Radiosynthesis and ex vivo evaluation of (R)-(-)-2-chloro-N-[1-11C-propyl]n-propylnorapomorphine:

Mikael Palner; Patrick McCormick; Nic Gillings; Mikael Begtrup; Alan A Wilson; Gitte Moos Knudsen

doi:10.1016/j.nucmedbio.2009.08.005

Radiosynthesis and ex vivo evaluation of (R)-(-)-2-chloro-N-[1-¹¹C-propyl]n-propylnorapomorphine:

Mikael Palner, Patrick McCormick, Nic Gillings, Mikael Begtrup, Alan A Wilson, Gitte Moos Knudsen

Molecular Neuroscience

3 Citationer (Scopus)

Abstract

INTRODUCTION: Several dopamine D(2) agonist radioligands have been used with positron emission tomography (PET), including [(11)C-]-(-)-MNPA, [(11)C-]-(-)-NPA and [(11)C]-(+)-PHNO. These radioligands are considered particularly powerful for detection of endogenous dopamine release, but they either provide PET brain images with limited contrast or have affinity for both D(2) and D(3) receptors. We here present the carbon-11 radiolabeling and ex vivo evaluation of 2-Cl-(-)-NPA, a novel PET-tracer candidate with high in vitro D(2)/D(3) selectivity. METHODS: 2-Cl-[(11)C]-(-)-NPA and [(11)C]-(-)-NPA were synthesized by a two step N-acylation-reduction process using [(11)C]-propionyl chloride. Awake rats were injected with either tracer, via the tail vein. The rats were decapitated at various times, the brains were removed and quickly dissected, and plasma metabolites were measured. Radioligand specificity, and P-glycoprotein involvement in brain uptake, was also assessed. RESULTS: 2-Cl-[(11)C]-(-)-NPA and [(11)C]-(-)-NPA were produced in high specific activity and purity. 2-Cl-[(11)C]-(-)-NPA accumulated slower in the striatum than [(11)C]-(-)-NPA, reaching maximum concentrations after 30 min. The maximal striatal uptake of 2-Cl-[(11)C]-(-)-NPA (standard uptake value 0.72+/-0.24) was approximately half that of [(11)C]-(-)-NPA (standard uptake value 1.37+/-0.18). Nonspecific uptake was similar for the two compounds. 2-Cl-[(11)C]-(-)-NPA was metabolized quickly, leaving only 17% of the parent compound in the plasma after 30 min. The specific binding of 2-Cl-[(11)C]-(-)-NPA was completely blocked and inhibition of P-glycoprotein did not alter the brain uptake. CONCLUSION: Ex vivo experiments showed, despite a favorable D(2)/D(3) selectivity, that 2-Cl-[(11)C]-(-)-NPA is inferior to [(11)C]-(-)-NPA as a PET tracer in rat, because of slower brain uptake and lower specific to nonspecific binding ratio.

Originalsprog	Engelsk
Tidsskrift	Nuclear Medicine and Biology
Vol/bind	37
Udgave nummer	1
Sider (fra-til)	35-40
ISSN	0969-8051
DOI	https://doi.org/10.1016/j.nucmedbio.2009.08.005
Status	Udgivet - jan. 2010

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10.1016/j.nucmedbio.2009.08.005

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@article{4d34c0704b9411df928f000ea68e967b,

title = "Radiosynthesis and ex vivo evaluation of (R)-(-)-2-chloro-N-[1-11C-propyl]n-propylnorapomorphine: ",

