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Nelson, B.J.B.; Wilson, J.; Andersson, J.D.; Wuest, F. Theranostic Imaging Surrogates for Targeted Alpha Therapy. Encyclopedia. Available online: https://encyclopedia.pub/entry/52028 (accessed on 19 May 2024).
Nelson BJB, Wilson J, Andersson JD, Wuest F. Theranostic Imaging Surrogates for Targeted Alpha Therapy. Encyclopedia. Available at: https://encyclopedia.pub/entry/52028. Accessed May 19, 2024.
Nelson, Bryce J. B., John Wilson, Jan D. Andersson, Frank Wuest. "Theranostic Imaging Surrogates for Targeted Alpha Therapy" Encyclopedia, https://encyclopedia.pub/entry/52028 (accessed May 19, 2024).
Nelson, B.J.B., Wilson, J., Andersson, J.D., & Wuest, F. (2023, November 24). Theranostic Imaging Surrogates for Targeted Alpha Therapy. In Encyclopedia. https://encyclopedia.pub/entry/52028
Nelson, Bryce J. B., et al. "Theranostic Imaging Surrogates for Targeted Alpha Therapy." Encyclopedia. Web. 24 November, 2023.
Theranostic Imaging Surrogates for Targeted Alpha Therapy
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This entry is adapted from the peer-reviewed paper 10.3390/ph16111622

Most targeted alpha therapy (TAT) radionuclides lack or possess insufficient co-emitted positrons or gamma rays for acquiring higher-quality positron emission tomography (PET) or single-photon emission computed tomography (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.

targeted alpha therapy alpha particle therapy PET imaging SPECT imaging targeted radionuclide therapy

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.
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 [5][6]. Radionuclides that have shown potential for TAT include 227Th, 225Ac, 224Ra, 223Ra, 212Pb, 211At, and 149Tb [1][2][7][8][9][10][11][12][13][14][15][16][17].
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.
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.

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 [18][19][20].
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.
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.
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.
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.

3. Theranostic Imaging Surrogates Proposed for Actinium-225

3.1. Lanthanum-133 (PET)

Lanthanum-133 (t1/2 = 3.9 h) has been synthesized via the 135Ba(p,3n)133La and 134Ba(p,2n)133La nuclear reactions on medical cyclotrons [21]. 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 [22]. Co-production of 135La (t1/2 = 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 [23].

3.2. Lanthanum-132 (PET)

Lanthanum-132 (t1/2 = 4.6 h) can be produced via the 132Ba(p,n)132La nuclear reaction using natural Ba metal target material [24][25][26][27]. 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 132La and 5.6 ± 1.1 MBq·µA−1·h−1 135La for irradiation with 11.9 MeV protons, with 132La activity approximately 5% relative to 135La activity at the end of bombardment [24][25]. Another study reported yields of 0.8 MBq 132La and 17.9 MBq 135La for 500 µA·min runs at 11.9 MeV [22]. 132La can be purified using DGA resin and complexed with chelators at molar activities suitable for radiopharmaceutical application [25].

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

Lanthanum-134 (t1/2 = 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 (t1/2 = 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 [28]. 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 [29][30].

3.4. Actinium-226 (SPECT)

Actinium-226 (t1/2 = 29.4 h) can be produced via high-energy proton spallation of a uranium carbide target or lower-energy proton bombardment of 226Ra (t1/2 = 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 [31].
An alternative production route could employ 226Ra target material and the 226Ra(p,n)226Ac nuclear reaction on a lower energy proton cyclotron [6][31][32][33].
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.

4. Theranostic Imaging Surrogates Proposed for Lead-212

Lead-203 (SPECT)

Lead-203 (t1/2 = 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 [18][21][34][35][36][37][38][39]. 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 [40]. However, irradiating natTl produces significant activities of 201Pb (t1/2 = 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 [35]. However, yields are limited due to the low nuclear reaction cross-section in this energy window [21].
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 [18][34][35][37][38].
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 [41]. In vivo preclinical and clinical SPECT imaging of uncomplexed and chelated 203Pb has been performed [39][42].
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. 

