Theranostic Imaging Surrogates for Targeted Alpha Therapy: Progress in Production, Purification, and Applications

Abstract

This article highlights recent developments of SPECT and PET diagnostic imaging surrogates for targeted alpha particle therapy (TAT) radiopharmaceuticals. It outlines the rationale for using imaging surrogates to improve diagnostic-scan accuracy and facilitate research, and the properties an imaging-surrogate candidate should possess. It evaluates the strengths and limitations of each potential imaging surrogate. Thirteen surrogates for TAT are explored: ¹³³La, ¹³²La, ¹³⁴Ce/¹³⁴La, and ²²⁶Ac for ²²⁵Ac TAT; ²⁰³Pb for ²¹²Pb TAT; ¹³¹Ba for ²²³Ra and ²²⁴Ra TAT; ¹²³I, ¹²⁴I, ¹³¹I and ²⁰⁹At for ²¹¹At TAT; ¹³⁴Ce/¹³⁴La for ²²⁷Th TAT; and ¹⁵⁵Tb and ¹⁵²Tb for ¹⁴⁹Tb TAT.

1. Introduction

Targeted alpha therapy (TAT) involves utilizing radiopharmaceuticals to precisely eliminate malignancies with alpha particle emissions, while sparing surrounding healthy tissues. These radiopharmaceuticals consist of alpha (α)-emitting radionuclides conjugated to a biological-targeting vector such as monoclonal antibodies, peptides, and nanocarriers [1]. Key advantages of TAT include highly selective radiation delivery to the target, reduced patient side effects, and the ability to assess radiopharmaceutical uptake and, therefore, patient eligibility using a diagnostic radionuclide before therapy [2].

While beta minus (β⁻) radiopharmaceuticals employing radionuclides such as ¹⁷⁷Lu have made significant advances in clinical care of advanced prostate and neuroendocrine tumors [3,4], alpha particle emissions are significantly more precise and cytotoxic than β⁻ emissions. This is attributed to the much larger size of alpha particles (7300 times the mass of electrons), their 2+ charge resulting in a highly ionized emission path, and high linear energy transfer that deposits their energy over a path length of only several cell diameters. These properties make alpha emitters ideal for combatting metastatic cancers and other systemic malignancies where traditional treatment avenues have failed [2,5,6,7].

Approximately 400 alpha-emitting radionuclides (5–100% emission intensity) are known; however, only radionuclides that possess a sufficiently long half-life, absence of long-lived toxic progeny, and feasible high-yield production routes are suitable for TAT consideration [8,9]. Radionuclides that have shown potential for TAT include ²²⁷Th, ²²⁵Ac, ²²⁴Ra, ²²³Ra, ²¹²Pb, ²¹¹At, and ¹⁴⁹Tb [1,2,10,11,12,13,14,15,16,17,18,19,20].

While the potency of TAT offers significantly enhanced therapeutic efficacy, TAT must be treated as a double-edged sword with the possibility of severe off-target toxicity to nontarget organs and tissues. This mandates a comprehensive understanding of the stability, pharmacokinetics, and dosimetry of any TAT radiopharmaceutical. During preclinical development, these data can be acquired from biodistribution studies in mice, where mice are sacrificed at multiple time points, and gamma-ray co-emissions are counted in the dissected organs and tissues.

Additionally, positron emission tomography (PET) and single-photon emission computed tomography (SPECT) scans can be acquired by exchanging the alpha-emitting radionuclide with a positron or gamma-ray-emitting diagnostic imaging radionuclide. This imaging–therapeutic duality is termed “theranostics”, and these PET and SPECT scans provide crucial information on dosimetry and monitor response to TAT.

Most TAT radionuclides lack or possess insufficient co-emitted positrons or gamma rays for acquiring higher-quality PET or SPECT scans. This motivated the development of chemically similar diagnostic imaging surrogates for TAT radionuclides. As the current supply of alpha-emitting radionuclides is scarce, utilizing imaging surrogates also has the potential to open more opportunities for TAT research to facilities without access to alpha-emitting radionuclides and serve as a bridge for centers planning to introduce TAT radiopharmaceuticals. Since many of these surrogates can be synthesized in existing cyclotron facilities, this can facilitate radiopharmaceutical developments. Additionally, imaging surrogates fit well into the existing research and clinical setup. As such, TAT imaging surrogates have the potential to assist the deployment of TAT radiopharmaceuticals in the clinic and accelerate the development of new TAT targeting vectors.

2. Properties of Ideal Imaging Surrogates for Alpha Emitters

Multiple factors determine what makes a suitable imaging surrogate for targeted alpha therapy. These include chemical properties, half-life, radioactive emission type and intensity, associated dosimetry, production ease and scalability, radionuclidic purity, economics, and radionuclide progeny considerations.

PET and SPECT scans that evaluate the pharmacokinetics and dosimetry of TAT radiopharmaceuticals are often performed with ⁶⁸Ga and ¹⁸F. However, ⁶⁸Ga, ¹⁸F, and other common imaging radionuclides often have substantially different chemical properties than alpha-emitting radionuclides. For some targeting vectors, this can result in differing biodistributions between the TAT radiopharmaceutical and its diagnostic counterpart [21,22,23]. Potential inconsistencies observed in diagnostic imaging scans and subsequent biodistribution of the therapeutic radiopharmaceutical could result in sub-optimal tumor dosing or unintended and destructive alpha-irradiation of healthy tissues.

Imaging surrogates should, therefore, possess a similar chemistry and half-life to ensure their biodistribution and dosimetry are similar to their paired alpha emitters. These surrogates are ideally isotopes of the same element possessing identical chemistries, such as ²²⁶Ac paired with ²²⁵Ac TAT, ²⁰³Pb paired with ²¹²Pb TAT, ²⁰⁹At paired with ²¹¹At, and ¹⁵⁵Tb or ¹⁵²Tb paired with ¹⁴⁹Tb TAT.

However, if suitable isotopes of the same element are not available, chemically similar elements in the same chemical group can be employed. These include ¹³³La, ¹³²La, or ¹³⁴Ce/¹³⁴La paired with ²²⁵Ac, ¹³⁴Ce/¹³⁴La, paired with ²²⁷Th, and ¹²³I, ¹²⁴I, or ¹³¹I, paired with ²¹¹At.