abstract = "INTRODUCTION: Several dopamine D(2) agonist radioligands have been used with positron emission tomography (PET), including [(11)C-]-(-)-MNPA, [(11)C-]-(-)-NPA and [(11)C]-(+)-PHNO. These radioligands are considered particularly powerful for detection of endogenous dopamine release, but they either provide PET brain images with limited contrast or have affinity for both D(2) and D(3) receptors. We here present the carbon-11 radiolabeling and ex vivo evaluation of 2-Cl-(-)-NPA, a novel PET-tracer candidate with high in vitro D(2)/D(3) selectivity. METHODS: 2-Cl-[(11)C]-(-)-NPA and [(11)C]-(-)-NPA were synthesized by a two step N-acylation-reduction process using [(11)C]-propionyl chloride. Awake rats were injected with either tracer, via the tail vein. The rats were decapitated at various times, the brains were removed and quickly dissected, and plasma metabolites were measured. Radioligand specificity, and P-glycoprotein involvement in brain uptake, was also assessed. RESULTS: 2-Cl-[(11)C]-(-)-NPA and [(11)C]-(-)-NPA were produced in high specific activity and purity. 2-Cl-[(11)C]-(-)-NPA accumulated slower in the striatum than [(11)C]-(-)-NPA, reaching maximum concentrations after 30 min. The maximal striatal uptake of 2-Cl-[(11)C]-(-)-NPA (standard uptake value 0.72+/-0.24) was approximately half that of [(11)C]-(-)-NPA (standard uptake value 1.37+/-0.18). Nonspecific uptake was similar for the two compounds. 2-Cl-[(11)C]-(-)-NPA was metabolized quickly, leaving only 17% of the parent compound in the plasma after 30 min. The specific binding of 2-Cl-[(11)C]-(-)-NPA was completely blocked and inhibition of P-glycoprotein did not alter the brain uptake. CONCLUSION: Ex vivo experiments showed, despite a favorable D(2)/D(3) selectivity, that 2-Cl-[(11)C]-(-)-NPA is inferior to [(11)C]-(-)-NPA as a PET tracer in rat, because of slower brain uptake and lower specific to nonspecific binding ratio.",

keywords = "Faculty of Health and Medical Sciences",

author = "Mikael Palner and Patrick McCormick and Nic Gillings and Mikael Begtrup and Wilson, {Alan A} and Knudsen, {Gitte Moos}",

note = "Keywords: PET; Agonist; D2; D3; Dopamine; Apomorphine; 2-Cl-[11C]-(-)-NPA; Radioligand; P-glycoprotein; Amphetamine. Further Organisations: Center for Integrated Molecular Brain Imaging: Mikael Palner; Mikael Begtrup; Gitte Moos Knudsen PET and Cyklotron Unit, Rigshospitalet: Nic Gillings",

year = "2010",

month = jan,

doi = "10.1016/j.nucmedbio.2009.08.005",

language = "English",

volume = "37",

pages = "35--40",

journal = "Nuclear Medicine and Biology",

issn = "0969-8051",

publisher = "Elsevier",

number = "1",

}

TY - JOUR

T1 - Radiosynthesis and ex vivo evaluation of (R)-(-)-2-chloro-N-[1-11C-propyl]n-propylnorapomorphine

AU - Palner, Mikael

AU - McCormick, Patrick

AU - Gillings, Nic

AU - Begtrup, Mikael

AU - Wilson, Alan A

AU - Knudsen, Gitte Moos

N1 - Keywords: PET; Agonist; D2; D3; Dopamine; Apomorphine; 2-Cl-[11C]-(-)-NPA; Radioligand; P-glycoprotein; Amphetamine. Further Organisations: Center for Integrated Molecular Brain Imaging: Mikael Palner; Mikael Begtrup; Gitte Moos Knudsen PET and Cyklotron Unit, Rigshospitalet: Nic Gillings

