In vitro evaluation of [3H]PI-2620 and structural derivatives in non-Alzheimer's tauopathies

Cassis Varlow; Chester A Mathis; Neil Vasdev

doi:10.1016/j.nucmedbio.2024.108891

In vitro evaluation of [³H]PI-2620 and structural derivatives in non-Alzheimer's tauopathies

Nucl Med Biol. 2024 Mar-Apr:130-131:108891. doi: 10.1016/j.nucmedbio.2024.108891. Epub 2024 Feb 19.

Authors

Cassis Varlow¹, Chester A Mathis², Neil Vasdev³

Affiliations

¹ Institute of Medical Science, University of Toronto, ON M5S 1A8, Canada; Brain Health Imaging Centre, Centre for Addiction and Mental Health, Toronto, ON M5T 1R8, Canada. Electronic address: Cassis.varlow@mail.utoronto.ca.
² Department of Radiology, University of Pittsburgh, PA 15213, USA.
³ Institute of Medical Science, University of Toronto, ON M5S 1A8, Canada; Brain Health Imaging Centre, Centre for Addiction and Mental Health, Toronto, ON M5T 1R8, Canada. Electronic address: neil.vasdev@utoronto.ca.

PMID: 38458074
DOI: 10.1016/j.nucmedbio.2024.108891

Abstract

Alzheimer's disease (AD) and non-AD tauopathies such as chronic traumatic encephalopathy (CTE), progressive supranuclear palsy (PSP), and corticobasal degeneration (CBD) are characterized by the abnormal aggregation of three-repeat (3R) and/or four-repeat (4R) tau isoforms. Several tau-PET tracers have been applied for human imaging of AD and non-AD tauopathies including [¹⁸F]PI-2620. Our objective is to evaluate [³H]PI-2620 and two promising structural derivatives, [³H]PI-2014 and [³H]F-4, using in vitro saturation assays and competitive binding assays against new chemical entities based on this scaffold in human AD tissues for comparison with PSP, CBD and CTE tissues. Thin section autoradiography was employed to assess specific binding and distribution of [³H]PI-2620 and [³H]F-4 in fresh-frozen human post-mortem AD, PSP, CBD and CTE tissues. Immunohistochemistry was performed for phospho-tau (AT8) and 4R-tau (RD4). Homogenate filtration binding assays were performed for saturation analysis and competitive binding studies against [³H]PI-2620. All compounds bound with high affinity in AD tissue. In PSP tissue [³H]PI-2620 demonstrated the highest affinity (5.3 nM) and in CBD tissue [³H]F-4 bound with the highest affinity (9.4 nM). Over 40 fluorinated derivatives based on PI-2620 and F-4 were screened in AD and PSP tissue. Notably, compound 2 was the most potent derivative in PSP tissue (K_i = 7.3 nM). By autoradiography, [³H]PI-2620 and [³H]F-4 demonstrated positive signals similar in intensity in AD, PSP and CTE tissues that were displaced by homologous blockade. Binding of both radiotracers aligned with immunostaining for 4R-tau. This work demonstrates that [³H]PI-2620 and [³H]F-4 show promise for imaging 4R-tau aggregates in non-AD tauopathies. PI-2620 continues to serve as a structural scaffold for PET radiotracers with higher affinity for non-AD tau over AD tau.

Keywords: 4-Repeat tau; Autoradiography; Neurodegeneration; PET; PI-2620; Pharmacology; Tau.

MeSH terms

Alzheimer Disease* / diagnostic imaging
Alzheimer Disease* / metabolism
Brain / metabolism
Humans
Nitroimidazoles*
Pyridines*
Tauopathies* / diagnostic imaging
Tauopathies* / metabolism
tau Proteins / metabolism

Substances

PI-2620
tau Proteins
F 4
Nitroimidazoles
Pyridines