Pretargeted PET imaging offers a powerful approach to improve nuclear imaging contrast and reduce systemic radiation exposure, yet its application in the brain has been limited by the blood-brain barrier (BBB). Here, we demonstrate, for the first time, successful pretargeted PET imaging of a brain target enabled by a bispecific antibody engineered for transferrin receptor-mediated BBB transcytosis. By combining this brain shuttle with a novel 18F-labeled tetrazine, we achieve specific, quantifiable detection of brain-localized A beta aggregates, validated through PET imaging and histological analysis. This proof-of-concept establishes a versatile, noninvasive imaging platform with broad potential for assessing biologic drug candidates and CNS targets previously considered intractable.
Pretargeted Immuno-PET Enables Monoclonal Antibody Imaging Beyond the Blood–Brain Barrier / Gustavsson, T.; Kustermann, T.; Hvass, L.; Wuensche, T. E.; Clausen, A. S.; Stotz, S.; Shalgunov, V.; Lopes Van Den Broek, S.; Knudsen, G. M.; Aldana, B.; Ferri, E.; Cannazza, G.; Niewoehner, J.; Gobbi, L.; Honer, M.; Battisti, U. M.; Kjaer, A.; Herth, M. M.. - In: MOLECULAR PHARMACEUTICS. - ISSN 1543-8384. - 22:12(2025), pp. 7600-7610. [10.1021/acs.molpharmaceut.5c01180]
Pretargeted Immuno-PET Enables Monoclonal Antibody Imaging Beyond the Blood–Brain Barrier
Ferri E.;Cannazza G.;
2025
Abstract
Pretargeted PET imaging offers a powerful approach to improve nuclear imaging contrast and reduce systemic radiation exposure, yet its application in the brain has been limited by the blood-brain barrier (BBB). Here, we demonstrate, for the first time, successful pretargeted PET imaging of a brain target enabled by a bispecific antibody engineered for transferrin receptor-mediated BBB transcytosis. By combining this brain shuttle with a novel 18F-labeled tetrazine, we achieve specific, quantifiable detection of brain-localized A beta aggregates, validated through PET imaging and histological analysis. This proof-of-concept establishes a versatile, noninvasive imaging platform with broad potential for assessing biologic drug candidates and CNS targets previously considered intractable.
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