It is also preferable that the physical half-life of the imaging surrogate is similar to its TAT counterpart. This permits the acquisition of biodistribution data for the full in vivo residence of the TAT radiopharmaceutical to assist preclinical development and initial clinical validation. For TAT employing radionuclides with long physical half-lives (²²⁵Ac, ²²³Ra, ²²⁴Ra, ²²⁷Th) and targeting vectors with long biological half-lives, using a long-lived imaging surrogate is crucial to confirm that the radiopharmaceutical remains at the target site for the extended duration without redistributing to and irradiating healthy tissues. While additional patient radiation dose might result from using a diagnostic radionuclide with a longer half-life, some targeting vectors such as antibodies may require longer circulation times to acquire sufficient quality images. For TAT employing long-lived radionuclides and targeting vectors with short biological half-lives, a radionuclide imaging surrogate with a shorter physical half-life may be used in certain situations. This can be a valuable tool for evaluating patient dosimetry, provided that the targeting vector exhibits rapid in vivo clearance, minimal off-target binding, and the radionuclide is stably incorporated within the radiopharmaceutical. Radiopharmaceutical pretargeting approaches may reduce the advantage of selecting diagnostic and therapeutic TAT radionuclides with similar half-lives; however, it is uncertain whether most theranostic targeting vectors will employ a pretargeting approach.

Regarding radioactive emissions, it is preferable that PET imaging surrogates possess a high positron branching ratio and low positron emission energy to facilitate high-resolution PET imaging and minimal co-emitted electrons and gamma/X-rays to reduce the radioactive dose. Radionuclides with lower positron branching ratios may require additional injected activity to resolve the same quality image. For SPECT imaging, radionuclides should possess lower energy gamma rays within the optimal energy window of scanners and minimal co-emitted electrons and gamma/X-rays.

To produce imaging surrogates, sufficient cyclotron or nuclear reactor facilities are required to synthesize the radionuclide. Target material (natural or isotopically enriched) should be available in adequate quantity and enrichment to support routine production, and a favorable nuclear cross-section must exist within the capabilities of production facilities. Radionuclide production should be performed safely, create few long-lived radionuclidic impurities, and be scalable to sufficient activities that allow distribution to clinical sites. Robust chemical-purification techniques must separate the imaging surrogate from potentially hazardous target material post-irradiation. Finally, the radionuclide progeny of the imaging surrogate should be considered since this can influence imaging quality and impact radioactive waste management.

Most radionuclides used in TAT are part of decay chains where each decay results in the recoil of the daughter nucleus with energy sufficient to liberate the daughter nucleus from the chelator into solution. Additionally, the alpha particle itself may induce radiolytic damage to the radiopharmaceutical, reducing the in vivo targeting and leading to further accumulation of radioactivity in nontarget tissue. These inherent physical properties are not easily covered by the surrogates in question, so they should be considered in experimental methods and conclusions.

In this article, a selection of 13 diagnostic imaging surrogates for promising alpha-emitting radionuclides have been highlighted for their production, purification, applications, and overall strengths and limitations.

3. Theranostic Imaging Surrogates Proposed for Actinium-225

Actinium-225 (t_1/2 = 9.9 d) has been explored extensively for TAT. Its long half-life permits extended dose delivery and decay via a cascade of six short-lived radionuclide progeny with four alpha particle emissions to near-stable ²⁰⁹Bi, making ²²⁵Ac particularly attractive for TAT. ²²⁵Ac studies have demonstrated efficacy in metastatic prostate cancer and neuroendocrine tumors, and additional radiopharmaceuticals are under development for other cancers [11,24,25,26,27,28,29,30] There are considerable efforts underway to significantly increase the ²²⁵Ac supply to meet the significant anticipated clinical demand [31,32,33,34].

However, ²²⁵Ac does not emit gamma rays of sufficient intensity for imaging. Although its ²¹³Bi and ²²¹Fr progeny possess gamma rays of suitable energy and intensity for SPECT imaging [9], the ²²⁵Ac activities injected into patients (~50–200 kBq/kg [11]) would be insufficient to resolve a high-quality image within a reasonable scan duration. Additionally, the supply of high-purity ²²⁵Ac from ²²⁵Ra/²²⁵Ac generators is limited, constraining AT development efforts [31]. While other sources of ²²⁵Ac from high-energy spallation reactions are available [32,35,36], these often contain a small activity of co-produced and inseparable ²²⁷Ac (t_1/2 = 21 y), which complicates radioactive waste management. Therefore, the desire to enable ²²⁵Ac imaging and enhance research throughput motivates the development of imaging surrogates.

For SPECT imaging, ²²⁶Ac is an elementally matched surrogate for ²²⁵Ac. Radiolanthanum isotopes ¹³³La, ¹³²La, and ¹³⁴La are particularly attractive for PET imaging of ²²⁵Ac due to the similar ionic radii of La³⁺ and Ac³⁺ (~1.03 and ~1.12 Å, respectively [37,38]) and their resulting similar chemistries. Both lanthanum and actinium possess similar chelation chemistry with chelators such as DOTA, macropa, and crown ethers, and exhibit similar in vivo biodistributions [39,40,41,42,43,44]. The subsequent sections will outline the properties, strengths, and limitations of ¹³³La, ¹³²La, ¹³⁴Ce/¹³⁴La, and ²²⁶Ac.

3.1. Lanthanum-133 (PET)

Lanthanum-133 (t_1/2 = 3.9 h) has been synthesized via the ¹³⁵Ba(p,3n)¹³³La and ¹³⁵Ba(p,2n)¹³³La nuclear reactions on medical cyclotrons [45]. Natural Ba metal can be used as a target material, with one study producing 231 MBq ¹³³La and 166 MBq ¹³⁵La for 500 µA·min cyclotron irradiations at 22 MeV. Subsequent chemical processing using a diglycolamide (DGA) resin produced a highly pure [¹³³La]LaCl₃ product that, when used to radiolabel DOTA and macropa chelators, achieved molar activities sufficient for preclinical and clinical application [40]. Co-production of ¹³⁵La (t_1/2 = 18.9 h (44)) is unavoidable using natural barium target material. While ¹³⁵La has potential applications for Auger-Meitner electron therapy, it would add additional patient radioactive dose and is undesirable for ¹³³La PET imaging applications.

