A Novel Brain PET Radiotracer for Imaging Alpha Synuclein Fibrils in Multiple System Atrophy

Ho Young Kim; Wai Kit Chia; Chia Ju Hsieh; Dinahlee Saturnino Guarino; Thomas J.A. Graham; Zsofia Lengyel-Zhand; Mark Schneider; Cosette Tomita; Marshall G. Lougee; Hee Jong Kim; Vinayak V. Pagar; Hsiaoju Lee; Catherine Hou; Benjamin A. Garcia; E. James Petersson; Jennifer O’Shea; Paul T. Kotzbauer; Chester A. Mathis; Virginia M.Y. Lee; Kelvin C. Luk; Robert H. Mach

doi:10.1021/acs.jmedchem.3c00779

A Novel Brain PET Radiotracer for Imaging Alpha Synuclein Fibrils in Multiple System Atrophy

Ho Young Kim, Wai Kit Chia, Chia Ju Hsieh, Dinahlee Saturnino Guarino, Thomas J.A. Graham, Zsofia Lengyel-Zhand, Mark Schneider, Cosette Tomita, Marshall G. Lougee, Hee Jong Kim, Vinayak V. Pagar, Hsiaoju Lee, Catherine Hou, Benjamin A. Garcia, E. James Petersson, Jennifer O’Shea, Paul T. Kotzbauer, Chester A. Mathis, Virginia M.Y. Lee, Kelvin C. LukRobert H. Mach

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Abstract

Abnormal α-synuclein (α-syn) aggregation characterizes α-synucleinopathies, including Parkinson’s disease (PD) and multiple system atrophy (MSA). However, no suitable positron emission tomography (PET) radiotracer for imaging α-syn in PD and MSA exists currently. Our structure-activity relationship studies identified 4-methoxy-N-(4-(3-(pyridin-2-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)phenyl)benzamide (4i) as a PET radiotracer candidate for imaging α-syn. In vitro assays revealed high binding of 4i to recombinant α-syn fibrils (inhibition constant (K_i) = 6.1 nM) and low affinity for amyloid beta (Aβ) fibrils in Alzheimer’s disease (AD) homogenates. However, [³H]4i also exhibited high specific binding to AD, progressive supranuclear palsy, and corticobasal degeneration tissues as well as PD and MSA tissues, suggesting notable affinity to tau. Nevertheless, the specific binding to pathologic α-syn aggregates in MSA post-mortem brain tissues was significantly higher than in PD tissues. This finding demonstrated the potential use of [¹¹C]4i as a PET tracer for imaging α-syn in MSA patients. Nonhuman primate PET studies confirmed good brain uptake and rapid washout for [¹¹C]4i.

Original language	English
Pages (from-to)	12185-12202
Number of pages	18
Journal	Journal of Medicinal Chemistry
Volume	66
Issue number	17
DOIs	https://doi.org/10.1021/acs.jmedchem.3c00779
State	Published - Sep 14 2023

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Kim, H. Y., Chia, W. K., Hsieh, C. J., Saturnino Guarino, D., Graham, T. J. A., Lengyel-Zhand, Z., Schneider, M., Tomita, C., Lougee, M. G., Kim, H. J., Pagar, V. V., Lee, H., Hou, C., Garcia, B. A., Petersson, E. J., O’Shea, J., Kotzbauer, P. T., Mathis, C. A., Lee, V. M. Y., ... Mach, R. H. (2023). A Novel Brain PET Radiotracer for Imaging Alpha Synuclein Fibrils in Multiple System Atrophy. Journal of Medicinal Chemistry, 66(17), 12185-12202. https://doi.org/10.1021/acs.jmedchem.3c00779

@article{ee114682c06e4a99a67789dff53fcbb5,

title = "A Novel Brain PET Radiotracer for Imaging Alpha Synuclein Fibrils in Multiple System Atrophy",

abstract = "Abnormal α-synuclein (α-syn) aggregation characterizes α-synucleinopathies, including Parkinson{\textquoteright}s disease (PD) and multiple system atrophy (MSA). However, no suitable positron emission tomography (PET) radiotracer for imaging α-syn in PD and MSA exists currently. Our structure-activity relationship studies identified 4-methoxy-N-(4-(3-(pyridin-2-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)phenyl)benzamide (4i) as a PET radiotracer candidate for imaging α-syn. In vitro assays revealed high binding of 4i to recombinant α-syn fibrils (inhibition constant (Ki) = 6.1 nM) and low affinity for amyloid beta (Aβ) fibrils in Alzheimer{\textquoteright}s disease (AD) homogenates. However, [3H]4i also exhibited high specific binding to AD, progressive supranuclear palsy, and corticobasal degeneration tissues as well as PD and MSA tissues, suggesting notable affinity to tau. Nevertheless, the specific binding to pathologic α-syn aggregates in MSA post-mortem brain tissues was significantly higher than in PD tissues. This finding demonstrated the potential use of [11C]4i as a PET tracer for imaging α-syn in MSA patients. Nonhuman primate PET studies confirmed good brain uptake and rapid washout for [11C]4i.",

