[²¹¹At]MABG (astatine-211 meta-astatobenzylguanidine) is an investigational alpha-particle radiopharmaceutical that substitutes astatine-211 for iodine-131 in the MIBG scaffold, preserving NET (SLC6A2)-mediated tumor-selective uptake while delivering high-LET alpha radiation instead of low-LET beta particles. Alpha-particle radiobiology and BRCAness synergy: Alpha particles (LET ~80 keV/μm) deposit energy ~400-fold more densely per unit path length than ¹³¹I beta particles (LET ~0.2 keV/μm). This high-LET radiation creates complex clustered DNA lesions — typically 2–3 DSBs and multiple base oxidations within a 10–20 base-pair window — that cannot be accurately resolved by the fast, error-prone NHEJ pathway and specifically require homologous recombination (HR) for faithful repair. In SDH-deficient PPGL, the BRCAness phenotype (Sulkowski et al. Nat Genet 2018, PMID 30013182; Nature 2020, PMID 32494005) — succinate-driven KDM4A/KDM4B inhibition → H3K9me3 persistence at DSBs → impaired TIP60/ATM → HR deficiency — means that [²¹¹At]MABG-induced complex clustered DSBs are especially cytotoxic in SDH-deficient tumor cells, because their HR impairment prevents accurate repair of these complex lesions. SDH-intact NET-expressing normal chromaffin cells, with functional HR, can resolve the same complex DSBs far more efficiently — providing a BRCAness-derived therapeutic window beyond NET-mediated selectivity alone. Physical advantages over ¹³¹I-MIBG: - Path length: At-211 alpha particles (50–80 μm ≈ single-cell diameter) vs. I-131 beta particles (~2mm) → confines radiation dose within or immediately adjacent to the tumor cell, reducing bystander irradiation of non-NET-expressing normal tissues - Half-life: At-211 (7.2h) vs. I-131 (8d) → shorter radiation isolation requirement; logistics advantage for outpatient administration - Relative biological effectiveness (RBE): alpha particles ~3–7× more lethal per unit Gy than beta particles; higher tumor-cell kill per disintegration - Decay: At-211 decays by alpha emission (42%) to ²⁰⁷Bi (stable) and by electron capture (58%) to ²¹¹Po which promptly alpha-decays to ²⁰⁷Pb (stable); 100% of At-211 atoms ultimately yield exactly one alpha particle Phase 1 clinical data: Okamoto et al. (Clin Cancer Res 2026, PMID 42490294) reported the first-in-human Phase 1 study of [²¹¹At]MABG in 10 patients with refractory MIBG-avid pheochromocytoma or paraganglioma. Single dose 2.1 MBq/kg was administered without dose-limiting toxicities; hematologic toxicity was acceptable (grade 1–2 thrombocytopenia and neutropenia). 1 confirmed partial response and 7 stable disease were observed. The study established clinical feasibility and a preliminary tolerability profile for alpha-particle MIBG therapy in this patient population. Panobinostat combination: As with Azedra, Martiniova et al. (Endocr Relat Cancer 2011, PMID 21098082) demonstrated panobinostat-mediated NET/SLC6A2 upregulation and increased MIBG uptake in PPGL cells — the same combination rationale applies to amplify [²¹¹At]MABG intracellular delivery. Key limitation: Phase 1 enrolled MIBG-avid PCC/PGL without SDH genotype stratification; the BRCAness × high-LET synergy hypothesis has not been tested in SDH-deficient preclinical models or in an SDH-stratified patient cohort. No randomized efficacy data. Evidence_score 26 (preclinical): mechanistic chain is well-supported (BRCAness established by Sulkowski; alpha-particle complex DSB biology is established radiobiology; NET-mediated selectivity is the mechanism behind FDA-approved Azedra), combined with first-in-human safety and early activity data (PMID 42490294), without SDH-stratified efficacy signals.