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

Mikael Palner; Patrick McCormick; Nicolas Gillings; Mikael Begtrup; Alan A Wilson; Gitte M 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, Nicolas Gillings, Mikael Begtrup, Alan A Wilson, Gitte M Knudsen

3 Citations (Scopus)

Abstract

Introduction: Several dopamine D₂ agonist radioligands have been used with positron emission tomography (PET), including [¹¹C-]-(-)-MNPA, [¹¹C-]-(-)-NPA and [¹¹C]-(+)-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 D₂ and D₃ 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 D₂/D₃ selectivity. Methods: 2-Cl-[¹¹C]-(-)-NPA and [¹¹C]-(-)-NPA were synthesized by a two step N-acylation-reduction process using [¹¹C]-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-[¹¹C]-(-)-NPA and [¹¹C]-(-)-NPA were produced in high specific activity and purity. 2-Cl-[¹¹C]-(-)-NPA accumulated slower in the striatum than [¹¹C]-(-)-NPA, reaching maximum concentrations after 30 min. The maximal striatal uptake of 2-Cl-[¹¹C]-(-)-NPA (standard uptake value 0.72±0.24) was approximately half that of [¹¹C]-(-)-NPA (standard uptake value 1.37±0.18). Nonspecific uptake was similar for the two compounds. 2-Cl-[¹¹C]-(-)-NPA was metabolized quickly, leaving only 17% of the parent compound in the plasma after 30 min. The specific binding of 2-Cl-[¹¹C]-(-)-NPA was completely blocked and inhibition of P-glycoprotein did not alter the brain uptake. Conclusion: Ex vivo experiments showed, despite a favorable D₂/D₃ selectivity, that 2-Cl-[¹¹C]-(-)-NPA is inferior to [¹¹C]-(-)-NPA as a PET tracer in rat, because of slower brain uptake and lower specific to nonspecific binding ratio.

Original language	English
Journal	Nuclear Medicine and Biology
Volume	37
Issue number	1
Pages (from-to)	35-40
Number of pages	6
ISSN	0969-8051
DOIs	https://doi.org/10.1016/j.nucmedbio.2009.08.005
Publication status	Published - 1 Jan 2010

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@article{c368710306bc4038988850b8448af351,

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

abstract = "Introduction: Several dopamine D2 agonist radioligands have been used with positron emission tomography (PET), including [11C-]-(-)-MNPA, [11C-]-(-)-NPA and [11C]-(+)-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 D2 and D3 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 D2/D3 selectivity. Methods: 2-Cl-[11C]-(-)-NPA and [11C]-(-)-NPA were synthesized by a two step N-acylation-reduction process using [11C]-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-[11C]-(-)-NPA and [11C]-(-)-NPA were produced in high specific activity and purity. 2-Cl-[11C]-(-)-NPA accumulated slower in the striatum than [11C]-(-)-NPA, reaching maximum concentrations after 30 min. The maximal striatal uptake of 2-Cl-[11C]-(-)-NPA (standard uptake value 0.72±0.24) was approximately half that of [11C]-(-)-NPA (standard uptake value 1.37±0.18). Nonspecific uptake was similar for the two compounds. 2-Cl-[11C]-(-)-NPA was metabolized quickly, leaving only 17% of the parent compound in the plasma after 30 min. The specific binding of 2-Cl-[11C]-(-)-NPA was completely blocked and inhibition of P-glycoprotein did not alter the brain uptake. Conclusion: Ex vivo experiments showed, despite a favorable D2/D3 selectivity, that 2-Cl-[11C]-(-)-NPA is inferior to [11C]-(-)-NPA as a PET tracer in rat, because of slower brain uptake and lower specific to nonspecific binding ratio.",

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

year = "2010",

month = jan,

day = "1",

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",

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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, Nicolas

AU - Begtrup, Mikael

AU - Wilson, Alan A

AU - Knudsen, Gitte M

PY - 2010/1/1

Y1 - 2010/1/1

N2 - Introduction: Several dopamine D2 agonist radioligands have been used with positron emission tomography (PET), including [11C-]-(-)-MNPA, [11C-]-(-)-NPA and [11C]-(+)-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 D2 and D3 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 D2/D3 selectivity. Methods: 2-Cl-[11C]-(-)-NPA and [11C]-(-)-NPA were synthesized by a two step N-acylation-reduction process using [11C]-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-[11C]-(-)-NPA and [11C]-(-)-NPA were produced in high specific activity and purity. 2-Cl-[11C]-(-)-NPA accumulated slower in the striatum than [11C]-(-)-NPA, reaching maximum concentrations after 30 min. The maximal striatal uptake of 2-Cl-[11C]-(-)-NPA (standard uptake value 0.72±0.24) was approximately half that of [11C]-(-)-NPA (standard uptake value 1.37±0.18). Nonspecific uptake was similar for the two compounds. 2-Cl-[11C]-(-)-NPA was metabolized quickly, leaving only 17% of the parent compound in the plasma after 30 min. The specific binding of 2-Cl-[11C]-(-)-NPA was completely blocked and inhibition of P-glycoprotein did not alter the brain uptake. Conclusion: Ex vivo experiments showed, despite a favorable D2/D3 selectivity, that 2-Cl-[11C]-(-)-NPA is inferior to [11C]-(-)-NPA as a PET tracer in rat, because of slower brain uptake and lower specific to nonspecific binding ratio.

AB - Introduction: Several dopamine D2 agonist radioligands have been used with positron emission tomography (PET), including [11C-]-(-)-MNPA, [11C-]-(-)-NPA and [11C]-(+)-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 D2 and D3 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 D2/D3 selectivity. Methods: 2-Cl-[11C]-(-)-NPA and [11C]-(-)-NPA were synthesized by a two step N-acylation-reduction process using [11C]-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-[11C]-(-)-NPA and [11C]-(-)-NPA were produced in high specific activity and purity. 2-Cl-[11C]-(-)-NPA accumulated slower in the striatum than [11C]-(-)-NPA, reaching maximum concentrations after 30 min. The maximal striatal uptake of 2-Cl-[11C]-(-)-NPA (standard uptake value 0.72±0.24) was approximately half that of [11C]-(-)-NPA (standard uptake value 1.37±0.18). Nonspecific uptake was similar for the two compounds. 2-Cl-[11C]-(-)-NPA was metabolized quickly, leaving only 17% of the parent compound in the plasma after 30 min. The specific binding of 2-Cl-[11C]-(-)-NPA was completely blocked and inhibition of P-glycoprotein did not alter the brain uptake. Conclusion: Ex vivo experiments showed, despite a favorable D2/D3 selectivity, that 2-Cl-[11C]-(-)-NPA is inferior to [11C]-(-)-NPA as a PET tracer in rat, because of slower brain uptake and lower specific to nonspecific binding ratio.

U2 - 10.1016/j.nucmedbio.2009.08.005

DO - 10.1016/j.nucmedbio.2009.08.005

M3 - Journal article

SN - 0969-8051

VL - 37

SP - 35

EP - 40

JO - Nuclear Medicine and Biology

JF - Nuclear Medicine and Biology

IS - 1

ER -

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

Abstract

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