Radiosynthesis and in vivo evaluation of [ 11C]MP-10 as a PET probe for imaging PDE10A in rodent and non-human primate brain

Zhude Tu; Jinda Fan; Shihong Li; Lynne A. Jones; Jinquan Cui; Prashanth K. Padakanti; Jinbin Xu; Dexing Zeng; Kooresh I. Shoghi; Joel S. Perlmutter; Robert H. MacH

doi:10.1016/j.bmc.2011.01.032

Radiosynthesis and in vivo evaluation of [ ¹¹C]MP-10 as a PET probe for imaging PDE10A in rodent and non-human primate brain

Zhude Tu, Jinda Fan, Shihong Li, Lynne A. Jones, Jinquan Cui, Prashanth K. Padakanti, Jinbin Xu, Dexing Zeng, Kooresh I. Shoghi, Joel S. Perlmutter, Robert H. MacH

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

54 Scopus citations

Abstract

2-((4-(1-[ ¹¹C]Methyl-4-(pyridin-4-yl)-1H-pyrazol-3-yl)phenoxy) methyl)-quinoline (MP-10), a specific PDE10A inhibitor (IC ₅₀ = 0.18 nM with 100-fold selectivity over other PDEs), was radiosynthesized by alkylation of the desmethyl precursor with [ ¹¹C]CH ₃I, ∼45% yield, >92% radiochemical purity, >370 GBq/μmol specific activity at end of bombardment (EOB). Evaluation in Sprague-Dawley rats revealed that [ ¹¹C]MP-10 had highest brain accumulation in the PDE10A enriched-striatum, the 30 min striatum: cerebellum ratio reached 6.55. MicroPET studies of [ ¹¹C]MP-10 in monkeys displayed selective uptake in striatum. However, a radiolabeled metabolite capable of penetrating the blood-brain-barrier may limit the clinical utility of [ ¹¹C]MP-10 as a PDE10A PET tracer.

Original language	English (US)
Pages (from-to)	1666-1673
Number of pages	8
Journal	Bioorganic and Medicinal Chemistry
Volume	19
Issue number	5
DOIs	https://doi.org/10.1016/j.bmc.2011.01.032
State	Published - Mar 1 2011
Externally published	Yes

Keywords

Carbon-11
Huntington's disease
MP-10
PDE10A
PET imaging

ASJC Scopus subject areas

Biochemistry
Molecular Medicine
Molecular Biology
Pharmaceutical Science
Drug Discovery
Clinical Biochemistry
Organic Chemistry

Access to Document

10.1016/j.bmc.2011.01.032

Cite this

@article{6e1c436e303e4f8f8ec4afb16e495c47,

title = "Radiosynthesis and in vivo evaluation of [ 11C]MP-10 as a PET probe for imaging PDE10A in rodent and non-human primate brain",

abstract = "2-((4-(1-[ 11C]Methyl-4-(pyridin-4-yl)-1H-pyrazol-3-yl)phenoxy) methyl)-quinoline (MP-10), a specific PDE10A inhibitor (IC 50 = 0.18 nM with 100-fold selectivity over other PDEs), was radiosynthesized by alkylation of the desmethyl precursor with [ 11C]CH 3I, ∼45% yield, >92% radiochemical purity, >370 GBq/μmol specific activity at end of bombardment (EOB). Evaluation in Sprague-Dawley rats revealed that [ 11C]MP-10 had highest brain accumulation in the PDE10A enriched-striatum, the 30 min striatum: cerebellum ratio reached 6.55. MicroPET studies of [ 11C]MP-10 in monkeys displayed selective uptake in striatum. However, a radiolabeled metabolite capable of penetrating the blood-brain-barrier may limit the clinical utility of [ 11C]MP-10 as a PDE10A PET tracer.",

keywords = "Carbon-11, Huntington's disease, MP-10, PDE10A, PET imaging",

author = "Zhude Tu and Jinda Fan and Shihong Li and Jones, {Lynne A.} and Jinquan Cui and Padakanti, {Prashanth K.} and Jinbin Xu and Dexing Zeng and Shoghi, {Kooresh I.} and Perlmutter, {Joel S.} and MacH, {Robert H.}",

