To summarize the current advances, molecular engineering principles, and translational progress of antibody-based positron emission tomography (PET) tracers specifically optimized for neuroimaging, with a focus on overcoming blood–brain barrier (BBB) limitations and enabling precision diagnostics in neurodegenerative diseases.

Traditional PET tracers for neurodegenerative disorders that target glucose metabolism, amyloid-β, or tau often lack specificity or sensitivity in early disease stages. Immuno-PET, which employs radiolabeled antibodies or engineered fragments, allows direct in vivo quantification of disease-relevant proteins, drug biodistribution, and target engagement. However, full-length monoclonal antibodies (~150 kDa) exhibit limited BBB penetration and slow kinetics, necessitating molecular engineering to produce smaller, faster-clearing constructs suitable for neuroimaging.

A structured literature search was performed in PubMed, Embase, and Web of Science (up to september 2025) using the terms (“immuno-PET” OR “antibody PET”) AND (“brain” OR “neuroimaging”) AND (“engineered” OR “nanobody” OR “bispecific”). Studies were eligible if they evaluated engineered PET antibodies or fragments targeting CNS pathologies. Extracted data included construct type, molecular weight, isotope compatibility, BBB strategies, pharmacokinetics, and preclinical or clinical findings.

Engineered constructs such as Fab/scFv fragments, minibodies, nanobodies, and bispecific antibodies, demonstrate improved BBB permeability, faster clearance, and favorable pairing with isotopes (^18F, ^64Cu, ^68Ga). Nanobody tracers have shown selective binding to amyloid-β, tau, α-synuclein, and TDP-43 in preclinical models, while bispecific designs enhance active BBB transcytosis. Early human studies with radiolabeled therapeutic antibodies and nanobody tracers confirm feasibility, safety, and measurable CNS signal, though absolute brain uptake remains low.