TY - JOUR

T1 - Evaluation of the α-synuclein PET radiotracer (d3)-[11C]MODAG-001 in pigs

AU - Raval, Nakul Ravi

AU - Madsen, Clara Aabye

AU - Shalgunov, Vladimir

AU - Nasser, Arafat

AU - Battisti, Umberto Maria

AU - Beaman, Emily Eufaula

AU - Juhl, Morten

AU - Jørgensen, Louise Møller

AU - Herth, Matthias Manfred

AU - Hansen, Hanne Demant

AU - Plavén-Sigray, Pontus

AU - Knudsen, Gitte Moos

N1 - Funding Information: This project has received funding from the European Union's Horizon 2020 research and innovation program under the Marie Skłodowska-Curie grant agreement No. 813528. This project also received funding from Parkinsonforeningen, Denmark (R16-A247). Pontus Plavén Sigray was supported by the Lundbeck Foundation ( R303-2018-3263 ). Vladimir Shalgunov was supported by the Lundbeck Foundation ( R303-2018-3567 ), the Novo Nordisk Foundation (grant agreement no. NNF18SA0034956 ), and BRIDGE – Translational Excellence Program at the Faculty of Health and Medical Sciences, University of Copenhagen . Publisher Copyright: © 2022 The Author(s)

PY - 2022

Y1 - 2022

N2 - Background: A positron emission tomography (PET) radiotracer to neuroimage α-synuclein aggregates would be a crucial addition for early diagnosis and treatment development in disorders such as Parkinson's disease, where elevated aggregate levels are a histopathological hallmark. The radiotracer (d3)-[11C]MODAG-001 has recently shown promise for visualization of α-synuclein pre-formed fibrils (α-PFF) in rodents. We here test the radiotracer in a pig model where proteins are intracerebrally injected immediately before scanning. Four pigs were injected in one hemisphere with 150 μg α-PFF, and in the other hemisphere, either 75 μg α-PFF or human brain homogenate from either dementia with Lewy bodies (DLB) or Alzheimer's disease (AD) was injected. All pigs underwent one or two (d3)-[11C]MODAG-001 PET scans, quantified with the non-invasive Logan graphical analysis using the occipital cortex as a reference region. Results: The α-PFF and AD homogenate injected brain regions had high uptake of (d3)-[11C]MODAG-001 compared to the occipital cortex or cerebellum. BPND values in 150 μg α-PFF injected regions was 0.78, and in the AD homogenate injected regions was 0.73. By contrast, the DLB homogenate injected region did not differ in uptake and clearance compared to the reference regions. The time-activity curves and BPND values in the 150 μg and 75 μg injected regions of α-PFFs show a dose-dependent effect, and the PET signal could be blocked by pretreatment with unlabeled MODAG-001. Conclusion: We find that both α-PFF and AD brain homogenates give rise to increased binding of (d3)-[11C]MODAG-001 when injected into the pig brain. Despite its limited specificity for cerebral α-synuclein pathology, (d3)-[11C]MODAG-001 shows promise as a lead tracer for future radiotracer development.

AB - Background: A positron emission tomography (PET) radiotracer to neuroimage α-synuclein aggregates would be a crucial addition for early diagnosis and treatment development in disorders such as Parkinson's disease, where elevated aggregate levels are a histopathological hallmark. The radiotracer (d3)-[11C]MODAG-001 has recently shown promise for visualization of α-synuclein pre-formed fibrils (α-PFF) in rodents. We here test the radiotracer in a pig model where proteins are intracerebrally injected immediately before scanning. Four pigs were injected in one hemisphere with 150 μg α-PFF, and in the other hemisphere, either 75 μg α-PFF or human brain homogenate from either dementia with Lewy bodies (DLB) or Alzheimer's disease (AD) was injected. All pigs underwent one or two (d3)-[11C]MODAG-001 PET scans, quantified with the non-invasive Logan graphical analysis using the occipital cortex as a reference region. Results: The α-PFF and AD homogenate injected brain regions had high uptake of (d3)-[11C]MODAG-001 compared to the occipital cortex or cerebellum. BPND values in 150 μg α-PFF injected regions was 0.78, and in the AD homogenate injected regions was 0.73. By contrast, the DLB homogenate injected region did not differ in uptake and clearance compared to the reference regions. The time-activity curves and BPND values in the 150 μg and 75 μg injected regions of α-PFFs show a dose-dependent effect, and the PET signal could be blocked by pretreatment with unlabeled MODAG-001. Conclusion: We find that both α-PFF and AD brain homogenates give rise to increased binding of (d3)-[11C]MODAG-001 when injected into the pig brain. Despite its limited specificity for cerebral α-synuclein pathology, (d3)-[11C]MODAG-001 shows promise as a lead tracer for future radiotracer development.

KW - Alpha-synuclein

KW - Amyloid-beta

KW - Brain imaging

KW - Intracerebral protein injection

KW - Larger animal PET

KW - PET tracer

KW - Pig model

KW - Positron emission tomography

U2 - 10.1016/j.nucmedbio.2022.08.001

DO - 10.1016/j.nucmedbio.2022.08.001

M3 - Journal article

C2 - 36095921

AN - SCOPUS:85137613937

VL - 114-115

SP - 42

EP - 48

JO - Nuclear Medicine and Biology

JF - Nuclear Medicine and Biology

SN - 0969-8051

ER -