Alternatively, natural or isotopically enriched BaCO₃ can be employed to simplify target preparation to boost ¹³³La yields and selectivity from co-produced ¹³⁵La. Another study irradiated [¹³⁵Ba]BaCO₃ at a 23.3 MeV proton energy, significantly improving ¹³³La/¹³⁵La selectivity relative to natural Ba target material, producing 214 MBq ¹³³La with 28 MBq ¹³⁵La using [¹³⁵Ba]BaCO₃, versus 59 MBq ¹³³La with 35 MBq ¹³⁵La using [^natBa]BaCO₃ [41]. Another approach involved irradiating isotopically enriched [¹³⁴Ba]BaCO₃ at a proton energy of 22 MeV, with subsequent purification yielding up to 1.2–1.8 GBq [¹³³La]LaCl₃ with 0.4% co-produced ¹³⁵La and a radionuclidic purity of >99.5%. The decay of ¹³³La into its long-lived daughter ¹³³Ba (t_1/2 = 10.6 y) resulted in 4 kBq ¹³³Ba per 100 MBq ¹³³La, which was deemed uncritical concerning dose and waste management [42].

As shown in Figure 1, ¹³³La PET imaging analysis was performed in Derenzo phantoms and compared with other common PET radionuclides, with ¹³³La found to have superior spatial resolution compared to ⁴⁴Sc, ⁶⁸Ga, and another radiolanthanum positron emitter, ¹³²La [41].

As depicted in Figure 2, PET imaging was performed with [¹³³La]La-PSMA I&T in a prostate cancer mouse model. The LNCaP prostate cancer tumors were delineated with high spatial resolution and minimal off-target uptake, demonstrating the potential for further ¹³³La PET imaging applications [41].

Strengths of ¹³³La include its 3.9 h half-life that allows sufficient time for separation and distribution to external clinics; a lower positron emission energy compared to ⁶⁸Ga, ⁴⁴Sc, and ¹³²La that results in a higher PET imaging spatial resolution [47]; and low energy and intensity co-emitted gamma rays that reduce the radioactive dose. Limitations include the production requirement of medium-energy cyclotron facilities; its lower positron branching ratio of 7.2% that may require additional injected activity relative to other PET radionuclides such as ¹⁸F; and its decay into relatively long-lived ¹³³Ba.

3.2. Lanthanum-132 (PET)

Lanthanum-132 (t_1/2 = 4.6 h) can be produced via the ¹³²Ba(p,n)¹³²La nuclear reaction using natural Ba metal target material [48,49,50,51]. This beam energy co-produces significant activities of ¹³⁵La and is just below the threshold of the ¹³³La production. One study reported yields of 0.26 ± 0.05 MBq·µA⁻¹·h^{−1 132}La and 5.6 ± 1.1 MBq·µA⁻¹·h^{−1 135}La for irradiation with 11.9 MeV protons, with ¹³²La activity approximately 5% relative to ¹³⁵La activity at the end of bombardment [48,49]. Another study reported yields of 0.8 MBq ¹³²La and 17.9 MBq ¹³⁵La for 500 µA·min runs at 11.9 MeV [40]. ¹³²La can be purified using DGA resin and complexed with chelators at molar activities suitable for radiopharmaceutical application [49]. A study using a tumor-targeting alkylphosphocholine, NM600, demonstrated significant tumor uptake of [¹³²La]La-NM600 and a similar biodistribution to [²²⁵Ac]Ac-NM600 using PET/CT imaging and ex vivo analysis [48].

Strengths of ¹³²La include its 4.6 h half-life, which allows ease of radiopharmaceutical preparation and distribution compared to shorter-lived PET emitters such as ⁶⁸Ga; its stable ¹³²Ba decay daughter; and its significant 41.2% positron branching ratio [9]. Limitations include severe cyclotron production constraints owing to the 0.1% natural isotopic abundance of ¹³²Ba target material; high energy and intensity co-emitted gamma rays that contribute to excess radioactive dose; and the high maximum positron emission energy of 3.67 MeV, which leads to a low PET spatial resolution and image blurring as shown in Figure 1.

3.3. Lanthanum-134/Cerium-134 (PET)

Lanthanum-134 (t_1/2 = 6.5 min) can be produced via irradiation of natural barium target material; however, its short half-life precludes its direct use for PET imaging. Cerium-134 (t_1/2 = 3.2 d) decays into ¹³⁴La, permitting an in vivo generator configuration where ¹³⁴Ce can be labelled to a targeting vector, with ¹³⁴La progeny used for PET imaging. Production involves irradiating ^natLa metal, with yields of 59 MBq·µA⁻¹·h⁻¹ at proton energies of 62.1–72.1 MeV [52]. A subsequent production route utilized 100 MeV protons to irradiate ^natLa metal, producing over 3 Ci of ¹³⁴Ce with a 100 µA irradiation for 30 h. Chemical purification can be performed with Bio-Rad AGMP-1 resin, where ¹³⁴Ce is eluted with 0.05 M HNO₃. ¹³⁴Ce can then be used to label DTPA in its 3+ oxidation state, allowing ¹³⁴Ce to act as a ²²⁵Ac imaging surrogate, while ¹³⁴Ce can label 3,4,3-LI(1,2-HOPO) in its 4+ oxidation state and act as a ²²⁷Th imaging surrogate [53,54]. A PET imaging phantom study investigating the spatial resolution and recovery coefficient of ¹³⁴La was found to be inferior and similar to ¹⁸F, respectively [52].

Strengths of ¹³⁴Ce/¹³⁴La include the 3.2 d half-life of ¹³⁴Ce, which permits PET imaging at extended time points after injection to track ²²⁵Ac and ²²⁷Th radiopharmaceuticals; the significant 63.6% positron branching ratio of ¹³⁴La [9]; the stable ¹³⁴Ba decay daughter of ¹³⁴La; and the ability for ¹³⁴Ce to act as a surrogate for both ²²⁵Ac and ²²⁷Th. Limitations include a scarcity of production facilities capable of achieving a ~100 MeV proton beam energy; the high positron emission energy of ¹³⁴La, which would result in lower PET spatial resolution; unavoidable co-produced radionuclidic impurities (¹³⁹Ce, t_1/2 = 137.6); and the potential for in vivo ¹³⁴La daughter redistribution following decay from ¹³⁴Ce that could blur PET imaging [9,39].

3.4. Actinium-226 (SPECT)

Actinium-226 (t_1/2 = 29.4 h) can be produced via high-energy proton spallation of a uranium carbide target or lower-energy proton bombardment of ²²⁶Ra (t_1/2 = 1600 y) target material. This involved bombarding a uranium carbide target with 480 MeV protons, with ²²⁶Ac separated using isotope separation online. This approach yielded 33.8 ± 2.7 MBq ²²⁶Ac for imaging purposes with high radionuclidic purity [55].

An alternative production route could employ ²²⁶Ra target material and the ²²⁶Ra(p,n)²²⁶Ac nuclear reaction on a lower energy proton cyclotron [9,55,56,57].

A phantom assembly with rods between 0.85 and 1.7 mm in diameter and a microSPECT/CT system was used to assess resolution using a high-energy ultra-high resolution (HEUHR) collimator and an extra ultra-high sensitivity (UHS) collimator. The primary 158 keV and 230 keV gamma photopeaks were reconstructed, with the 158 keV photopeak images demonstrating slightly better contrast recovery. For resolution, as depicted in Figure 3, the HEUHR collimator resolved all rods, while the UHS collimator could only resolve rods >1.3 mm and >1.5 mm for the 158 keV and 230 keV photopeaks, respectively [55]. This demonstrated the feasibility of using ²²⁶Ac as a SPECT imaging surrogate for ²²⁵Ac.

Advantages of ²²⁶Ac include its relatively long 29.4 h half-life compared to ¹³²La and ¹³³La, permitting imaging at extended time points, and its identical chemical properties to ²²⁵Ac. Limitations include challenges associated with routine irradiation of hazardous ²²⁶Ra target material, significant β⁻ co-emissions that would increase patient dose, and its decay to β⁻ emitting ²²⁶Th (t_1/2 = 30 min), which further decays via multiple alpha and β⁻ emitting progeny before stabilizing at ²⁰⁶Pb [9].

4. Theranostic Imaging Surrogates Proposed for Lead-212

Lead-212 (t_1/2 = 10.6 h) has cultivated a significant interest for TAT due to its payload of one alpha and two β⁻ particles in its decay chain and the rapid decay of its progeny to stable ²⁰⁸Pb. A recent study using a ²¹²Pb somatostatin analogue demonstrated a significant antitumor effect in patients with metastatic neuroendocrine tumors, and additional radiopharmaceuticals are under development to treat other cancers [1,58,59,60,61,62]. Production of ²¹²Pb involves synthesizing its parent radionuclide, ²²⁸Th (t_1/2 = 1.9 y), via ²²⁶Ra irradiation in a nuclear reactor or high-energy proton spallation of ²³²Th target material. ²¹²Pb can then be extracted in a convenient generator setup from ²²⁸Th or one of its intermediate progeny, ²²⁴Ra (t_1/2 = 3.6 d) [12,63,64,65,66,67].

Previous clinical trials have employed imaging techniques with conventional radiometals such as ⁶⁸Ga [58]. While direct SPECT imaging of ²¹²Pb can be performed using its 239 keV (44%) gamma emissions [9], it is desirable to have an imaging surrogate that can be used for research owing to the limited supply of ²¹²Pb and to provide the most accurate pre-therapy scans to assess patient eligibility for ²¹²Pb TAT radiopharmaceuticals. While no positron-emitting Pb isotopes are suitable for use as ²¹²Pb imaging surrogates, multiple gamma-ray emitters exist, with ²⁰³Pb being a prime candidate for SPECT imaging.

Lead-203 (SPECT)

Lead-203 (t_1/2 = 51.9 h) emits X-rays and a primary 279 keV (81%) gamma photon that can be used for SPECT imaging. ²⁰³Pb has been synthesized via ²⁰³Tl(p,n)²⁰³Pb, ²⁰³Tl(d,2n)²⁰³Pb, and ²⁰⁵Tl(p,3n)²⁰³Pb nuclear reactions on cyclotrons [21,45,63,64,68,69,70,71]. Natural thallium metal can be used as a target material; however, significant precautions must be taken owing to the high toxicity of Tl, and its low thermal conductivity and melting point (304 °C) that makes it prone to melt or sublime under intense heat of a cyclotron beam. Natural Tl metal has been used as a target material, with one technique bombarding ^natTl at 25–26 MeV, producing up to 21 GBq ²⁰³Pb five days after end of bombardment [61]. However, irradiating ^natTl produces significant activities of ²⁰¹Pb (t_1/2 = 9.3 h), which must be permitted to decay significantly to achieve a ²⁰³Pb product with high radionuclidic impurity. ²⁰³Pb can be produced at lower proton energies using natural or isotopically enriched ²⁰³Tl and the ²⁰³Tl(p,n)²⁰³Pb nuclear reaction ^63,71, with one process yielding up to 138.7 ± 5.1 MBq ²⁰³Pb [64]. However, yields are limited due to the low nuclear reaction cross-section in this energy window [45]. Alternatively, isotopically enriched ²⁰⁵Tl can be irradiated at 23–24 MeV proton energies to produce ²⁰³Pb via the ²⁰⁵Tl(p,3n)²⁰³Pb reaction. This produces significant activities of ²⁰³Pb (>12 GBq at the end of purification) with a high radionuclidic purity (>99.9%) made possible by the near absence of ²⁰³Tl and its resulting ²⁰¹Pb co-production ^21,63. Enriched ²⁰³Tl can also be bombarded with deuterons to produce ²⁰³Pb via the ²⁰³Tl(d,2n)²⁰³Pb reaction; however, this production route has a lower maximum cross-section compared to the ²⁰⁵Tl(p,3n)²⁰³Pb reaction, and ²⁰³Tl (29.5% natural isotopic abundance) is more expensive to enrich than ²⁰⁵Tl (70.5% natural isotopic abundance).

²⁰³Pb can be separated using ion exchange resins such as Pb resin, carboxymethyl resin, and Dowex-1X8 anion exchange resin. This can yield a concentrated ²⁰³Pb product in [²⁰³Pb]PbCl₂ or [²⁰³Pb]Pb(OAc)₂, with direct and rapid room temperature radiolabeling of [²⁰³Pb]Pb(OAc)₂ using chelators such as DOTA, PSC, and TCMC. Radiolabeling achieves very high molar activities, and ²⁰³Pb chelate complexes have been shown to be highly stable in human serum up to 120 h [21,63,64,69,70].

Phantom imaging of ²⁰³Pb has been performed, with imaging spatial-resolution results comparable to ^99mTc for 1.6–4.8 mm diameter fillable rod regions [72]. In vivo preclinical and clinical SPECT imaging of uncomplexed and chelated ²⁰³Pb has been performed [71,73]. Studies have included ^203/212Pb-labeled PSMA and gastrin-releasing peptide receptor-targeting agents for imaging and radiotherapy of prostate-cancer-bearing mice [60,61,74,75], and ^203/212Pb-labeled anti-melanin antibodies and melanocortin subtype 1 receptor targeting ligands for imaging and therapy of melanoma-bearing mice [59,72,73,76,77,78,79]. As shown in Figure 4, a PSMA-targeting ²⁰³Pb agent, [²⁰³Pb]Pb-CA012, exhibited a comparable biodistribution to [¹⁷⁷Lu]Lu-PSMA 617 with high tumor uptake relative to other tissues [74].

