Pretargeted Immuno-PET Enables Monoclonal Antibody Imaging Beyond the Blood-Brain Barrier

Tobias Gustavsson; Thomas Kustermann; Lars Hvass; Thomas E Wuensche; Anne Skovsbo Clausen; Sophie Stotz; Vladimir Shalgunov; Sara Lopes van den Broek; Gitte M Knudsen; Blanca Aldana; Elena Ferri; Giuseppe Cannazza; Jens Niewoehner; Luca Gobbi; Michael Honer; Umberto Maria Battisti; Andreas Kjaer; Matthias M Herth

doi:10.1021/acs.molpharmaceut.5c01180

Pretargeted Immuno-PET Enables Monoclonal Antibody Imaging Beyond the Blood-Brain Barrier

Tobias Gustavsson, Thomas Kustermann, Lars Hvass, Thomas E Wuensche, Anne Skovsbo Clausen, Sophie Stotz, Vladimir Shalgunov, Sara Lopes van den Broek, Gitte M Knudsen, Blanca Aldana, Elena Ferri, Giuseppe Cannazza, Jens Niewoehner, Luca Gobbi, Michael Honer, Umberto Maria Battisti, Andreas Kjaer^*, Matthias M Herth

^*Corresponding author for this work

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 Aβ 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.

Original language	English
Journal	Molecular Pharmaceutics
Volume	22
Issue number	12
Pages (from-to)	7600-7610
Number of pages	11
ISSN	1543-8384
DOIs	https://doi.org/10.1021/acs.molpharmaceut.5c01180
Publication status	Published - 1 Dec 2025

Keywords

Imaging CNS
blood−brain barrier
pretargeting
tetrazine ligation
transferrin receptor

Access to Document

10.1021/acs.molpharmaceut.5c01180Licence: CC BY-NC-ND

Cite this

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. (2025). Pretargeted Immuno-PET Enables Monoclonal Antibody Imaging Beyond the Blood-Brain Barrier. Molecular Pharmaceutics, 22(12), 7600-7610. https://doi.org/10.1021/acs.molpharmaceut.5c01180

Gustavsson, T, Kustermann, T, Hvass, L, Wuensche, TE, Clausen, AS, Stotz, S, Shalgunov, V, Lopes van den Broek, S, Knudsen, GM, Aldana, B, Ferri, E, Cannazza, G, Niewoehner, J, Gobbi, L, Honer, M, Battisti, UM, Kjaer, A & Herth, MM 2025, 'Pretargeted Immuno-PET Enables Monoclonal Antibody Imaging Beyond the Blood-Brain Barrier', Molecular Pharmaceutics, vol. 22, no. 12, pp. 7600-7610. https://doi.org/10.1021/acs.molpharmaceut.5c01180

@article{5c3204db720947dfbab120c326c42bbe,

title = "Pretargeted Immuno-PET Enables Monoclonal Antibody Imaging Beyond the Blood-Brain Barrier",

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 Aβ 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.",

keywords = "Imaging CNS, blood−brain barrier, pretargeting, tetrazine ligation, transferrin receptor",

author = "Tobias Gustavsson and Thomas Kustermann and Lars Hvass and Wuensche, \{Thomas E\} and Clausen, \{Anne Skovsbo\} and Sophie Stotz and Vladimir Shalgunov and \{Lopes van den Broek\}, Sara and Knudsen, \{Gitte M\} and Blanca Aldana and Elena Ferri and Giuseppe Cannazza and Jens Niewoehner and Luca Gobbi and Michael Honer and Battisti, \{Umberto Maria\} and Andreas Kjaer and Herth, \{Matthias M\}",

year = "2025",

month = dec,

day = "1",

doi = "10.1021/acs.molpharmaceut.5c01180",

language = "English",

volume = "22",

pages = "7600--7610",

journal = "Molecular Pharmaceutics",

issn = "1543-8384",

publisher = "American Chemical Society",

number = "12",

}

TY - JOUR

T1 - Pretargeted Immuno-PET Enables Monoclonal Antibody Imaging Beyond the Blood-Brain Barrier

AU - Gustavsson, Tobias

AU - Kustermann, Thomas

AU - Hvass, Lars

AU - Wuensche, Thomas E

AU - Clausen, Anne Skovsbo

AU - Stotz, Sophie

AU - Shalgunov, Vladimir

AU - Lopes van den Broek, Sara

AU - Knudsen, Gitte M

AU - Aldana, Blanca

AU - Ferri, Elena

AU - Cannazza, Giuseppe

AU - Niewoehner, Jens

AU - Gobbi, Luca

AU - Honer, Michael

AU - Battisti, Umberto Maria

AU - Kjaer, Andreas

AU - Herth, Matthias M

PY - 2025/12/1

Y1 - 2025/12/1

N2 - 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 Aβ 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.

AB - 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 Aβ 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.

KW - Imaging CNS

KW - blood−brain barrier

KW - pretargeting

KW - tetrazine ligation

KW - transferrin receptor

UR - https://www.scopus.com/pages/publications/105023418795

U2 - 10.1021/acs.molpharmaceut.5c01180

DO - 10.1021/acs.molpharmaceut.5c01180

M3 - Journal article

C2 - 41198055

SN - 1543-8384

VL - 22

SP - 7600

EP - 7610

JO - Molecular Pharmaceutics

JF - Molecular Pharmaceutics

IS - 12

ER -

Pretargeted Immuno-PET Enables Monoclonal Antibody Imaging Beyond the Blood-Brain Barrier

Abstract

Keywords

Access to Document

Other files and links

Fingerprint

Cite this