Head-to-Head Comparison of Tau-PET Radioligands for Imaging TDP-43 in Post-Mortem ALS Brain

• Published in: Molecular imaging and biology Vol. 25; no. 3; pp. 513 - 527
• Main Authors: Knight, Ashley C., Morrone, Christopher D., Varlow, Cassis, Yu, Wai Haung, McQuade, Paul, Vasdev, Neil
• Format: Journal Article
• Language: English
• Published: Cham Springer International Publishing 01.06.2023; Springer Nature B.V
• Subjects: Aggregates; Alzheimer's disease; Amyotrophic lateral sclerosis; Amyotrophic Lateral Sclerosis - diagnostic imaging; Amyotrophic Lateral Sclerosis - genetics; Amyotrophic Lateral Sclerosis - metabolism; Autoradiography; Brain; Brain - metabolism; Cerebellum; Cortex (frontal); Cortex (motor); Deoxyribonucleic acid; DNA; DNA-Binding Proteins - metabolism; Guanosine Triphosphate; Humans; Imaging; Inclusions; Medical imaging; Medicine; Medicine & Public Health; Neurodegenerative diseases; Neuroimaging; Pathology; Positron emission; Positron emission tomography; Positron-Emission Tomography - methods; Radioactive tracers; Radioisotopes; Radiology; Research Article; Tau protein; Therapeutic applications; Tissues; Tritium; β-Amyloid; APN-1607; Flortaucipir; Radioligand binding; TDP-43; β-Amyloid; ALS; MK-6240; Tau; Autoradiographyz; PET
• ISSN: 1536-1632; 1860-2002; 1860-2002
• DOI: 10.1007/s11307-022-01779-1

Purpose In vivo detection of transactivation response element DNA binding protein-43 kDa (TDP-43) aggregates through positron emission tomography (PET) would impact the ability to successfully develop therapeutic interventions for a variety of neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS).  The purpose of the present study is to evaluate the ability of six tau PET radioligands to bind to TDP-43 aggregates in post-mortem brain tissues from ALS patients. Procedures Herein, we report the first head-to-head evaluation of six tritium labeled isotopologs of tau-targeting PET radioligands, [ 3 H]MK-6240 (a.k.a. florquinitau), [ 3 H]Genentech Tau Probe-1 (GTP-1), [ 3 H]JNJ-64326067(JNJ-067), [ 3 H]CBD-2115, [ 3 H]flortaucipir, and [ 3 H]APN-1607, and their ability to bind to the β-pleated sheet structures of aggregate TDP-43 in post-mortem ALS brain tissues by autoradiography and immunostaining methods. Post-mortem frontal cortex, motor cortex, and cerebellum tissues were evaluated, and binding intensity was aligned with areas of elevated phosphorylated tau (ptau), pTDP-43, and β -amyloid. Results Negligible binding was observed with [ 3 H]MK-6240, [ 3 H]JNJ-067, and [ 3 H]GTP-1. While [ 3 H]CBD-2115 displayed marginal specific binding, this binding did not significantly correlate with the distribution of pTDP-43 and AT8 inclusions. Of the remaining ligands, the distribution of [ 3 H]flortaucipir did not significantly correlate to pTDP-43 pathology; however, specific binding trends to a positive relationship with tau. Finally, [ 3 H]APN-1607 relates most strongly to amyloid load and does not indicate pTDP-43 pathology as confirmed by [ 3 H]PiB distribution in sister sections. Conclusions Our results demonstrate the prominent nature of mixed pathology in ALS, and do not support the application of [ 3 H]MK-6240, [ 3 H]JNJ-067, [ 3 H]GTP-1, [ 3 H]CBD-2115, [ 3 H]flortaucipir, or [ 3 H]APN-1607 for selective imaging TDP-43 in ALS for clinical research with the currently available in vitro data. Identification of potent and selective radiotracers for TDP-43 remains an ongoing challenge.