Strengths of ²⁰³Pb include its relatively long 51.9 h half-life, which permits imaging at extended time points to inform ²¹²Pb TAT dosimetry; its relatively clean X-ray and gamma photon emission spectrum that enables SPECT imaging using a low or high-energy collimator; its ability to rapidly and stably radiolabel targeting vectors under mild chemical conditions at room temperature (similar to ²¹²Pb); and established production processes that provide ²⁰³Pb with high radionuclidic purity in yields suitable for multiple patients per production run. Limitations include risks associated with preparing and irradiating highly toxic thallium targets and potential uncertainties with using ²⁰³Pb pharmacokinetic data for ²¹²Pb therapy planning due to the release of ²¹²Bi progeny during ²¹²Pb decay [80].

5. Theranostic Imaging Surrogates Proposed for Radium-223/224

Radium-223 (t_1/2 = 11.4 d) is used as an alpha therapy for men with bone-metastatic castration-resistant prostate cancer. It works as a calcium-mimetic by accumulating in and irradiating osteoblastic lesions, while sparing most surrounding healthy tissue [81]. It is the only FDA-proved alpha-particle-emitting radiopharmaceutical (Xofigo^®) and has been used to treat over 18,000 patients since 2013 [82]. However, unlike targeted alpha therapy, ²²³Ra is currently administered as a [²²³Ra]RaCl₂ salt in an aqueous buffer without a chelator or biological-targeting agent. Therefore, the established clinical efficacy and safety of ²²³Ra makes it an attractive TAT candidate [82]. Similarly, ²²⁴Ra (t_1/2 = 3.6 d) has been employed in a dual targeting strategy with ²¹²Pb, where ²²⁴Ra accumulates at primary bone cancer sites or bone metastases, while extra-skeletal metastases can be targeted with a ²¹²Pb-labeled cancer-specific vector [83,84]. [²²⁴Ra]RaCl₂ (marketed as ²²⁴SpondylAT^® (Eckert & Ziegler, Berlin, Germany) has also been used to treat bone and joint disease, ankylosing spondylitis [85], while ²²⁴Ra is also under investigation for a novel brachytherapy called diffusing alpha-emitter radiation therapy (DaRT). In DaRT, ²²⁴Ra-infused seeds are inserted into solid tumors, which are then irradiated with alpha emissions released during the diffusion and subsequent decay cascade of its ²²⁰Rn progeny [86,87,88,89,90,91,92,93,94,95]. Both ²²³Ra and ²²⁴Ra are currently produced in significant activities as by-products and decay daughters of neutron irradiation of ²²⁶Ra in a nuclear reactor. With proven purification techniques, this positions these radionuclides well for TAT [67,96,97].

²²³Ra has recently been stably complexed with the chelator macropa, where a [²²³Ra]Ra–macropa complex exhibited rapid clearance and low ²²³Ra bone absorption, suggesting in vivo stability. This has opened the possibility of using ²²³Ra complexed using functionalized chelators to target metastases beyond the bone, similar to other radionuclides used in targeted alpha therapy [82,98].

While ²²³Ra possesses several gamma emissions within an energy window suitable for SPECT imaging (²²³Ra: 269 keV, (13%); 154 keV (6%); ²²⁴Ra: 241 keV (4.1%)), the low intensity of these gamma photons would likely be insufficient to generate a high-quality SPECT image when considering the relatively low injected therapeutic activity (~50 kBq/kg) injected [9,81]. Similarly, a relatively low injection activity of ²²⁴Ra due to its 3.6 d half-life could complicate direct SPECT imaging. Therefore, an imaging surrogate is desirable to assess the viability of ^223/224Ra radiopharmaceuticals, with ¹³¹Ba emerging as a candidate.

Barium-131 (SPECT)

Barium-131 (t_1/2 = 11.5 d) decays via electron capture to ¹³¹Cs (t_1/2 = 9.7 d) and subsequently to stable ¹³¹Xe, emitting gamma rays suitable for SPECT imaging (496 keV (48%); 216 keV (20%); 124 keV (30%); 371 keV (14%)) [9]. Additionally, approaches designed to sequester Ra (nanoparticles, chelation via macropa or ligands based on the arene scaffold) [99,100] should be transferrable owing to the proven use of Ba as a non-radioactive surrogate for Ra [101]. Therefore, the favorable imaging emissions of ¹³¹Ba compared to other Ba radionuclides (^135mBa, ^133mBa), and the similar half-life and chemistry of ¹³¹Ba to ^223/224Ra positions ¹³¹Ba as a promising surrogate to track in vivo ^223/224Ra biodistribution.

¹³¹Ba can be produced via neutron irradiation of isotopically enriched ¹³⁰Ba (natural abundance = 0.1%) in a nuclear reactor, which would co-produce significant activities of ¹³³Ba [45,102]. Alternatively, ¹³¹Ba can be produced via proton irradiation of natural cesium target material in a cyclotron via the ¹³³Cs(p,3n)¹³³Ba nuclear reaction with a small ¹³³Ba contamination (0.01%) at beam energies of 27.5 MeV [45,101]. A 4 h irradiation yielded 190 ± 26 MBq ¹³¹Ba, and an SR resin was used to separate ¹³¹Ba from the Cs target material. ¹³¹Ba was subsequently successfully radiolabeled to macropa, and exhibited stability in human serum [101].

SPECT imaging was performed in a cylindrical syringe, which enabled visualization of the radionuclide distribution. However, image quality was limited due to artifacts caused by the higher energy gamma photon emissions. As highlighted in Figure 5, small animal SPECT/CT was performed with [¹³¹Ba]Ba(NO₃)₂, showing ¹³¹Ba accumulation within the entire skeleton 1 h post-injection, which was still present 24 h after injection. Additional SPECT imaging was performed with [¹³¹Ba]Ba-macropa, with rapid clearance observed through the intestines and gallbladder [101]. This demonstrated the feasibility of using ¹³¹Ba as a SPECT imaging surrogate for ^223/224Ra.

Advantages of ¹³¹Ba include its relatively long half-life, which is similar to ²²³Ra, permitting imaging at extended time points; the ability to sequester ¹³¹Ba in the macropa chelator similar to ²²³Ra; and established ¹³¹Ba production routes. Limitations include higher energy gamma photon emissions, which increase unintended patient dose and can cause image artifacts. The presence of co-produced ¹³³Ba may also require additional dosimetric analysis. Additionally, the decay of ¹³¹Ba to ¹³¹Cs with X-ray emissions adds a suboptimal patient radioactive dose compared to an imaging radionuclide with direct decay to stable progeny. Finally, further improvements in the cyclotron production route would be required to synthesize enough activity for multiple patients in a single batch.

