Pretargeted imaging beyond the blood–brain barrier: From concept to reality

Pretargeted positron emission tomography (PET) is emerging as a transformative approach for imaging biologics in the brain, overcoming the limitations of direct radiolabeling. Conventional methods with long-lived radionuclides suffer from high radiation exposure, off-target accumulation, and suboptimal imaging properties. Pretargeting separates the targeting from the imaging step, enabling the use of short-lived radionuclides such as fluorine-18, the clinical gold standard, and thereby allowing high-contrast, low-dose imaging. Realizing this strategy in the brain remains challenging due to the restrictive blood-brain barrier, pharmacokinetic constraints, and the requirement for efficient in vivo click chemistry. Recent progress spanning in silico design, in vitro validation, and in vivo studies has now demonstrated successful pretargeting with BBB-shuttled antibodies and antisense oligonucleotides in rodents, non-human primates, and Alzheimer's disease models. Together, these studies demonstrate that what was once considered utopian has now become reality.