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

Radium-223 (t1/2 = 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 [43]. It is the only FDA-proved alpha-particle-emitting radiopharmaceutical (Xofigo®) and has been used to treat over 18,000 patients since 2013 [44]. 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 [44]. Similarly, 224Ra (t1/2 = 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 [45][46]. [224Ra]RaCl2 (marketed as 224SpondylAT® (Eckert & Ziegler, Berlin, Germany) has also been used to treat bone and joint disease, ankylosing spondylitis [47], while 224Ra is also under investigation for a novel brachytherapy called diffusing alpha-emitter radiation therapy (DaRT).
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 [44][48].
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 [6][43].

Barium-131 (SPECT)

Barium-131 (t1/2 = 11.5 d) decays via electron capture to 131Cs (t1/2 = 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%)) [6]. Additionally, approaches designed to sequester Ra (nanoparticles, chelation via macropa or ligands based on the arene scaffold) [49][50] should be transferrable owing to the proven use of Ba as a non-radioactive surrogate for Ra [51]. 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 [21][52]. Alternatively, 131Ba can be produced via proton irradiation of natural cesium target material in a cyclotron via the 133Cs(p,3n)131Ba nuclear reaction with a small 133Ba contamination (0.01%) at beam energies of 27.5 MeV [21][51]. 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 [51].
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.

6. Theranostic Imaging Surrogates Proposed for Astatine-211

Astatine-211 (t1/2 = 7.2 h) has garnered interest for TAT owing to its decay to either 207Bi (t1/2 = 31.6 y) via alpha emission or to 211Pb via electron capture followed by alpha decay to stable 207Pb [6]. Therefore, each 211At decay yields one alpha particle. The 211At decay chain also emits few high-energy gamma photons, which avoids excess radiation dose [5]. 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 (t1/2 = 14.6 h) in a generator configuration [5][53][54].
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 [55]. 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 (t1/2 = 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 [56]. Its X-ray emissions and primary gamma photopeak of 159 keV (83.6%) are well suited for SPECT imaging [6].
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 [57][58].
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 (t1/2 = 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 [6]. 124I is typically produced using isotopically enriched 124Te and the 124Te(d,2n)124I or 124Te(p,n)124I nuclear reactions [59][60]. Applications in nuclear medicine and research have been extensive, including thyroid and parathyroid imaging, studies of neurotransmitter receptors, and monoclonal antibody imaging in cancer [59].
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 (Emean = 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 [6].

6.3. Iodine-131 (SPECT)

Iodine-131 (t1/2 = 8.0 d) undergoes β− decay to stable 131Xe, and similar to 123I and 124I, it is primarily used for treating thyroid malignancies [56]. 131I can be produced in a nuclear reactor by irradiating either 130Te or uranium targets [61].
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 [6].

6.4. Astatine-209 (SPECT)

Astatine-209 (t1/2 = 5.4 h) decays via alpha emissions (4%) to 205Bi (t1/2 = 14.9 d) followed by decay to stable 205Pb, or via electron capture (96%) to 209Po (t1/2 = 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 [62].

7. Theranostic Imaging Surrogates Proposed for Thorium-227

Thorium-227 (t1/2 = 18.7 d) decays via alpha emission to 223Ra and can be harvested from a generator containing 227Ac (t1/2 = 21.8 y) that is produced via nuclear reactor irradiation of 226Ra [63]. 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 [64]. 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.

8. Theranostic Imaging Surrogates Proposed for Terbium-149

8.1. Terbium-155 (SPECT)

Terbium-155 (t1/2 = 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%) [6]. 155Tb can be produced via the 156Gd(p,2n)155Tb reaction at 23 MeV, or the 155Gd(p,n)155Tb reaction at 10 MeV [65]. 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).

8.2. Terbium-152 (PET)

Terbium-152 (t1/2 = 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 [66]. 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 [67].

9. 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.

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Subjects: Radiology, Nuclear Medicine & Medical Imaging
Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register :
Bryce J. B. Nelson
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John Wilson
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Jan D. Andersson
,
Frank Wuest
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Update Date: 27 Nov 2023
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