Dataset Information

Structure-Activity Relationships of Styrylquinoline and Styrylquinoxaline Derivatives as α-Synuclein Imaging Probes.

ABSTRACT: Synucleinopathies are characterized by the deposition of α-synuclein (α-syn) aggregates before the onset of clinical symptoms. Therefore, in vivo imaging of α-syn may contribute to early diagnosis of these diseases and has attracted much attention in recent years. However, no clinically useful probes have been reported. In the present study, 16 quinoline/quinoxaline derivatives with different styryl and fluorine groups were evaluated in order to develop α-syn imaging probes. Among them, SQ3, which is a quinoline analogue with a p-(dimethylamino)styryl group and fluoroethoxy group at the 2- and 7- positions of the skeleton, displayed moderate selectivity for α-syn aggregates over β-amyloid (Aβ) aggregates (K _i = 230 nM), while maintaining high binding affinity for α-syn aggregates (K _i = 39.3 nM). In a biodistribution study, [¹⁸F]SQ3 exhibited high uptake (2.08% ID/g at 2 min after intravenous injection) into a normal mouse brain. Taken together, we demonstrate that [¹⁸F]SQ3 has basic properties as a lead compound for the development of a useful α-syn imaging probe.

SUBMITTER: Nakagawa K

PROVIDER: S-EPMC9575165 | biostudies-literature | 2022 Oct

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Structure-Activity Relationships of Styrylquinoline and Styrylquinoxaline Derivatives as α-Synuclein Imaging Probes.

Nakagawa Kohei K Watanabe Hiroyuki H Kaide Sho S Ono Masahiro M

ACS medicinal chemistry letters 20220926 10

Synucleinopathies are characterized by the deposition of α-synuclein (α-syn) aggregates before the onset of clinical symptoms. Therefore, <i>in vivo</i> imaging of α-syn may contribute to early diagnosis of these diseases and has attracted much attention in recent years. However, no clinically useful probes have been reported. In the present study, 16 quinoline/quinoxaline derivatives with different styryl and fluorine groups were evaluated in order to develop α-syn imaging probes. Among them, S ...[more]

PMID: 36262393

Similar Datasets

Project description:A library of 10 Mn-containing complexes capable of switching reversibly between the Mn(II) and Mn(III) oxidation states was prepared and evaluated for potential usage as MRI reporters of tissue redox activity. We synthesized N-(2-hydroxybenzyl)-N,N',N'-ethylenediaminetriacetic acid (HBET) and N-(2-hydroxybenzyl-N,N',N'-trans-1,2-cyclohexylenediaminetriacetic acid (CyHBET) ligands functionalized (-H, -OMe, -NO2) at the 5-position of the aromatic ring. The Mn(II) complexes of all ligands and the Mn(III) complexes of the 5-H and 5-NO2 functionalized ligands were synthesized and isolated, but the Mn(III) complexes with the 5-OMe functionalized ligands were unstable. (1)H relaxivity of the 10 isolable complexes was measured at pH 7.4 and 37 °C, 1.4 T. Thermodynamic stability, pH-dependent complex speciation, hydration state, water exchange kinetics of the Mn(II) complexes, and pseudo-first order reduction kinetics of the Mn(III) complexes were studied using a combination of pH-potentiometry, UV-vis spectroscopy, and (1)H and (17)O NMR measurements. The effects of ligand structural and electronic modifications on the Mn(II/III) redox couple were studied by cyclic voltammetry. The Mn(II) complexes are potent relaxation agents as compared to the corresponding Mn(III) species with [Mn(II)(CyHBET)(H2O)](2-) exhibiting a 7.5-fold higher relaxivity (3.3 mM(-1) s(-1)) than the oxidized form (0.4 mM(-1) s(-1)). At pH 7.4, Mn(II) exists as a mixture of fully deprotonated (ML) and monoprotonated (HML) complexes and Mn(II) complex stability decreases as the ligands become more electron-releasing (pMn for 10 μM [Mn(II)(CyHBET-R')(H2O)](2-) decreases from 7.6 to 6.2 as R' goes from -NO2 to -OMe, respectively). HML speciation increases as the electron-releasing nature of the phenolato-O donor increases. The presence of a water coligand is maintained upon conversion from HML to ML, but the water exchange rate of ML is faster by up to 2 orders of magnitude (k(ex)(310) for H[Mn(II)(CyHBET)(H2O)](-) and [Mn(II)(CyHBET)(H2O)](2-) are 1.2 × 10(8) and 1.0 × 10(10) s(-1), respectively). The Mn(II/III) redox potential can be tuned over a range of 0.30 V (E(1/2) = 0.27-0.57 V) through electronic modifications to the 5-substituent of the aromatic ligand component. However, care must be taken in tuning the ligand electronics to avoid Mn(III)-ligand autoredox. Taken together, these results serve to establish criteria for optimizing Mn(III) versus Mn(II) relaxivity differentials, complex stability, and Mn(II/III) redox potential.

Dataset Information

Structure-Activity Relationships of Styrylquinoline and Styrylquinoxaline Derivatives as α-Synuclein Imaging Probes.

Publications

Structure-Activity Relationships of Styrylquinoline and Styrylquinoxaline Derivatives as α-Synuclein Imaging Probes.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets