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标题：Synthesis and pharmacokinetic characterisation of a fluorine-18 labelled brain shuttle peptide fusion dimeric affibody
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作者：Takahiro Morito ; Ryuichi Harada ; Ren Iwata 等
期刊名称：Scientific Reports
电子版ISSN：2045-2322
出版年度：2021
卷号：11
期号：1
页码：2588
DOI：10.1038/s41598-021-82037-2
出版社：Springer Nature
摘要：Abstract Brain positron emission tomography (PET) imaging with radiolabelled proteins is an emerging concept that potentially enables visualization of unique molecular targets in the brain. However, the pharmacokinetics and protein radiolabelling methods remain challenging. Here, we report the performance of an engineered, blood–brain barrier (BBB)-permeable affibody molecule that exhibits rapid clearance from the brain, which was radiolabelled using a unique fluorine-18 labelling method, a cell-free protein radiosynthesis (CFPRS) system. AS69, a small (14 kDa) dimeric affibody molecule that binds to the monomeric and oligomeric states of α-synuclein, was newly designed for brain delivery with an apolipoprotein E (ApoE)-derived brain shuttle peptide as AS69-ApoE (22 kDa). The radiolabelled products 18 F-AS69 and 18 F-AS69-ApoE were successfully synthesised using the CFPRS system. Notably, 18 F-AS69-ApoE showed higher BBB permeability than 18 F-AS69 in an ex vivo study at 10 and 30 min post injection and was partially cleared from the brain at 120 min post injection. These results suggest that small, a brain shuttle peptide-fused fluorine-18 labelled protein binders can potentially be utilised for brain molecular imaging.
其他摘要：Abstract Brain positron emission tomography (PET) imaging with radiolabelled proteins is an emerging concept that potentially enables visualization of unique molecular targets in the brain. However, the pharmacokinetics and protein radiolabelling methods remain challenging. Here, we report the performance of an engineered, blood–brain barrier (BBB)-permeable affibody molecule that exhibits rapid clearance from the brain, which was radiolabelled using a unique fluorine-18 labelling method, a cell-free protein radiosynthesis (CFPRS) system. AS69, a small (14 kDa) dimeric affibody molecule that binds to the monomeric and oligomeric states of α-synuclein, was newly designed for brain delivery with an apolipoprotein E (ApoE)-derived brain shuttle peptide as AS69-ApoE (22 kDa). The radiolabelled products 18 F-AS69 and 18 F-AS69-ApoE were successfully synthesised using the CFPRS system. Notably, 18 F-AS69-ApoE showed higher BBB permeability than 18 F-AS69 in an ex vivo study at 10 and 30 min post injection and was partially cleared from the brain at 120 min post injection. These results suggest that small, a brain shuttle peptide-fused fluorine-18 labelled protein binders can potentially be utilised for brain molecular imaging.