6. Theranostic Imaging Surrogates Proposed for Astatine-211

Astatine-211 (t_1/2 = 7.2 h) has garnered interest for TAT owing to its decay to either ²⁰⁷Bi (t_1/2 = 31.6 y) via alpha emission or to ²¹¹Pb via electron capture followed by alpha decay to stable ²⁰⁷Pb [9]. Therefore, each ²¹¹At decay yields one alpha particle. The ²¹¹At decay chain also emits few high-energy gamma photons, which avoids excess radiation dose [8]. ²¹¹At can be produced in medium-energy alpha cyclotrons using bismuth target material and the ²⁰⁹Bi(α,2n)²¹¹At nuclear reaction or via heavy ion irradiation and the ²⁰⁹Bi(⁷Li,5n)²¹¹Rn reaction, where ²¹¹At is obtained via decay of its longer-lived parent ²¹¹Rn (t_1/2 = 14.6 h) in a generator configuration [8,103,104]. Production yields of up to 6.6 GBq have been reported, which would be sufficient for clinical radiopharmaceutical production for several patients and distribution several hours from the production site [8,105].

²¹¹At was initially investigated for treating thyroid disorders and is currently being evaluated in clinical trials for multiple myeloma, leukemia, myelodysplastic syndromes, thyroid cancer, and malignant pheochromocytoma [106]. While direct SPECT imaging of ²¹¹At is possible using the X-rays emitted during ²¹¹At decay to ²¹¹Po, it is desirable to have an imaging surrogate to perform pre-therapy assessment scans and research, owing to the limited supply and short half-life of ²¹¹At that generally precludes its use at facilities located more than several hours from a production site. Several candidates exist for use as ²¹¹At diagnostic imaging surrogates: chemically identical ²⁰⁹At, or chemically similar ¹²³I, ¹²⁴I and ¹³¹I.

6.1. Iodine-123 (SPECT)

Iodine-123 (t_1/2 = 13.2 h) decays via electron capture to near-stable ¹²³Te, and is commonly used in nuclear medicine and research of various malignancies and biological processes, including thyroid diseases and tumor imaging [107]. Its X-ray emissions and primary gamma photopeak of 159 keV (83.6%) are well suited for SPECT imaging [9].

¹²³I is primarily produced via the ¹²⁴Xe(p,2n)¹²³I nuclear reaction using a highly enriched ¹²⁴Xe gas target, which enables ¹²³I production with a high yield and radionuclidic purity. The subsequent ¹²³I product is commercially available in dilute NaOH solutions [108,109].

Strengths of ¹²³I include its favorable emission spectrum for SPECT imaging, similar half-life relative to ²¹¹At, and commercial availability. Limitations include hazards associated with volatile radioactive products, the lower image quality of SPECT images to PET imaging, and the low natural abundance (0.095%) of ¹²⁴Xe target material.

6.2. Iodine-124 (PET)

Iodine-124 (t_1/2 = 4.2 d) undergoes positron decay to stable ¹²⁴Te and is employed for PET imaging studies. Its relatively long half-life allows extended radiosynthesis, quantitative imaging over several days, and distribution to sites far from production facilities [9]. ¹²⁴I is typically produced using isotopically enriched ¹²⁴Te and the ¹²⁴Te(d,2n)¹²⁴I or ¹²⁴Te(p,n)¹²⁴I nuclear reactions [110,111]. Applications in nuclear medicine and research have been extensive, including thyroid and parathyroid imaging, studies of neurotransmitter receptors, and monoclonal antibody imaging in cancer [110].

Strengths of ¹²⁴I include its long half-life that eases logistics and allows imaging at extended time points. Limitations include hazards associated with volatile radioactive products; a relatively low positron branching ratio (22.7%); relatively high average positron emission energy (E_mean = 820 keV) that results in a lower spatial resolution compared to other PET radionuclides; and co-emitted gamma rays (603 keV (63%), 1691 keV (11%)) that increase dose and shielding requirements [9].

6.3. Iodine-131 (SPECT)

Iodine-131 (t_1/2 = 8.0 d) undergoes β⁻ decay to stable ¹³¹Xe, and similar to ¹²³I and ¹²⁴I, it is primarily used for treating thyroid malignancies [107]. ¹³¹I can be produced in a nuclear reactor by irradiating either ¹³⁰Te or uranium targets [112].

Strengths of ¹³¹I include its 8 d half-life that permits imaging at extended time points, commercial availability, and primary 364 keV (81.5%) gamma emission that is well suited for SPECT imaging. However, limitations include hazards associated with volatile radioactive products and significant β⁻ emissions that would increase patient dose [9].

6.4. Astatine-209 (SPECT)

Astatine-209 (t_1/2 = 5.4 h) decays via alpha emissions (4%) to ²⁰⁵Bi (t_1/2 = 14.9 d) followed by decay to stable ²⁰⁵Pb, or via electron capture (96%) to ²⁰⁹Po (t_1/2 = 124 y). During decay to ²⁰⁹Po, X-rays and gamma emissions (545 keV (91.0%), 195 keV (22.6%), and 239 keV (12.4%) enable SPECT imaging. ²⁰⁹At can be produced via high-energy proton spallation of a uranium carbide target, followed by online surface ionization and A = 213 isobars separation. This can yield ²⁰⁹At in activities on the order of 10² MBq [113]. Subsequent chemical purification employs a Te column to obtain purified ²⁰⁹At [113,114]. As shown in Figure 6, subsequent studies using ²⁰⁹At for phantom imaging demonstrated that image reconstruction with ²⁰⁹At X-ray emissions was superior to using its gamma emissions [114]. Additionally, in vivo imaging measurements of ²⁰⁹At uptake in mice matched ex vivo measurements within 10%. This demonstrated the potential of using ²⁰⁹At to accurately determine astatine biodistributions [114].

Strengths include identical chemistry to ²¹¹At, which would give more certainty to ²⁰⁹At pharmacokinetic data. Limitations include alpha emissions in ²⁰⁹At decay that would require dosimetric evaluation; numerous high-energy gamma rays that complicate shielding and increase patient dose; the need to consider longer-lived ²⁰⁵Bi in dosimetry evaluations; and production/logistical challenges associated with distributing relatively short-lived ²⁰⁹At from a limited number of facilities capable of high-energy proton spallation and separation of ²¹¹At from actinide targets [8].

