Receptor-targeted image-guided Radionuclide Therapy (TRT) is increasingly recognized as a promising approach to cancer treatment. In particular, the potential for clinical translation of receptor-targeted alpha-particle therapy is receiving considerable attention as an approach that can improve outcomes for cancer patients. Higher Linear-energy Transfer (LET) of alpha-particles (compared to beta particles) for this purpose results in an increased incidence of double-strand DNA breaks and improved-localized cancer-cell damage. Recent clinical studies provide compelling evidence that alpha-TRT has the potential to deliver a significantly more potent anti-cancer effect compared with beta-TRT. Generator-produced 212Pb (which decays to alpha emitters 212Bi and 212Po) is a particularly promising radionuclide for receptor-targeted alpha-particle therapy. A second attractive feature that distinguishes 212Pb alpha-TRT from other available radionuclides is the possibility to employ elementallymatched isotope 203Pb as an imaging surrogate in place of the therapeutic radionuclide. As direct non-invasive measurement of alpha-particle emissions cannot be conducted using current medical scanner technology, the imaging surrogate allows for a pharmacologically-inactive determination of the pharmacokinetics and biodistribution of TRT candidate ligands in advance of treatment. Thus, elementally-matched 203Pb labeled radiopharmaceuticals can be used to identify patients who may benefit from 212Pb alpha-TRT and apply appropriate dosimetry and treatment planning in advance of the therapy. In this review, we provide a brief history on the use of these isotopes for cancer therapy; describe the decay and chemical characteristics of 203/212Pb for their use in cancer theranostics and methodologies applied for production and purification of these isotopes for radiopharmaceutical production. In addition, a medical physics and dosimetry perspective is provided that highlights the potential of 212Pb for alpha-TRT and the expected safety for 203Pb surrogate imaging. Recent and current preclinical and clinical studies are presented. The sum of the findings herein and observations presented provide evidence that the 203Pb/212Pb theranostic pair has a promising future for use in radiopharmaceutical theranostic therapies for cancer.

²⁰³Pb and ²¹²Pb have emerged as promising theranostic isotopes for image-guided α-particle radionuclide therapy for cancers. Here, we report a cyclen-based Pb specific chelator (PSC) that is conjugated to tyr³-octreotide via a PEG₂ linker (PSC-PEG-T) targeting somatostatin receptor subtype 2 (SSTR2). PSC-PEG-T could be labeled efficiently to purified ²¹²Pb at 25 °C and also to ²¹²Bi at 80 °C. Efficient radiolabeling of mixed ²¹²Pb and ²¹²Bi in PSC-PEG-T was also observed at 80 °C. Post radiolabeling, stable Pb(II) and Bi(III) radiometal complexes in saline were observed after incubating [²⁰³Pb]Pb-PSC-PEG-T for 72 h and [²¹²Bi]Bi-PSC-PEG-T for 5 h. Stable [²¹²Pb]Pb-PSC-PEG-T and progeny [²¹²Bi]Bi-PSC-PEG-T were identified after storage in saline for 24 h. In serum, stable radiometal/radiopeptide were observed after incubating [²⁰³Pb]Pb-PSC-PEG-T for 55 h and [²¹²Pb]Pb-PSC-PEG-T for 24 h. In vivo biodistribution of [²¹²Pb]Pb-PSC-PEG-T in tumor-free CD-1 Elite mice and athymic mice bearing AR42J xenografts revealed rapid tumor accumulation, excellent tumor retention and fast renal clearance of both ²¹²Pb and ²¹²Bi, with no in vivo redistribution of progeny ²¹²Bi. Single-photon emission computed tomography (SPECT) imaging of [²⁰³Pb]Pb-PSC-PEG-T and [²¹²Pb]Pb-PSC-PEG-T in mice also demonstrated comparable accumulation in AR42J xenografts and renal clearance, confirming the theranostic potential of the elementally identical ²⁰³Pb/²¹²Pb radionuclide pair.

The rapid expansion of the industrial chemical space has outpaced regulatory oversight, creating a critical regulatory and environmental blind spot regarding unregulated high-consequence chemicals with limited hazard characterization. While conventional QSAR models focus on predictive accuracy for known chemicals, they often lack the decision-oriented screening required for environmental risk management. Here, we present a "proactive discovery" framework designed to unveil hidden high-consequence threats among 16,000+ structural analogs of toxic industrial chemicals (TICs). The central contribution of this work is the integration of multiple hazard endpoints, including acute, dermal, ocular, respiratory, flammability, reactivity, and aquatic toxicity, onto a single regulatory-aligned 0-4 scale, rather than the prediction of any individual endpoint. By integrating National Fire Protection Association (NFPA) and Globally Harmonized System (GHS) standards into a unified hazard scale, we enable consistent risk prioritization across multiple endpoints. Strictly validated against an independent external set of 112 compounds, the framework demonstrated a "safety-first" predictive capability. To address environmental safety blind spots, the model was optimized to prioritize sensitivity for the highest-hazard category (Class 4). This strategy minimizes false negatives, ensuring that potential ecotoxicological hazards and high-consequence threats are not overlooked in environmental risk assessments. Crucially, this study moves beyond method development to actionable discovery. Applied to more than 16,000 structural analogs of toxic industrial chemicals, this multi-endpoint prioritization identifies a small, actionable subset of unregulated compounds that are classified at the maximum hazard level in two or more endpoints simultaneously, and are therefore strong candidates for immediate regulatory attention. We identified 20 high-priority unregulated candidates, including novel isocyanates and organolead analogs, that exhibit "Dual-Threats" of extreme acute toxicity to mammals and severe risks to aquatic ecosystems. These candidates display hazard profiles that warrant comparison to highly regulated toxic agents (including chemical warfare agents) for precautionary prioritization. Furthermore, our feature importance analysis reveals key molecular determinants driving toxicity, providing mechanistic support for these high-hazard predictions. By openly providing a prioritized list of 20 unregulated high-consequence agents, this study offers an actionable roadmap for policymakers and experimentalists to preemptively secure the chemical safety landscape against emerging high-consequence chemicals.

Lead‐212 ( ²¹² Pb)‐based targeted alpha therapy is a promising approach for somatostatin receptor subtype 2 (SSTR2)‐positive neuroendocrine tumors (NETs), yet chelator selection can markedly influence radiochemical and biological behavior. An integrated computational and experimental approach is used to compare DOTA‐, PSC‐, and DOTAM‐conjugated Tyr ³ ‐octreotate (TATE). Density functional theory (DFT) reveals distinct differences in lead(II) (Pb ²⁺ ) and bismuth(III) (Bi ³⁺ ) complexes, including interaction energies, coordination geometry, electrostatic properties, conformational flexibility, and kinetic accessibility. Experimental evaluation with ²⁰³ Pb demonstrates >98% radiolabeling efficiency and >97% apparent radiochemical stability for all three conjugates, while cellular uptake, biodistribution, single‐photon emission computed tomography/computed tomography (SPECT/CT) imaging, and dosimetry reveal marked chelator‐dependent differences. DOTAM‐TATE exhibits high and sustained tumor uptake but greater normal‐organ retention, whereas PSC‐TATE combines substantial tumor uptake with lower renal and systemic retention, resulting in the most favorable tumor‐to‐kidney profile. Together, these findings show that Pb‐chelator performance reflects a balance among thermodynamic stabilization, coordination kinetics, conformational adaptability, and physicochemical properties, providing mechanistic guidance for the rational design of Pb‐based targeted radiopharmaceuticals.