note = "Funding Information: Financial support for these studies was provided by the National Institute of Health under 5R33MH081281-04 (RHM), NS058714, 1R21NS061025-01A2 and Intramural grant MIR-11-009 of Mallinckrodt Institute of Radiology in Washington University School of Medicine . The authors gratefully thank Christina M. Zukas, John Hood, Darryl Craig, Ruike Wang, Aixiao Li and Junfeng Li for their excellent technical assistance for the microPET studies in non-human primate. ",

year = "2011",

month = mar,

day = "1",

doi = "10.1016/j.bmc.2011.01.032",

language = "English (US)",

volume = "19",

pages = "1666--1673",

journal = "Bioorganic and Medicinal Chemistry",

issn = "0968-0896",

publisher = "Elsevier Limited",

number = "5",

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TY - JOUR

T1 - Radiosynthesis and in vivo evaluation of [ 11C]MP-10 as a PET probe for imaging PDE10A in rodent and non-human primate brain

AU - Tu, Zhude

AU - Fan, Jinda

AU - Li, Shihong

AU - Jones, Lynne A.

AU - Cui, Jinquan

AU - Padakanti, Prashanth K.

AU - Xu, Jinbin

AU - Zeng, Dexing

AU - Shoghi, Kooresh I.

AU - Perlmutter, Joel S.

AU - MacH, Robert H.

N1 - Funding Information: Financial support for these studies was provided by the National Institute of Health under 5R33MH081281-04 (RHM), NS058714, 1R21NS061025-01A2 and Intramural grant MIR-11-009 of Mallinckrodt Institute of Radiology in Washington University School of Medicine . The authors gratefully thank Christina M. Zukas, John Hood, Darryl Craig, Ruike Wang, Aixiao Li and Junfeng Li for their excellent technical assistance for the microPET studies in non-human primate.

PY - 2011/3/1

Y1 - 2011/3/1

N2 - 2-((4-(1-[ 11C]Methyl-4-(pyridin-4-yl)-1H-pyrazol-3-yl)phenoxy) methyl)-quinoline (MP-10), a specific PDE10A inhibitor (IC 50 = 0.18 nM with 100-fold selectivity over other PDEs), was radiosynthesized by alkylation of the desmethyl precursor with [ 11C]CH 3I, ∼45% yield, >92% radiochemical purity, >370 GBq/μmol specific activity at end of bombardment (EOB). Evaluation in Sprague-Dawley rats revealed that [ 11C]MP-10 had highest brain accumulation in the PDE10A enriched-striatum, the 30 min striatum: cerebellum ratio reached 6.55. MicroPET studies of [ 11C]MP-10 in monkeys displayed selective uptake in striatum. However, a radiolabeled metabolite capable of penetrating the blood-brain-barrier may limit the clinical utility of [ 11C]MP-10 as a PDE10A PET tracer.

AB - 2-((4-(1-[ 11C]Methyl-4-(pyridin-4-yl)-1H-pyrazol-3-yl)phenoxy) methyl)-quinoline (MP-10), a specific PDE10A inhibitor (IC 50 = 0.18 nM with 100-fold selectivity over other PDEs), was radiosynthesized by alkylation of the desmethyl precursor with [ 11C]CH 3I, ∼45% yield, >92% radiochemical purity, >370 GBq/μmol specific activity at end of bombardment (EOB). Evaluation in Sprague-Dawley rats revealed that [ 11C]MP-10 had highest brain accumulation in the PDE10A enriched-striatum, the 30 min striatum: cerebellum ratio reached 6.55. MicroPET studies of [ 11C]MP-10 in monkeys displayed selective uptake in striatum. However, a radiolabeled metabolite capable of penetrating the blood-brain-barrier may limit the clinical utility of [ 11C]MP-10 as a PDE10A PET tracer.

KW - Carbon-11

KW - Huntington's disease

KW - MP-10

KW - PDE10A

KW - PET imaging

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