Development of Radiolabeled Ligands Targeting the Glutamate Binding Site of the N-Methyl-d-aspartate Receptor as Potential Imaging Agents for Brain

Lucia Tamborini; Ying Chen; Catherine A. Foss; Andrea Pinto; Andrew G. Horti; Stephen F. Traynelis; Carlo De Micheli; Ronnie C. Mease; Kasper B. Hansen; Paola Conti; Martin G. Pomper

doi:10.1021/acs.jmedchem.6b01344

Development of Radiolabeled Ligands Targeting the Glutamate Binding Site of the N-Methyl-d-aspartate Receptor as Potential Imaging Agents for Brain

Lucia Tamborini
, Ying Chen
, Catherine A. Foss
, Andrea Pinto
, Andrew G. Horti
, Stephen F. Traynelis
, Carlo De Micheli
, Ronnie C. Mease
, Kasper B. Hansen
, Paola Conti
, Martin G. Pomper

Division of Biological and Biomedical Sciences

Research output: Contribution to journal › Article › peer-review

18 Scopus citations

Abstract

Abnormal activity of various N-methyl-d-aspartate receptor (NMDAR) subtypes has been implicated in a wide variety of neurological disorders such as Alzheimer's disease, schizophrenia, and epilepsy. Imaging agents for PET and SPECT that target NMDARs in a subtype-selective fashion may enable better characterization of those disorders and enhance drug development. On the basis of a pyrazoline derivative that demonstrated neuroprotective effects in vivo, we synthesized a series of para-substituted analogues and measured their affinities to various NMDAR subtypes. Compounds 4a-c and 4e showed greater, nanomolar affinity for the GluN1/2A subtype versus GluN1/2B. Dicarbomethoxy (pro-drug) analogues of [^124/125I]4d and [¹¹C]4e (i.e., [^124/125I]11d and [¹¹C]11e) were generated and tested for NMDAR binding specificity in ex vivo autoradiography and brain biodistribution studies. Although NMDAR-specific binding could be demonstrated for [¹²⁵I]11d and [¹¹C]11e through autoradiography and biodistribution studies, imaging of neither [¹²⁴I]11d nor [¹¹C]11e could demonstrate brain penetration sufficient for detection by PET.

Original language	English
Pages (from-to)	11110-11119
Number of pages	10
Journal	Journal of Medicinal Chemistry
Volume	59
Issue number	24
DOIs	https://doi.org/10.1021/acs.jmedchem.6b01344
State	Published - Dec 22 2016

Funding

This work was supported by National Institutes of Health (P20GM103546 and R01NS097536 to K.B.H., R01NS065371 to S.F.T., and R01CA134675 to M.G.P.). A.P. acknowledges the financial support to the present research by the University of Milan (Piano di Sostegno alla Ricerca 2015/2017-Linea 2A).

Funder number
R01NS097536, P20GM103546, R01NS065371
R01CA134675

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10.1021/acs.jmedchem.6b01344

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Tamborini, L., Chen, Y., Foss, C. A., Pinto, A., Horti, A. G., Traynelis, S. F., De Micheli, C., Mease, R. C., Hansen, K. B., Conti, P., & Pomper, M. G. (2016). Development of Radiolabeled Ligands Targeting the Glutamate Binding Site of the N-Methyl-d-aspartate Receptor as Potential Imaging Agents for Brain. Journal of Medicinal Chemistry, 59(24), 11110-11119. https://doi.org/10.1021/acs.jmedchem.6b01344

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title = "Development of Radiolabeled Ligands Targeting the Glutamate Binding Site of the N-Methyl-d-aspartate Receptor as Potential Imaging Agents for Brain",

abstract = "Abnormal activity of various N-methyl-d-aspartate receptor (NMDAR) subtypes has been implicated in a wide variety of neurological disorders such as Alzheimer's disease, schizophrenia, and epilepsy. Imaging agents for PET and SPECT that target NMDARs in a subtype-selective fashion may enable better characterization of those disorders and enhance drug development. On the basis of a pyrazoline derivative that demonstrated neuroprotective effects in vivo, we synthesized a series of para-substituted analogues and measured their affinities to various NMDAR subtypes. Compounds 4a-c and 4e showed greater, nanomolar affinity for the GluN1/2A subtype versus GluN1/2B. Dicarbomethoxy (pro-drug) analogues of [124/125I]4d and [11C]4e (i.e., [124/125I]11d and [11C]11e) were generated and tested for NMDAR binding specificity in ex vivo autoradiography and brain biodistribution studies. Although NMDAR-specific binding could be demonstrated for [125I]11d and [11C]11e through autoradiography and biodistribution studies, imaging of neither [124I]11d nor [11C]11e could demonstrate brain penetration sufficient for detection by PET.",

author = "Lucia Tamborini and Ying Chen and Foss, \{Catherine A.\} and Andrea Pinto and Horti, \{Andrew G.\} and Traynelis, \{Stephen F.\} and \{De Micheli\}, Carlo and Mease, \{Ronnie C.\} and Hansen, \{Kasper B.\} and Paola Conti and Pomper, \{Martin G.\}",

