The Critical Dosing Interval in Oncology Pretargeted Radionuclide Imaging and Therapy: Mechanisms, Optimization, and Dosimetric Impact

Pretargeting decouples biologic recognition from radionuclide delivery by administering a primary carrier (P)─such as an antibody, engineered scaffold, nanoparticle, or cell product─bearing capture handles, followed after a delay by a fast-clearing secondary agent (S) retained at target sites through a defined recognition pair (e.g., IEDDA, SPAAC, hybridization, or bsAb-hapten binding). This split-dose architecture suppresses blood-pool background, shortens time-to-readout, and can reduce normal-tissue absorbed dose relative to directly labeled biologics. Across platforms, the P-S dosing interval is the key coordinating variable: it must align (i) high tumor surface-accessible capture-site availability with (ii) sufficiently low circulating P to avoid off-target capture, while matching (iii) S clearance and (iv) radionuclide half-life and workflow constraints. If mistimed, S is consumed in blood and organs, inflating marrow or renal exposure and lowering tumor yield; if optimized, the interval converts biochemical specificity into measurable contrast and therapeutic index. This review focuses on oncology-oriented applications, which currently provide the strongest evidence base for interval optimization in pretargeted radionuclide imaging and therapy. We propose an interval-first design framework: map P blood and tumor kinetics, quantify time-dependent accessible-site dynamics, and perform interval-aware simulations of image quality and dosimetry. We also highlight when clearing or masking agents can expand the actionable window, enabling same-day PET with short-lived nuclides, and propose a minimum reporting checklist to improve reproducibility and cross-study comparison.