7. Theranostic Imaging Surrogates Proposed for Thorium-227

Thorium-227 (t_1/2 = 18.7 d) decays via alpha emission to ²²³Ra and can be harvested from a generator containing ²²⁷Ac (t_1/2 = 21.8 y) that is produced via nuclear reactor irradiation of ²²⁶Ra [115]. Thorium can be complexed with octadentate 3,2-hydroxypyridinone (3,2-HOPO) chelators attached to biological-targeting vectors ¹¹⁵. Ongoing clinical studies involving ²²⁷Th TAT include targeting tumors expressing human epidermal growth factor receptor 2 (HER2), PSMA, mesothelin (MSLN), and CD22 [116]. ²²⁷Th does emit a 236 keV (12.9%) gamma photon that would be suitable for SPECT imaging. However, the long half-life of ²²⁷Th relative to other TAT radionuclides would likely result in a low injected therapeutic activity, which could be insufficient for direct imaging ⁹. Therefore, an imaging surrogate to assess ²²⁷Th radiopharmaceutical pharmacokinetics is desirable, with the ¹³⁴Ce/¹³⁴La PET imaging pair showing promise (see Section 3.3). A significant uncertainty of using any theranostic imaging pair with ²²⁷Th involves its long-lived ²²³Ra progeny, which has the potential for substantial redistribution and alpha irradiation of healthy tissue after decay from ²²⁷Th. This would significantly complicate direct comparisons between imaging and inferred therapeutic dosimetry and require further study.

8. Theranostic Imaging Surrogates Proposed for Terbium-149

Terbium-149 (t_1/2 = 4.1 h) is a unique radionuclide for TAT. It emits low-energy alpha particles with a short tissue range and decays via several daughter radionuclides to stable ¹⁴⁵Nd and ¹⁴¹Pr, without any subsequent alpha emissions [9]. This absence of alpha-emitting progeny is regarded as a potential strength for ¹⁴⁹Tb TAT. ¹⁴⁹Tb is produced via high-energy proton spallation of a tantalum target followed by online isotope separation or ³He bombardment of a ¹⁵¹Eu target [19,20,117,118]. 100 MBq of ¹⁴⁹Tb was obtained in a solution suitable for preclinical applications and successfully labeled to a DOTANOC targeting vector [118]. While PET images were successfully obtained using [¹⁴⁹Tb]Tb-DOTANOC in a mouse model, ¹⁴⁹Tb possesses a relatively low positron branching ratio (21%) and relatively high positron emission energy (E_mean = 805 keV). These physical factors could present challenges to obtaining high-quality clinical PET images. Additionally, due to limited production and the resulting extreme scarcity of ¹⁴⁹Tb, imaging surrogates would be helpful research tools to evaluate its potential for TAT. Two surrogate candidates are ¹⁵⁵Tb and ¹⁵²Tb.

8.1. Terbium-155 (SPECT)

Terbium-155 (t_1/2 = 5.3 d) decays via electron capture to stable ¹⁵⁵Gd, with X-ray and gamma-ray emissions including 87 keV (32%), 105 keV (25%), 180 keV (7.5%), and 262 keV (5%) [9]. ¹⁵⁵Tb can be produced via the ¹⁵⁶Gd(p,2n)¹⁵⁵Tb reaction at 23 MeV, or the ¹⁵⁵Gd(p,n)¹⁵⁵Tb reaction at 10 MeV [119]. The ¹⁵⁶Gd(p,2n)¹⁵⁵Tb has higher demonstrated production yields (up to 1.7 GBq); however, it has a lower radionuclidic purity compared to the final product of the ¹⁵⁵Gd(p,n)¹⁵⁵Tb reaction (200 MBq yield). Subsequently, phantom and in vivo SPECT/CT studies were successfully performed with [¹⁵⁵Tb]Tb-DOTATOC, demonstrating a similar image quality to ¹¹¹In [119,120].

Advantages of ¹⁵⁵Tb include its accessible production routes that can synthesize multi-patient activities per run, decay to stable ¹⁵⁵Gd, and its long half-life that enables long-duration imaging. Limitations include relatively low imaging performance compared to other diagnostic radionuclides, such as PET emitters.

8.2. Terbium-152 (PET)

Terbium-152 (t_1/2 = 17.5 h) decays via positron emission to near-stable ¹⁵²Gd with a positron branching ratio of 20.3% and an average positron energy of 1140 keV [121]. Several primary co-emitted gamma rays include 344 keV (63.5%), 271 keV (9.5%), 586 keV (9.2%), and 779 keV (5.5%). ¹⁵²Tb synthesis is extremely limited, with the existing production route involving high-energy proton spallation of a tantalum target at 1.4 GeV and online isotope separation [122]. Following chemical separation, phantom studies revealed increased image noise due to the smaller positron branching ratio of ¹⁵²Tb, and subsequently [¹⁵²Tb]Tb-DOTANOC was administered to a patient and used to acquire PET scans [121].

Advantages of ¹⁵²Tb include a relatively long half-life permitting imaging at extended time points and its decay to near-stable ¹⁵²Gd. Limitations include the scarcity of facilities capable of achieving proton energies for production, the higher average positron emission energy, and significant co-emitted gamma rays that increase the radioactive dose.

9. Summary and Outlook for Alpha-Emitter Imaging Surrogates

As highlighted in this article, multiple SPECT and PET imaging surrogates have demonstrated the potential to enhance clinical TAT applications and research.

Table 1. Summary of prominent TAT radionuclides and their proposed theranostic SPECT and PET imaging surrogates.

