TY - JOUR

T1 - The Structural Combination of SIL and MODAG Scaffolds Fails to Enhance Binding to α-Synuclein but Reveals Promising Affinity to Amyloid β

AU - Di Nanni, Adriana

AU - Saw, Ran Sing

AU - Bowden, Gregory D.

AU - Bidesi, Natasha S.R.

AU - Bjerregaard-Andersen, Kaare

AU - Korat, Špela

AU - Herth, Matthias M.

AU - Pichler, Bernd J.

AU - Herfert, Kristina

AU - Maurer, Andreas

N1 - Funding Information: We thank Albert D. Windhorst and Daniëlle Vugts for their guidance and support in the radiolabeling of [H]SIL26. This project was funded by the European Union’s Horizon 2020 research and innovation program under the Marie Skłodowska-Curie grant agreement No. 813528. 3 Publisher Copyright: © 2023 by the authors.

PY - 2023

Y1 - 2023

N2 - A technique to image α-synuclein (αSYN) fibrils in vivo is an unmet scientific and clinical need that would represent a transformative tool in the understanding, diagnosis, and treatment of various neurodegenerative diseases. Several classes of compounds have shown promising results as potential PET tracers, but no candidate has yet exhibited the affinity and selectivity required to reach clinical application. We hypothesized that the application of the rational drug design technique of molecular hybridization to two promising lead scaffolds could enhance the binding to αSYN up to the fulfillment of those requirements. By combining the structures of SIL and MODAG tracers, we developed a library of diarylpyrazoles (DAPs). In vitro evaluation through competition assays against [3H]SIL26 and [3H]MODAG−001 showed the novel hybrid scaffold to have preferential binding affinity for amyloid β (Aβ) over αSYN fibrils. A ring-opening modification on the phenothiazine building block to produce analogs with increased three-dimensional flexibility did not result in an improved αSYN binding but a complete loss of competition, as well as a significant reduction in Aβ affinity. The combination of the phenothiazine and the 3,5-diphenylpyrazole scaffolds into DAP hybrids did not generate an enhanced αSYN PET tracer lead compound. Instead, these efforts identified a scaffold for promising Aβ ligands that may be relevant to the treatment and monitoring of Alzheimer’s disease (AD).

AB - A technique to image α-synuclein (αSYN) fibrils in vivo is an unmet scientific and clinical need that would represent a transformative tool in the understanding, diagnosis, and treatment of various neurodegenerative diseases. Several classes of compounds have shown promising results as potential PET tracers, but no candidate has yet exhibited the affinity and selectivity required to reach clinical application. We hypothesized that the application of the rational drug design technique of molecular hybridization to two promising lead scaffolds could enhance the binding to αSYN up to the fulfillment of those requirements. By combining the structures of SIL and MODAG tracers, we developed a library of diarylpyrazoles (DAPs). In vitro evaluation through competition assays against [3H]SIL26 and [3H]MODAG−001 showed the novel hybrid scaffold to have preferential binding affinity for amyloid β (Aβ) over αSYN fibrils. A ring-opening modification on the phenothiazine building block to produce analogs with increased three-dimensional flexibility did not result in an improved αSYN binding but a complete loss of competition, as well as a significant reduction in Aβ affinity. The combination of the phenothiazine and the 3,5-diphenylpyrazole scaffolds into DAP hybrids did not generate an enhanced αSYN PET tracer lead compound. Instead, these efforts identified a scaffold for promising Aβ ligands that may be relevant to the treatment and monitoring of Alzheimer’s disease (AD).

KW - 3,5-diphenylpyrazole

KW - DLB

KW - MSA

KW - PD

KW - PET tracer

KW - phenothiazine

KW - positron emission tomography

KW - α-synuclein

U2 - 10.3390/molecules28104001

DO - 10.3390/molecules28104001

M3 - Journal article

C2 - 37241742

AN - SCOPUS:85160373000

VL - 28

JO - Molecules

JF - Molecules

SN - 1420-3049

IS - 10

M1 - 4001

ER -