Targeted radionuclide therapy (TRT) has emerged as a promising strategy for cancer treatment. While TRT offers potent therapeutic efficacy, its clinical application requires careful control due to the risk of systemic toxicity arising from off-target distribution of radionuclides. A key strategy to minimize such toxicity and enhance targeting efficiency lies in selecting an appropriate chelator that forms highly stable complexes with radionuclides and maintains their integrity under physiological conditions. This study aimed to computationally assess the chelation compatibility of four clinically relevant chelators (DOTA, NOTA, NODAGA, and TETA) with various therapeutic and diagnostic radionuclides. Chelator-radionuclide interactions were evaluated using density functional theory (DFT) computational modeling. The thermodynamic stabilities of the chelator-radionuclide complexes were evaluated using interaction energies (Eint), with lower values indicating stronger coordination. Coordination geometries, compatibility between internal cavity volumes of chelators and radii of radionuclides, and charge distributions upon chelation were also assessed to provide a comprehensive evaluation. Computational predictions were validated against existing literature to assess their agreement in coordination geometries and chelator-radionuclide compatibility. DOTA exhibited moderate-to-strong chelation affinity across various radionuclides, generally forming stable 8-coordinate complexes, but with a marked preference for medium-sized ions (e.g., Lu3+: -4.99 eV vs Ac3+: -2.45 eV; Eint). NOTA and NODAGA, which possess smaller cavity volumes (7.29 Å3 and 4.56 Å3, respectively; vs 15.29 Å3 for DOTA), showed strong size-selective affinity toward smaller metal ions. TETA, structurally flexible, preferentially formed stable 6-coordinate complexes with smaller trivalent ions such as Ga3+ (-4.32 eV; Eint). Charge neutrality was identified as a critical factor for chelation, as neutral complexes exhibited more homogeneous electrostatic environments and improved stability compared to charged complexes. This computational study identifies three key factors─cavity volume compatibility, structural rigidity/flexibility, and charge neutrality─as critical determinants of chelator-radionuclide stability. By providing predictive insights into chelation behavior, our validated DFT modeling supports the rational selection and optimization of chelators, with direct implications for the development of safer and more effective theranostic radiopharmaceuticals in TRT.

Designing and interpreting early phase trials of theranostic radiopharmaceuticals remains challenging because it is difficult to isolate effective levels of activity in enriched patient populations that would be worth following up in later-phase development. This study explores the known challenges and emerging opportunities for clinical research on patients with uterine cervical cancer. We identified eight randomized combination trials for advanced-stage uterine cervix cancer that were activated between 2011 and 2022 and tabulated their results to determine whether combinations were better than individual constituents and which suitable study population is best situated for the study of a new theranostic agent. In this overview, we discuss exploitable vulnerabilities and radiobiology of cancer-associated fibroblasts, as these stromal cells are targets for nuclear and therapeutic radiation medicine. We also discuss investigational drugs that hold promise for the theranostic treatment of persistent, recurrent, or metastatic uterine cervical cancer, including inhibitors of fibroblast activation protein-alpha and ribonucleotide reductase. In our expert opinion, the development of a theranostic radiopharmaceutical should pursue the eventual goal of being tested in a randomized phase II monotherapy setting.