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doi = "10.1021/acs.jmedchem.6b01344",

language = "English",

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Tamborini, L, Chen, Y, Foss, CA, Pinto, A, Horti, AG, Traynelis, SF, De Micheli, C, Mease, RC, Hansen, KB, Conti, P & Pomper, MG 2016, 'Development of Radiolabeled Ligands Targeting the Glutamate Binding Site of the N-Methyl-d-aspartate Receptor as Potential Imaging Agents for Brain', Journal of Medicinal Chemistry, vol. 59, no. 24, pp. 11110-11119. https://doi.org/10.1021/acs.jmedchem.6b01344

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T1 - Development of Radiolabeled Ligands Targeting the Glutamate Binding Site of the N-Methyl-d-aspartate Receptor as Potential Imaging Agents for Brain

AU - Tamborini, Lucia

AU - Chen, Ying

AU - Foss, Catherine A.

AU - Pinto, Andrea

AU - Horti, Andrew G.

AU - Traynelis, Stephen F.

AU - De Micheli, Carlo

AU - Mease, Ronnie C.

AU - Hansen, Kasper B.

AU - Conti, Paola

AU - Pomper, Martin G.

PY - 2016/12/22

Y1 - 2016/12/22

N2 - Abnormal activity of various N-methyl-d-aspartate receptor (NMDAR) subtypes has been implicated in a wide variety of neurological disorders such as Alzheimer's disease, schizophrenia, and epilepsy. Imaging agents for PET and SPECT that target NMDARs in a subtype-selective fashion may enable better characterization of those disorders and enhance drug development. On the basis of a pyrazoline derivative that demonstrated neuroprotective effects in vivo, we synthesized a series of para-substituted analogues and measured their affinities to various NMDAR subtypes. Compounds 4a-c and 4e showed greater, nanomolar affinity for the GluN1/2A subtype versus GluN1/2B. Dicarbomethoxy (pro-drug) analogues of [124/125I]4d and [11C]4e (i.e., [124/125I]11d and [11C]11e) were generated and tested for NMDAR binding specificity in ex vivo autoradiography and brain biodistribution studies. Although NMDAR-specific binding could be demonstrated for [125I]11d and [11C]11e through autoradiography and biodistribution studies, imaging of neither [124I]11d nor [11C]11e could demonstrate brain penetration sufficient for detection by PET.

AB - Abnormal activity of various N-methyl-d-aspartate receptor (NMDAR) subtypes has been implicated in a wide variety of neurological disorders such as Alzheimer's disease, schizophrenia, and epilepsy. Imaging agents for PET and SPECT that target NMDARs in a subtype-selective fashion may enable better characterization of those disorders and enhance drug development. On the basis of a pyrazoline derivative that demonstrated neuroprotective effects in vivo, we synthesized a series of para-substituted analogues and measured their affinities to various NMDAR subtypes. Compounds 4a-c and 4e showed greater, nanomolar affinity for the GluN1/2A subtype versus GluN1/2B. Dicarbomethoxy (pro-drug) analogues of [124/125I]4d and [11C]4e (i.e., [124/125I]11d and [11C]11e) were generated and tested for NMDAR binding specificity in ex vivo autoradiography and brain biodistribution studies. Although NMDAR-specific binding could be demonstrated for [125I]11d and [11C]11e through autoradiography and biodistribution studies, imaging of neither [124I]11d nor [11C]11e could demonstrate brain penetration sufficient for detection by PET.

UR - https://www.scopus.com/pages/publications/85007174623

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DO - 10.1021/acs.jmedchem.6b01344

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SN - 0022-2623

VL - 59

SP - 11110

EP - 11119

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 24

ER -

Development of Radiolabeled Ligands Targeting the Glutamate Binding Site of the N-Methyl-d-aspartate Receptor as Potential Imaging Agents for Brain

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