PY - 2010/1

Y1 - 2010/1

N2 - INTRODUCTION: Several dopamine D(2) agonist radioligands have been used with positron emission tomography (PET), including [(11)C-]-(-)-MNPA, [(11)C-]-(-)-NPA and [(11)C]-(+)-PHNO. These radioligands are considered particularly powerful for detection of endogenous dopamine release, but they either provide PET brain images with limited contrast or have affinity for both D(2) and D(3) receptors. We here present the carbon-11 radiolabeling and ex vivo evaluation of 2-Cl-(-)-NPA, a novel PET-tracer candidate with high in vitro D(2)/D(3) selectivity. METHODS: 2-Cl-[(11)C]-(-)-NPA and [(11)C]-(-)-NPA were synthesized by a two step N-acylation-reduction process using [(11)C]-propionyl chloride. Awake rats were injected with either tracer, via the tail vein. The rats were decapitated at various times, the brains were removed and quickly dissected, and plasma metabolites were measured. Radioligand specificity, and P-glycoprotein involvement in brain uptake, was also assessed. RESULTS: 2-Cl-[(11)C]-(-)-NPA and [(11)C]-(-)-NPA were produced in high specific activity and purity. 2-Cl-[(11)C]-(-)-NPA accumulated slower in the striatum than [(11)C]-(-)-NPA, reaching maximum concentrations after 30 min. The maximal striatal uptake of 2-Cl-[(11)C]-(-)-NPA (standard uptake value 0.72+/-0.24) was approximately half that of [(11)C]-(-)-NPA (standard uptake value 1.37+/-0.18). Nonspecific uptake was similar for the two compounds. 2-Cl-[(11)C]-(-)-NPA was metabolized quickly, leaving only 17% of the parent compound in the plasma after 30 min. The specific binding of 2-Cl-[(11)C]-(-)-NPA was completely blocked and inhibition of P-glycoprotein did not alter the brain uptake. CONCLUSION: Ex vivo experiments showed, despite a favorable D(2)/D(3) selectivity, that 2-Cl-[(11)C]-(-)-NPA is inferior to [(11)C]-(-)-NPA as a PET tracer in rat, because of slower brain uptake and lower specific to nonspecific binding ratio.

AB - INTRODUCTION: Several dopamine D(2) agonist radioligands have been used with positron emission tomography (PET), including [(11)C-]-(-)-MNPA, [(11)C-]-(-)-NPA and [(11)C]-(+)-PHNO. These radioligands are considered particularly powerful for detection of endogenous dopamine release, but they either provide PET brain images with limited contrast or have affinity for both D(2) and D(3) receptors. We here present the carbon-11 radiolabeling and ex vivo evaluation of 2-Cl-(-)-NPA, a novel PET-tracer candidate with high in vitro D(2)/D(3) selectivity. METHODS: 2-Cl-[(11)C]-(-)-NPA and [(11)C]-(-)-NPA were synthesized by a two step N-acylation-reduction process using [(11)C]-propionyl chloride. Awake rats were injected with either tracer, via the tail vein. The rats were decapitated at various times, the brains were removed and quickly dissected, and plasma metabolites were measured. Radioligand specificity, and P-glycoprotein involvement in brain uptake, was also assessed. RESULTS: 2-Cl-[(11)C]-(-)-NPA and [(11)C]-(-)-NPA were produced in high specific activity and purity. 2-Cl-[(11)C]-(-)-NPA accumulated slower in the striatum than [(11)C]-(-)-NPA, reaching maximum concentrations after 30 min. The maximal striatal uptake of 2-Cl-[(11)C]-(-)-NPA (standard uptake value 0.72+/-0.24) was approximately half that of [(11)C]-(-)-NPA (standard uptake value 1.37+/-0.18). Nonspecific uptake was similar for the two compounds. 2-Cl-[(11)C]-(-)-NPA was metabolized quickly, leaving only 17% of the parent compound in the plasma after 30 min. The specific binding of 2-Cl-[(11)C]-(-)-NPA was completely blocked and inhibition of P-glycoprotein did not alter the brain uptake. CONCLUSION: Ex vivo experiments showed, despite a favorable D(2)/D(3) selectivity, that 2-Cl-[(11)C]-(-)-NPA is inferior to [(11)C]-(-)-NPA as a PET tracer in rat, because of slower brain uptake and lower specific to nonspecific binding ratio.

KW - Faculty of Health and Medical Sciences

U2 - 10.1016/j.nucmedbio.2009.08.005

DO - 10.1016/j.nucmedbio.2009.08.005

M3 - Journal article

C2 - 20122666

SN - 0969-8051

VL - 37

SP - 35

EP - 40

JO - Nuclear Medicine and Biology

JF - Nuclear Medicine and Biology

IS - 1

ER -