Peptide receptor radionuclide therapy (PRRT) using α-particle emitters has potential to provide improved patient outcomes over those achieved with β-particle PRRT. A promising candidate radiopharmaceutical pair, PSC-PEG2-TOC (VMT-α-NET) conjugated to 203Pb for SPECT/CT imaging or 212Pb for α-PRRT, is currently in early-phase clinical trials for patients with neuroendocrine tumors (NETs). Here, we present the imaging and dosimetry characteristics of this theranostic approach. Methods: A phase 0 imaging trial of [203Pb]Pb-VMT-α-NET was conducted between January and December of 2023. Ten participants with somatostatin receptor type 2 (SSTR2)-positive NETs underwent SPECT/CT and blood sampling at 1, 4, 24, and 48 h after intravenous infusion of approximately 185 MBq of [203Pb]Pb-VMT-α-NET. The diagnostic performance of [203Pb]Pb-VMT-α-NET was evaluated through lesion-by-lesion comparison against baseline SSTR2 PET/CT. A subset of lesions was further analyzed for signal-to-noise ratio to determine the optimal diagnostic imaging time point after [203Pb]Pb-VMT-α-NET administration. Patient-specific dosimetry of [212Pb]Pb-VMT-α-NET was derived from 203Pb imaging and performed assuming local α- and β-particle energy deposition in tumors and normal organs. Effects of daughter ion relocation were considered using a whole-body pharmacokinetic model on the basis of parameters published by the International Commission on Radiological Protection. Results: Of the 162 total lesions identified on SSTR2 PET/CT scans, only 97 were detected on [203Pb]Pb-VMT-α-NET SPECT/CT. The highest signal-to-noise ratio for lesions occurred 4 h after [203Pb]Pb-VMT-α-NET administration. Sensitivity was 94% for lesions larger than 1 cm versus 35% for lesions no larger than 1 cm or nonmeasurable lesions. The effective dose associated with [203Pb]Pb-VMT-α-NET administration was 0.038 mSv/MBq (1.40 mSv/mCi). Estimated dosimetry for [212Pb]Pb-VMT-α-NET (mean ± SD, not adjusted for relative biologic effectiveness) based on [203Pb]Pb-VMT-α-NET SPECT/CT was 15 ± 4.7 mGy/MBq for the kidneys, 8.4 ± 4.1 mGy/MBq for the spleen, 2.5 ± 0.8 mGy/MBq for the liver, 0.324 ± 0.108 mGy/MBq for the blood, 0.270 ± 0.081 mGy/MBq for the whole body, and 29.6 ± 25.8 mGy/MBq for tumors. Renal absorbed dose projections for 212Pb were estimated to carry an overall standard uncertainty (k = 1) of 15.3%. Conclusion: [203Pb]Pb-VMT-α-NET appears to be a safe and effective SPECT/CT tracer for imaging NETs larger than 1 cm and for normal organ and tumor radiation dosimetry. The chemically matched 203/212Pb theranostic pair offers the potential for a dosimetry-driven personalized treatment paradigm.

203/212Pb is a promising theranostic isotope pair for targeted alpha therapy (TAT) of neuroendocrine tumors (NET). VMT-α-NET is a novel SSTR2 targeting peptide that can be labeled with both isotopes. The aim of this work was to perform first clinical investigations of [203/212Pb]Pb-VMT-α-NET regarding imaging, biokinetics, tolerability and response. 12 patients (9 m/3 w; mean age 71, range 60–84) with progressive metastatic GEP-NET grade 1–3 received diagnostic imaging with [203Pb]Pb-VMT-α-NET (4.9 MBq/kg bw) up to 24 h p.i. (whole body SPECT/CT) and, if eligible, a single dose of [212Pb]Pb-VMT-α-NET therapy (1.2 MBq/kg bw) after exhaustion of all current therapies (including [177Lu]Lu- [225Ac]Ac-DOTATATE), and post-treatment imaging with [212Pb]Pb-VMT-α-NET up to 24 h p.i. (whole body SPECT/CT). Clinical and laboratory parameters were monitored. A visual and quantitative comparison was made with [68 Ga]Ga-DOTATATE PET scans before and 3 months after therapy. No high-grade adverse effects were observed in all patients evaluated with [203Pb]Pb-VMT-α-NET. All patients showed an initial high, but lesion-dependent heterogeneous intratumoral accumulation, comparable to [68 Ga]Ga-DOTATATE PET. Treatment with [212Pb]Pb-VMT-α-NET was also well tolerated by all patients without high-grade or serious adverse side effects. Post-therapeutic PET scans and tumor marker controls showed stable findings in all patients up to 3 months after treatment. Imaging with [203Pb]Pb-VMT-α-NET followed by a single dose of [212Pb]Pb-VMT-α-NET appears to be well tolerated with promising efficacy, even in a heterogenous and heavily pretreated patient population. Further studies are warranted to examine tolerability and efficacy over multiple treatment cycles in larger patient populations.

Small cell lung cancer (SCLC) has a 6% 5-year overall survival rate. C-X-C chemokine receptor 4 (CXCR4) is an attractive target for theranostic agents, is highly expressed in SCLCs, and can be targeted with pentixather using the theranostic pair 212Pb/203Pb. The hypothesis that 212Pb/203Pb-pentixather can be used safely and effectively for imaging and therapy in SCLC in xenograft models was tested. SPECT-CT imaging and biodistribution studies of tumor-bearing mice injected with 203Pb-pentixather demonstrated CXCR4 expression-dependent uptake and accumulation of radioligand in the kidneys and livers. Dosimetry calculations were performed to estimate 212Pb-pentixather uptake in tumor and normal tissue. 212Pb-Pentixather treatment (37-111 kBq/g) of SCLC xenografts (DMS273 and H69AR) significantly prolonged survival and delayed tumor growth. CBCs of mice at 30 days after treatment demonstrated adequate retention of bone marrow function. NSG mice allografted with human hCD34+ bone marrow were treated with 212Pb-pentixather (37-111 kBq/g) to assess damage to human hematopoietic stem cells, demonstrating cytopenias in peripheral blood CBCs at 13-18 days after treatment, resolving by days 28-31. Flow cytometry of bone marrow in these animals at days 28-31 demonstrated a significantly reduced frequency of the human hematopoietic marker CD45 and reconstitution of the bone marrow with murine CD45+ lineages. 203Pb-Pentixather can be used to image CXCR4-expressing SCLC xenografts. Treatment with high-LET alpha emitter 212Pb-pentixather significantly prolonged overall survival, and recovery of mouse bone marrow from 212Pb-pentixather was significantly greater than that of human bone marrow.

(1) Background: As the demand for 212Pb for clinical theranostics rises, empirical studies that examine the radiation safety implications of different 224Ra sources are needed to facilitate discussions with local authorities for the translation of 203/212Pb theranostics routine clinical practice. (2) Methods: Environmental 220Rn (Thoron) emanation was detected by a RAD7 detector in the vicinity of respective 212Pb sources and additional alpha-dosimeters to detect 220Rn during generator elution, radiosynthesis, and quality control. Personnel gamma exposure was measured using whole-body and ring dosimeters. Generators included those based on wet-chemical-process- and emanation-based technology. (3) Results: During generator handling, varying levels of 220Rn were observed in the vicinity of generators. An additional monthly whole-body dose must be considered when handling different sources of 212Pb generators, and this depends upon local shielding and the handling approaches toward use of the technology. (4) Conclusions: 224Ra in any form (including radionuclide generators) should always be handled within a fume hood to keep potential contamination and exposure to personnel as low as reasonably achievable. Following standard practices of radiation safety, generators of 212Pb can be used safely for theranostic applications.

Background 203 Pb and 212 Pb show promise as theragnostic agents for targeted alpha therapy (TAT) because two chemically identical isotopes can be used for diagnostic imaging and treatment. In the 212 Pb decay chain, in addition to alpha and beta particles, a large number of photons are emitted, those with an energy of 239 keV and the characteristic X-rays of 212 Pb could be used for imaging. 203 Pb decays by photon emission with an energy of 279 keV, which appears suitable for gamma camera imaging. The aim of this study was to investigate suitable imaging protocols and to characterize the scintigraphic imaging properties and their implications for the clinical feasibility as theragnostic isotopes. Methods Planar and SPECT/CT images were obtained with medium- and high-energy collimators on a Siemens Symbia Intevo 6 using a NEMA image quality phantom in various phantom setups and another body-shaped phantom with several inserts. Different energy windows were investigated and measurements were evaluated in terms of sensitivity, count rate performance, spatial resolution, contrast recovery, lesion detectability, and image quantification. Results Evaluation of image quality showed superior imaging characteristics for 203 Pb compared to 212 Pb regarding spatial resolution, contrast recovery, image noise, and quantification accuracy. Both medium- and high- energy collimators were suitable for 203 Pb imaging, with the medium energy collimators showed slightly better imaging properties. Images obtained with the HE collimators in the 79 keV energy window showed the best visual image quality for 212 Pb. Due to high-energy photon emissions from 212 Pb daughter nuclides (e.g., 2.6 MeV from 208 Tl), dead time related count losses occurred even at low activities (20% count loss at 20 MBq for MELP collimators). Conclusions According to our results and first-in-human imaging studies, SPECT/CT imaging with the 203/212 Pb theragnostic pair is clinically feasible. 203 Pb is an appropriate imaging surrogate to investigate pharmacokinetics and perform predictive dosimetry. The less favorable imaging characteristics of 212 Pb make image quantification and post-treatment dosimetry challenging and require further research.