author = "Kim, {Ho Young} and Chia, {Wai Kit} and Hsieh, {Chia Ju} and {Saturnino Guarino}, Dinahlee and Graham, {Thomas J.A.} and Zsofia Lengyel-Zhand and Mark Schneider and Cosette Tomita and Lougee, {Marshall G.} and Kim, {Hee Jong} and Pagar, {Vinayak V.} and Hsiaoju Lee and Catherine Hou and Garcia, {Benjamin A.} and Petersson, {E. James} and Jennifer O{\textquoteright}Shea and Kotzbauer, {Paul T.} and Mathis, {Chester A.} and Lee, {Virginia M.Y.} and Luk, {Kelvin C.} and Mach, {Robert H.}",

note = "Publisher Copyright: {\textcopyright} 2023 American Chemical Society.",

year = "2023",

month = sep,

day = "14",

doi = "10.1021/acs.jmedchem.3c00779",

language = "English",

volume = "66",

pages = "12185--12202",

journal = "Journal of Medicinal Chemistry",

issn = "0022-2623",

number = "17",

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Kim, HY, Chia, WK, Hsieh, CJ, Saturnino Guarino, D, Graham, TJA, Lengyel-Zhand, Z, Schneider, M, Tomita, C, Lougee, MG, Kim, HJ, Pagar, VV, Lee, H, Hou, C, Garcia, BA, Petersson, EJ, O’Shea, J, Kotzbauer, PT, Mathis, CA, Lee, VMY, Luk, KC & Mach, RH 2023, 'A Novel Brain PET Radiotracer for Imaging Alpha Synuclein Fibrils in Multiple System Atrophy', Journal of Medicinal Chemistry, vol. 66, no. 17, pp. 12185-12202. https://doi.org/10.1021/acs.jmedchem.3c00779

TY - JOUR

T1 - A Novel Brain PET Radiotracer for Imaging Alpha Synuclein Fibrils in Multiple System Atrophy

AU - Kim, Ho Young

AU - Chia, Wai Kit

AU - Hsieh, Chia Ju

AU - Saturnino Guarino, Dinahlee

AU - Graham, Thomas J.A.

AU - Lengyel-Zhand, Zsofia

AU - Schneider, Mark

AU - Tomita, Cosette

AU - Lougee, Marshall G.

AU - Kim, Hee Jong

AU - Pagar, Vinayak V.

AU - Lee, Hsiaoju

AU - Hou, Catherine

AU - Garcia, Benjamin A.

AU - Petersson, E. James

AU - O’Shea, Jennifer

AU - Kotzbauer, Paul T.

AU - Mathis, Chester A.

AU - Lee, Virginia M.Y.

AU - Luk, Kelvin C.

AU - Mach, Robert H.

PY - 2023/9/14

Y1 - 2023/9/14

N2 - Abnormal α-synuclein (α-syn) aggregation characterizes α-synucleinopathies, including Parkinson’s disease (PD) and multiple system atrophy (MSA). However, no suitable positron emission tomography (PET) radiotracer for imaging α-syn in PD and MSA exists currently. Our structure-activity relationship studies identified 4-methoxy-N-(4-(3-(pyridin-2-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)phenyl)benzamide (4i) as a PET radiotracer candidate for imaging α-syn. In vitro assays revealed high binding of 4i to recombinant α-syn fibrils (inhibition constant (Ki) = 6.1 nM) and low affinity for amyloid beta (Aβ) fibrils in Alzheimer’s disease (AD) homogenates. However, [3H]4i also exhibited high specific binding to AD, progressive supranuclear palsy, and corticobasal degeneration tissues as well as PD and MSA tissues, suggesting notable affinity to tau. Nevertheless, the specific binding to pathologic α-syn aggregates in MSA post-mortem brain tissues was significantly higher than in PD tissues. This finding demonstrated the potential use of [11C]4i as a PET tracer for imaging α-syn in MSA patients. Nonhuman primate PET studies confirmed good brain uptake and rapid washout for [11C]4i.

AB - Abnormal α-synuclein (α-syn) aggregation characterizes α-synucleinopathies, including Parkinson’s disease (PD) and multiple system atrophy (MSA). However, no suitable positron emission tomography (PET) radiotracer for imaging α-syn in PD and MSA exists currently. Our structure-activity relationship studies identified 4-methoxy-N-(4-(3-(pyridin-2-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)phenyl)benzamide (4i) as a PET radiotracer candidate for imaging α-syn. In vitro assays revealed high binding of 4i to recombinant α-syn fibrils (inhibition constant (Ki) = 6.1 nM) and low affinity for amyloid beta (Aβ) fibrils in Alzheimer’s disease (AD) homogenates. However, [3H]4i also exhibited high specific binding to AD, progressive supranuclear palsy, and corticobasal degeneration tissues as well as PD and MSA tissues, suggesting notable affinity to tau. Nevertheless, the specific binding to pathologic α-syn aggregates in MSA post-mortem brain tissues was significantly higher than in PD tissues. This finding demonstrated the potential use of [11C]4i as a PET tracer for imaging α-syn in MSA patients. Nonhuman primate PET studies confirmed good brain uptake and rapid washout for [11C]4i.

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U2 - 10.1021/acs.jmedchem.3c00779

DO - 10.1021/acs.jmedchem.3c00779

M3 - Article

C2 - 37651366

AN - SCOPUS:85171309703

SN - 0022-2623

VL - 66

SP - 12185

EP - 12202

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 17

ER -

A Novel Brain PET Radiotracer for Imaging Alpha Synuclein Fibrils in Multiple System Atrophy

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