies investigated brachytherapy using 224 Ra-loaded diffusing α-emitter radiation therapy (DaRT) wires or seeds, which minimizes the damage to surrounding normal tissues [ 332 ]. The first-in-human clinical study based on DaRT was reported in 2020 and involved the implantation of 224 Ra seeds to treat squamous cancers of the skin and head [ 333 ]. Complete response to the 224 Ra-DaRT treatment was observed in 22 of the 28 patients; the remaining 6 patients showed only a partial response (>30% tumor reduction) [ 333 ]. Like 224 Ra, 223 Ra was also studied for the treatment of bone skeletal metastasis. The first clinical study (phase I) in prostate and breast cancer patients was reported by Nilsson et al. in 2005 [ 334 ]. Later, the favorable clinical results (phase II/III) of [ 223 Ra]RaCl 2 to treat metastatic PCa led to FDA approval of [ 223 Ra]RaCl 2 (Xofigo ® ; Bayer) in 2013 [ 335 , 336 ]. Several clinical trials of 223 Ra-based radionuclide therapy in combination with chemotherapy (docetaxel, paclitaxel), hormonal therapy (abiraterone, enzalutamide), and immunotherapy are ongoing ( Table 28 ).

7.4.3. Production and Availability

223 Ra is mainly produced from 227 Ac/ 227 Th generators, where 223 Ra is separated from 227 Ac/ 227 Th mother radionuclides using separation columns [ 300 , 350 ]. On the other hand, 224 Ra is usually produced from a 228 Th generator, where 228 Th is immobilized on actinide resin, which allows regular elution of 224 Ra in 1M HCl [ 351 ].

7.5. Thorium-227

7.5.1. General Information

227 Th (a progenitor of 223 Ra) is an α-emitting radionuclide that decays to 223 Ra, which further decays by a series of α and β − emissions before stabilizing to 207 Pb [ 352 ] ( Table 29 ). 227 Th can be readily chelated with 3, 2-hydroxypyridone-N-oxide (HOPO). When 227 Th is conjugated with tumor-targeting moieties, they are collectively called targeted thorium-227 conjugates (TTCs) [ 353 ].

7.5.2. Clinical Practice

There are four clinical trials listed for 227 Th-based TTCs registered in the US National Library of Medicine. These trials are based on 227 Th-labeled anti-PSMA-HOPO (Bay 2315497) and 227 Th-labeled anti-mesothelin-HOPO for the treatment of PCa ( NCT03724747 ) [ 355 ] and mesothelioma (Bay 2287411), respectively. The remaining two trials are based on 227 Th-labeled epratuzumab-HOPO (Bay 1862864) and 227 Th-labeled trastuzumab-HOPO (Bay 2701439) to treat CD22-positive non-Hodgkin’s lymphoma and HER2-positive breast or gastric cancers, respectively ( Table 30 ). 89 Zr-labeled HOPO has the potential to serve as a PET surrogate for TTCs, which could support the clinical development of novel TTCs by providing crucial pharmacokinetic and pharmacodynamic information [ 356 ].

7.5.3. Production and Availability

227 Th is produced as a decay product of the parent β − emitter 227 Ac (t 1/2 = 21.8 year) [ 357 ]. The longer half-life of 227 Th (t 1/2 = 18.7 days) allows for the shipment of cGMP-grade 227 Th solution worldwide [ 357 ].

7.6. Radioisotopes of Astatine

7.6.1. General Information

Astatine-221 ( 211 At) is an α-emitting therapeutic radionuclide that decays into two branches either by α-emission (42%) to 207 Bi (t 1/2 = 33.9 y) or by EC (58%) to 211 Po (t 1/2 = 516 ms); both eventually decay to a stable 207 Pb [ 361 ]. Each decay yields one α particle and the emission of characteristic X-rays (70–90 keV) through the decay of 211 Po and could be used for SPECT imaging and quantification of 211 At [ 361 ]. 209 At (t 1/2 = 5.4 h) is another isotope that predominantly decays by β + emission (96%) and has been introduced as a theranostic pair to 211 At ( Table 31 ) [ 361 ]. 211 At is a more attractive radionuclide than other α-emitting radionuclides because of its suitable half-life of 7.2 h, the absence of long-lived and/or toxic progenies, and its feasibility to be produced in decent quantities [ 361 ].

7.6.2. Clinical Practice

Although 211 At-labeled TAT agents were discovered more than 30 years ago, only a few clinical studies using 211 At-labeled Abs have been published. Zalutsky et al. reported on the application of 211 At-labeled chimeric anti-tenascin mAb 81C6 (71–347 MBq) in recurrent brain tumor patients with an encouraging median survival time of 52 weeks compared to 23 weeks reported for recurrent glioblastoma multiforme patients treated with best care [ 362 ]. Another clinical study of intraperitoneal α particle therapy was reported using [ 211 At]At-MX35(Fab) in relapsed ovarian cancer patients [ 363 ]. The results showed that there was no apparent radiation-induced toxicity discovered in patients for up to 12 years and no decreased tolerance to relapse therapy. The clinical investigation of 211 At-labeled radiopharmaceuticals is summarized in Table 32 .

7.6.3. Production and Availability

The most common route is the cyclotron/accelerator-based production of 211 At through alpha irradiation of 209 Bi (natural Bi) via a 209 Bi(α,2n) 211 At nuclear reaction [ 364 , 365 ]. However, only a limited number of cyclotrons with α-beam and with > 25 MeV energy are available in the field, limiting the overall 211 At availability [ 364 ]. Other methods include the use of 211 Rn/ 211 At generators [ 366 ]. One of the potential advantages of using 211 Rn/ 211 At generators is the longer half-life of 211 Rn (t 1/2 = 14.6 h) compared with 211 At (t 1/2 = 7.2 h), facilitating wider distribution of 211 At.

8. Conclusions

In summary, the development of radiometal-based radiopharmaceuticals, including their production, purification, bifunctional chelating agents, and biomarker discoveries, have significantly advanced the application of various radiometals in medicine in the last two decades. Both radiometal-based imaging and radionuclide therapy are changing the lives of patients on a daily basis due to the advancements made in the last 20 years. The field of α-emitting radiotherapy is emerging. Several clinical trials are currently under investigation. Further advances in the production and availability of these α-emitters along with the management of radioactive progeny should permit the cost-effective clinical adoption of TAT compared to traditional chemotherapeutics. Indeed, the future of the radiometal-based radiopharmaceutical industry appears to be very bright.

Acknowledgments

The authors thank Desiree Lanzino for her assistance in editing the manuscript. The authors would like to thank the Division of Nuclear Medicine, Department of Radiology, Mayo Clinic, Rochester, MN, USA for financially supporting the writing of this manuscript.

Abbreviations

Author Contributions

S.S. and M.K.P. both contributed to manuscript writing, reviewing, and editing. All authors have read and agreed to the published version of the manuscript.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Data are contained within the article.

Conflicts of Interest

The authors declare no conflict of interest.

Funding Statement

The writing of the review article was financially supported by the Division of Nuclear Medicine, Department of Radiology, Mayo Clinic, Rochester, MN, USA.

Footnotes

Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

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Associated Data

Data Availability Statement

Data are contained within the article.