Toward Novel [F-18]Fluorine-Labeled Radiotracers for the Imaging of alpha-Synuclein Fibrils

Uzuegbunam, Bright C.; Li, Junhao; Paslawski, Wojciech; Weber, Wolfgang; Svenningsson, Per; Agren, Hans und Yousefi, Behrooz Hooshyar (2022): Toward Novel [F-18]Fluorine-Labeled Radiotracers for the Imaging of alpha-Synuclein Fibrils. In: Frontiers in Aging Neuroscience, Bd. 14, 830704

Abstract

The accumulation of alpha-synuclein aggregates (alpha-syn) in the human brain is an occurrence common to all alpha-synucleinopathies. Non-invasive detection of these aggregates in a living brain with a target-specific radiotracer is not yet possible. We have recently discovered that the inclusion of a methylenedioxy group in the structure of diarylbisthiazole (DABTA)-based tracers improves binding affinity and selectivity to alpha-syn. Subsequently, complementary in silico modeling and machine learning (ML) of tracer-protein interactions were employed to predict surface sites and structure-property relations for the binding of the ligands. Based on this observation, we developed a small focused library of DABTAs from which 4-(benzo[d][1,3]dioxol-5-yl)-4 & PRIME;-(3-[F-18]fluoro-4-methoxyphenyl)-2,2 & PRIME;-bithiazole [F-18]d(2), 6-(4 & PRIME;-(3-[F-18]fluoro-4-methoxyphenyl)-[2,2 & PRIME;-bithiazol]-4-yl)-[1,3]dioxolo[4,5-b]pyridine [F-18]d(4), 4-(benzo [d][1,3]dioxol-5-yl)-4 & PRIME;-(6-[F-18]fluoropyridin-3-yl)-2,2 & PRIME;-bithiazole [F-18]d(6), and 6-(4 & PRIME;-(6-[F-18]fluoropyridin-3-yl)-[2,2 & PRIME;-bithiazol]-4-yl)-[1,3]dioxolo[4,5-b]pyridine [F-18]d(8) were selected based on their high binding affinity to alpha-syn and were further evaluated. Binding assay experiments carried out with the non-radioactive versions of the above tracers d(2), d(4), d(6), and d(8) showed high binding affinity of the ligands to alpha-syn: 1.22, 0.66, 1.21, and 0.10 nM, respectively, as well as excellent selectivity over beta-amyloid plaques (A beta) and microtubular tau aggregates (> 200-fold selectivity). To obtain the tracers, their precursors were radiolabeled either via an innovative ruthenium-mediated (SNAr) reaction ([F-18]d(2) and [F-18]d(4)) or typical SNAr reaction ([F-18]d(6) and [F-18]d(8)) with moderate-to-high radiochemical yields (13% - 40%), and high molar activity > 60 GBq/mu mol. Biodistribution experiments carried out with the tracers in healthy mice revealed that [F-18]d(2) and [F-18]d(4) showed suboptimal brain pharmacokinetics: 1.58 and 4.63 %ID/g at 5 min post-injection (p.i.), and 1.93 and 3.86 %ID/g at 60 min p.i., respectively. However, [F-18]d(6) and [F-18]d(8) showed improved brain pharmacokinetics: 5.79 and 5.13 %ID/g at 5 min p.i.;1.75 and 1.07 %ID/g at 60 min p.i.;and 1.04 and 0.58 %ID/g at 120 min p.i., respectively. The brain uptake kinetics of [F-18]d(6) and [F-18]d(8) were confirmed in a dynamic PET study. Both tracers also showed no brain radiometabolites at 20 min p.i. in initial in vivo stability experiments carried out in healthy mice. [F-18]d(8) seems very promising based on its binding properties and in vivo stability, thus encouraging further validation of its usefulness as a radiotracer for the in vivo visualization of alpha-syn in preclinical and clinical settings. Additionally, in silico and ML-predicted values correlated with the experimental binding affinity of the ligands.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• ISSN: 1663-4365
• Sprache: Englisch