Alpha Emitter	Proposed Imaging Surrogate	Half-Life	Key Decay Progeny	Key Imaging Emissions	Primary Production Routes	Production Status and References
225Ac		9.9 d	211Fr, 217At, 213Bi, 213Po, 209Tl, 209Pb, 209Bi (stable)	γ: 100 keV (1%), 218 keV (11.4%)	229Th generator, 226Ra proton/photonuclear reactions, 232Th spallation	Routine production [31,32,33,34]
	133La	3.9 h	133Ba	β+: 460 keV (mean), 7.2%	135Ba or 134Ba proton irradiation	Research [40,41,42]
	132La	4.8 h	132Ba (stable)	β+: 1290 keV (mean), 42.1%	132Ba proton irradiation	Research [48,49,50]
	134Ce/134La	3.2 d/6.5 min	134Ba (stable)	β+: 1217 keV (mean), 63.6%	High-energy 139La proton irradiation	Research [52,53,54]
	226Ac	29.4 h	226Ra, 226Th, 222Ra, 218Rn, 214Po, 210Pb, 210Bi, 210Po, 206Pb (stable)	γ: 230 keV (26.9%), 158 keV (17.5%)	226Ra proton irradiation	Research [55]
212Pb		10.6 h	212Bi, 212Po, 208Tl, 208Pb (stable)	γ: 239 keV (44%)	228Th generator	Routine production [12,63,64,65,66,67]
	203Pb	51.9 h	203Tl (stable)	γ: 279 keV (81%) X-ray: 73 keV (37%), 71 keV (22%)	205Tl proton irradiation, 203Tl proton or deutron irradiation	Routine production [21,63,64,68,69,70,71]
223Ra		11.4 d	219Rn, 215Po, 215At, 211Pb, 211Bi, 211Po, 207Tl, 207Pb (stable)	γ: 269 keV (13%), 154 keV (6%)	226Ra nuclear reactor irradiation	Routine production [67,96,97]
224Ra		3.6 d	220Rn, 216Po, 212Pb, 212Bi, 212Po, 208Tl, 208Pb (stable)	γ: 241 keV (4%)	228Th generator	Routine production [67,96,97]
	131Ba	11.5 d	131Cs	γ: 496 keV (48%), 124 keV (30%), 216 keV (20%), 371 keV (14%)	133Cs proton irradiation	Research [101,102]
211At		7.2 h	207Bi, 211Po, 207Pb (stable)	X-ray: 79 keV (21%)	209Bi alpha particle irradiation	Routine production [8,103,104,105]
	123I	13.2 h	123Te (near stable)	γ: 159 keV (83.6%)	124Xe proton irradiation	Routine production [108,109]
	124I	4.2 d	123Te (stable)	β+: 820 keV (mean), 22.7%	124Te proton or deutron irradiation	Routine production [110,111]
	131I	8.0 d	131Xe (stable)	γ: 364 keV (89.6%)	130Te or uranium nuclear reactor irradiation	Routine production [112]
	209At	5.4 h	209Po, 209Bi, 205Bi, 205Pb, 205Tl	γ: 545 keV (91%), 239 keV (12.4%), 195 keV (22.6%)	Proton spallation of uranium carbide	Research [113,114]
227Th		18.7 d	223Ra, 219Rn, 215Po, 215At, 211Pb, 211Bi, 211Po, 207Tl, 207Pb (stable)	γ: 235 keV (12.9%)	226Ra nuclear reactor irradiation	Routine production [115]
	134Ce/134La	3.2 d/6.5 min	134Ba (stable)	β+: 1217 keV (mean), 63.6%	High-energy 139La proton irradiation	Research [52,53,54]
149Tb		4.1 h	149Gd, 149Eu, 149Sm (stable), 145Eu, 145Sm, 145Pm, 145Nd (stable)	β+: 720 keV (mean), 7.1% γ: 165 keV (26.4%)	151Eu helium-3 bombardment, proton spallation of Ta	Research [19,20,117,118]
	155Tb	5.3 d	155Gd (stable)	γ: 87 keV (32%), 105 keV (25%), 180 keV (7.5%), and 262 keV (5%).	155Gd proton irradiation	Research [119]
	152Tb	17.5 h	152Gd (near stable)	β+: 1140 keV (mean), 20.3%	Proton spallation of Ta	Research [122]

presents a summary of proposed theranostic imaging surrogates for alpha emitters, along with their properties and production status.

Production capabilities must be augmented to enable more patients and research efforts to benefit from TAT imaging surrogates. Existing medium-energy cyclotron facilities are well positioned to improve the supply chain of imaging surrogates such as ¹³³La, ²⁰³Pb, and ¹⁵⁵Tb by adapting and optimizing established production techniques to the unique capabilities of each facility. A stable supply of isotopically enriched accelerator target material will be required to support growing production efforts for many of these radionuclides. Other imaging surrogates such as ²²⁶Ra, ¹⁵²Tb, ²⁰⁹At, and ¹³⁴Ce/¹³⁴La require high-energy accelerators, bombarding hazardous target material, and techniques such as mass separation to enable their production. While these surrogates have demonstrated research potential, their widespread deployment for radiopharmaceutical development and clinical application may be limited owing to the scarcity of facilities capable of their production.

Except for ¹⁴⁹Tb, which possesses a single alpha emission in its decay chain, most TAT radionuclides, including ²²⁵Ac, ²¹²Pb, ²²³Ra, ²²⁴Ra, ²²⁷Th, and ²¹¹At, possess a cascade of decay progeny that are released from the original target site due to recoil energy and deposit additional alpha radiation in surrounding healthy tissues. While the highlighted imaging surrogates are well positioned to provide more accurate dosimetry data for the TAT parent radionuclide decay, there will be a degree of uncertainty regarding the dose from alpha-emitting decay progeny. This uncertainty will depend on the type of malignancy, internalization within targeted cells, and other factors within the disease microenvironment that influence the radiopharmaceutical pharmacokinetics. However, this limitation does not negate the improved accuracy of biodistribution dosimetry data conferred by using imaging surrogates matched to the TAT parent radionuclide, particularly when radionuclides are stably bound to their targeting vector. Therefore, TAT imaging surrogates have the potential to assist the preclinical development and clinical deployment of TAT radiopharmaceuticals and represent a significant improvement over conventional PET and SPECT imaging radionuclides currently paired with TAT.

10. Conclusions

Recent preclinical and clinical advances in targeted alpha therapy have spurred significant interest in utilizing alpha-emitting radiopharmaceuticals to treat metastatic cancers and other malignancies. Despite their strong potential, TAT radiopharmaceuticals suffer from an acute supply shortage of alpha-emitting radionuclides due to production constraints. This severely restricts the availability for patient therapy and slows the development of new TAT radiopharmaceuticals. Additionally, many alpha-emitting radionuclides do not possess radioactive emissions suitable for diagnostic imaging. This often leads to diagnostic radiopharmaceuticals being employed with suboptimally paired imaging radionuclides that possess different chemistries from their therapeutic counterpart, which can potentially result in different radiopharmaceutical biodistributions. Therefore, increasing the availability of SPECT and PET imaging TAT surrogates has strong potential to improve the accuracy of dosimetry and treatment tracking, and enhance TAT research output by using more economical and less potent diagnostic radionuclides for preclinical radiopharmaceutical development. Therefore, TAT imaging surrogates hold potential to improve the accuracy of diagnostic scans, equipping clinicians and researchers with more accurate biodistribution and dosimetry data that they can use to expedite the development and deployment of novel TAT radiopharmaceuticals.