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Meeting ReportPoster - PhysicianPharm

Monoamine Oxidase-A is Upregulated in Post-Mortem Human Alzheimer’s Disease and Parkinson’s Disease Brain

Jogeshwar Mukherjee, Christopher Liang, Amina Syed, Phuc Lam, Rommani Mondal, Tonya Mukherjee and Krystal Patel
Journal of Nuclear Medicine May 2021, 62 (supplement 1) 1609;
Jogeshwar Mukherjee
1Radiological Sciences University of California-Irvine Irvine CA United States
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Christopher Liang
1Radiological Sciences University of California-Irvine Irvine CA United States
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Amina Syed
1Radiological Sciences University of California-Irvine Irvine CA United States
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Phuc Lam
1Radiological Sciences University of California-Irvine Irvine CA United States
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Rommani Mondal
1Radiological Sciences University of California-Irvine Irvine CA United States
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Tonya Mukherjee
1Radiological Sciences University of California-Irvine Irvine CA United States
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Krystal Patel
1Radiological Sciences University of California-Irvine Irvine CA United States
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Abstract

1609

Objectives: Monoamine oxidases play a significant role in the pathogenesis of neurodegeneration. The role of the brain isozyme, MAO-A in neurodegeneration is less known. We report evaluation of our newly developed fluoroalkylated azaindole, [18F]FAZIN3 as a novel, reversibly binding PET imaging agent for MAO-A in Alzheimer’s disease (AD) and Parkinson’s disease (PD). [18F]FAZIN3 was compared to the known MAO-A PET radiotracer, [18F]Fluoroethyl Harmol ([18F]FEH) to further support the role of MAO-A in AD and PD. Human post-mortem brain autoradiographic studies of [18F]FAZIN3 and [18F]FEH were carried out in cognitively normal (CN) controls, AD, and PD brains containing anterior cingulate (AC) and corpus callosum (CC).

Methods: [18F]FAZIN3 and [18F]FEH were prepared by reacting the tosylate precursors using high specific activity [18F]fluoride from PETNET. [18F]FAZIN3 and [18F]FEH were purified by HPLC and used for in vitro studies. Human post-mortem brain tissues consisted of AC (grey matter, GM) and CC (white matter, WM). Brain slices (10 μm thick) were obtained on a Leica 1850 cryotome. Controls (CN), n=6; age 81-90 total Tangle=1 to 3.5, no Lewy body (LB); PD, n=6, age 77-89, total Tangle= 2 to 7, LB III-IV; AD, n=6, age 77-89, total Tangle = 10 to 15; no LB. Brain slices were incubated [18F]FAZIN3 or [18F]FEH (approx. 1 μCi/cc) in PBS (pH 7.4) buffer at 25oC for 60 min and subsequently washed with PBS buffer. Nonspecific binding was measured using 10 μM clorgyline. Tau binding by [18F]FAZIN3 was confirmed in the presence of MK-6240 (10 μM). Optiquant program, was used for regions of interest analysis and digital light units/ mm2 (DLU/mm2) used to quantify percentage binding of [18F]FAZIN3 or [18F]FEH. Immunostaining with anti-Tau, anti-Aβ and ubiquitin for LB was done on adjacent sections of all subjects. [125I]IPPI, a Tau-binding radiotracer and [18F]Flotaza, an Aβ plaque binding PET radiotracer, developed in our laboratory were used in adjacent slices to confirm immunostaining results and correlate with [18F]FAZIN3 and [18F]FEH binding in the AD brains.

Results: The gray matter (GM) were clearly delineated in the AD autoradiographic images of [18F]FEH (Fig-1B) and [18F]FAZIN3 (Fig-1D), with an average GM/WM>2 for [18F]FEH and GM/WM>3 for [18F]FAZIN3. The binding correlated well with the high binding of [125I]IPPI to Tau (GM/WM>4) and [18F]Flotaza to Aβ plaques (GM/WM>100) consistent with cortical binding corresponding to anti-Aβ (Fig-1A) and anti-Tau (Fig-1C). All CN subjects exhibited lower [18F]FEH and [18F]FAZIN3 binding in the GM (Fig-1J,K) compared to the AD and PD subjects. Ubiquitin confirmed presence of LB (Fig-1G). All PD subjects exhibited significantly higher binding of [18F]FEH (Fig-1F) and [18F]FAZIN3 (Fig-1I) in GM compared to CN subjects. Average GM/WM=1.5-2 for [18F]FEH and GM/WM>3 for [18F]FAZIN3 for the PD subjects. Nonspecific binding of [18F]FEH was found to be higher than [18F]FAZIN3. Conclusion: Increased [18F]FEH and [18F]FAZIN3 binding in PD and AD brains compared to CN brain samples suggests a significant upregulation of MAO-A in neurodegeneration.Figure-1: Binding of [18F]FEH and [18F]FAZIN3 in post-mortem AD, PD and CN human brain tissue. Figs. 1A-D are AD brain sections of the same AD subject showing anti-Aβ immunostain (A), [18F]FEH binding autoradiographs in the grey matter (GM) regions (B), anti-Tau immunostain of adjacent sections (C), and [18F]FAZIN3 binding autoradiographs in the GM regions (D). Figs. 1E-I are PD brain sections of the same PD subject showing PD brain section with white matter (WM, corpus callosum, CC) (E), [18F]FEH binding autoradiographs in the grey matter (GM) regions (F), ubiquitin staining of Lewy bodies (G), H&E staining of adjacent section (H) and [18F]FAZIN3 binding autoradiographs in the GM regions (I). Fig. 1J is [18F]FEH binding autoradiographs of control subject and Fig.1K is [18F]FAZIN3 binding autoradiograph of the same control subject.

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Journal of Nuclear Medicine
Vol. 62, Issue supplement 1
May 1, 2021
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Monoamine Oxidase-A is Upregulated in Post-Mortem Human Alzheimer’s Disease and Parkinson’s Disease Brain
Jogeshwar Mukherjee, Christopher Liang, Amina Syed, Phuc Lam, Rommani Mondal, Tonya Mukherjee, Krystal Patel
Journal of Nuclear Medicine May 2021, 62 (supplement 1) 1609;

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Monoamine Oxidase-A is Upregulated in Post-Mortem Human Alzheimer’s Disease and Parkinson’s Disease Brain
Jogeshwar Mukherjee, Christopher Liang, Amina Syed, Phuc Lam, Rommani Mondal, Tonya Mukherjee, Krystal Patel
Journal of Nuclear Medicine May 2021, 62 (supplement 1) 1609;
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