TY - JOUR

T1 - A Fluorescent Probe as a Lead Compound for a Selective α-Synuclein PET Tracer

T2 - Development of a Library of 2-Styrylbenzothiazoles and Biological Evaluation of [18F]PFSB and [18F]MFSB

AU - Di Nanni, Adriana

AU - Saw, Ran Sing

AU - Battisti, Umberto M.

AU - Bowden, Gregory D.

AU - Boeckermann, Adam

AU - Bjerregaard-Andersen, Kaare

AU - Pichler, Bernd J.

AU - Herfert, Kristina

AU - Herth, Matthias M.

AU - Maurer, Andreas

N1 - Funding Information: This project has received funding from the European Union’s Horizon 2020 research and innovation program under the Marie Skłodowska-Curie grant agreement no. 813528. The authors acknowledge support from the Open Access Publishing Fund of the University of Tübingen. Human brain samples were supplied by the Neurobiobank München, which was supported with funding provided by the German Federal Ministry of Education and Research. They thank Dr. Viktoria Ruf and colleagues for preparing the samples and the corresponding scientific documentation. Publisher Copyright: © 2023 The Authors. Published by American Chemical Society.

PY - 2023

Y1 - 2023

N2 - A method to detect and quantify aggregated α-synuclein (αSYN) fibrils in vivo would drastically impact the current understanding of multiple neurodegenerative diseases, revolutionizing their diagnosis and treatment. Several efforts have produced promising scaffolds, but a notable challenge has hampered the establishment of a clinically successful αSYN positron emission tomography (PET) tracer: the requirement of high selectivity over the other misfolded proteins amyloid β (Aβ) and tau. By designing and screening a library of 2-styrylbenzothiazoles based on the selective fluorescent probe RB1, this study aimed at developing a selective αSYN PET tracer. [3H]PiB competition binding assays identified PFSB (Ki = 25.4 ± 2.3 nM) and its less lipophilic analogue MFSB, which exhibited enhanced affinity to αSYN (Ki = 10.3 ± 4.7 nM) and preserved selectivity over Aβ. The two lead compounds were labeled with fluorine-18 and evaluated using in vitro autoradiography on human brain slices, where they demonstrated up to 4-fold increased specific binding in MSA cases compared to the corresponding control, reasonably reflecting selective binding to αSYN pathology. In vivo PET imaging showed [18F]MFSB successfully crosses the blood-brain barrier (BBB) and is taken up in the brain (SUV = 1.79 ± 0.02). Although its pharmacokinetic profile raises the need for additional structural optimization, [18F]MFSB represents a critical step forward in the development of a successful αSYN PET tracer by overcoming the major challenge of αSYN/Aβ selectivity.

AB - A method to detect and quantify aggregated α-synuclein (αSYN) fibrils in vivo would drastically impact the current understanding of multiple neurodegenerative diseases, revolutionizing their diagnosis and treatment. Several efforts have produced promising scaffolds, but a notable challenge has hampered the establishment of a clinically successful αSYN positron emission tomography (PET) tracer: the requirement of high selectivity over the other misfolded proteins amyloid β (Aβ) and tau. By designing and screening a library of 2-styrylbenzothiazoles based on the selective fluorescent probe RB1, this study aimed at developing a selective αSYN PET tracer. [3H]PiB competition binding assays identified PFSB (Ki = 25.4 ± 2.3 nM) and its less lipophilic analogue MFSB, which exhibited enhanced affinity to αSYN (Ki = 10.3 ± 4.7 nM) and preserved selectivity over Aβ. The two lead compounds were labeled with fluorine-18 and evaluated using in vitro autoradiography on human brain slices, where they demonstrated up to 4-fold increased specific binding in MSA cases compared to the corresponding control, reasonably reflecting selective binding to αSYN pathology. In vivo PET imaging showed [18F]MFSB successfully crosses the blood-brain barrier (BBB) and is taken up in the brain (SUV = 1.79 ± 0.02). Although its pharmacokinetic profile raises the need for additional structural optimization, [18F]MFSB represents a critical step forward in the development of a successful αSYN PET tracer by overcoming the major challenge of αSYN/Aβ selectivity.

U2 - 10.1021/acsomega.3c04292

DO - 10.1021/acsomega.3c04292

M3 - Journal article

C2 - 37663501

AN - SCOPUS:85168991767

VL - 8

SP - 31450

EP - 31467

JO - ACS Omega

JF - ACS Omega

SN - 2470-1343

IS - 34

ER -