ABSTRACT:212 Pb emerges as a compelling in vivo α-particle generator for targeted α therapy due to its favorable half-life ( t1/2 = 10.6 hours) aligning with the biological half-lives of small peptides and its potent α-particle emissions within the decay series. However, one of the challenges with 212 Pb is to perform appropriate image-guided dosimetry. To date, all the data have been extrapolated from its imaging analog, 203 Pb. We present the first-in-human posttherapy image-guided dosimetric estimates of a single cycle of 212 Pb VMT-α-peptide, administered in a 41-year-old woman with an advanced grade 2 NET. The patient also demonstrated partial response on treatment.

The objective of this research was the development and evaluation of 203Pb-labelled panitumumab (203Pb-PSC-panitumumab) as an immuno-SPECT radioligand for the detection of EGFR + head and neck squamous cell carcinoma (HNSCC) in a patient-derived xenograft (PDX) mouse model. The 51.9 h physical half-life and favourable γ-emission (279 keV; 81

This review article explores the evolving landscape of Molecular Radiotherapy (MRT), emphasizing Peptide Receptor Radionuclide Therapy (PRRT) for neuroendocrine tumours (NETs). The primary focus is on the transition from β-emitting radiopharmaceuticals to α-emitting agents in PRRT, offering a critical analysis of the radiobiological basis, clinical applications, and ongoing developments in Targeted Alpha Therapy (TAT). Through an extensive literature review, the article delves into the mechanisms and effectiveness of PRRT in targeting somatostatin subtype 2 receptors, highlighting both its successes and limitations. The discussion extends to the emerging paradigm of TAT, underlining its higher potency and specificity with α-particle emissions, which promise enhanced therapeutic efficacy and reduced toxicity. The review critically evaluates preclinical and clinical data, emphasizing the need for standardised dosimetry and a deeper understanding of the dose-response relationship in TAT. The review concludes by underscoring the significant potential of TAT in treating SSTR2-overexpressing cancers, especially in patients refractory to β-PRRT, while also acknowledging the current challenges and the necessity for further research to optimize treatment protocols.

Although pancreatic ductal adenocarcinoma (PDAC) is associated with limited treatment options and poor patient outcomes, targeted α-particle therapy (TAT) represents a promising development in the field. TAT shows potential in treating metastatic cancers, including those that have become resistant to conventional treatments. Among the most auspicious radionuclides stands the in vivo α-generator 212Pb. Combined with the imaging-compatible radionuclide 203Pb, this theranostic match is a promising modality rapidly translating into the clinic. Methods: Using the pretargeting approach between a radiolabeled 1,2,4,5-tetrazine (Tz) tracer and a trans-cyclooctene (TCO) modified antibody, imaging and therapy with radiolead were performed on a PDAC tumor xenograft mouse model. For therapy, 3 cohorts received a single administration of 1.1, 2.2, or 3.7 MBq of the pretargeting agent, [212Pb]Pb-DO3A-PEG7-Tz, whereby administered activity levels were guided by dosimetric analysis. Results: The treated mice were holistically evaluated; minimal-to-mild renal tubular necrosis was observed. At the same time, median survival doubled for the highest-dose cohort (10.7 wk) compared with the control cohort (5.1 wk). Conclusion: This foundational study demonstrated the feasibility and safety of pretargeted TAT with 212Pb in PDAC while considering dose limitations and potential adverse effects.