Binding characteristics and sensitivity to endogenous dopamine of [11C]‐(+)‐PHNO, a new agonist radiotracer for imaging the high‐affinity state of D2 receptors in vivo using positron emission tomography

[11C]‐(+)‐PHNO (4‐propyl‐9‐hydroxynaphthoxazine) is a new agonist radioligand that provides a unique opportunity to measure the high‐affinity states of the D2 receptors (D2‐high) using positron emission tomography (PET). Here we report on the distribution, displaceablity, specificity and modeling of...

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Veröffentlicht in:	Journal of neurochemistry Jg. 97; H. 4; S. 1089 - 1103
Hauptverfasser:	Ginovart, Nathalie, Galineau, Laurent, Willeit, Matthaeus, Mizrahi, Romina, Bloomfield, Peter M., Seeman, Philip, Houle, Sylvain, Kapur, Shitij, Wilson, Alan A.
Format:	Journal Article
Sprache:	Englisch
Veröffentlicht:	Oxford, UK Blackwell Publishing Ltd 01.05.2006 Blackwell
Schlagworte:	Amphetamine - pharmacology Animals Binding sites Binding Sites - physiology Binding, Competitive - drug effects Binding, Competitive - physiology Biological and medical sciences Brain - diagnostic imaging Brain - metabolism Brain Chemistry - drug effects Brain Chemistry - physiology Carbon Radioisotopes - metabolism Cats Cell receptors Cell structures and functions Central nervous system Central neurotransmission. Neuromudulation. Pathways and receptors Comparative analysis Corpus Striatum - drug effects Corpus Striatum - metabolism D2 receptors dopamine Dopamine - metabolism Dopamine Agonists - metabolism Dopamine Agonists - pharmacokinetics Dopamine Antagonists - metabolism Dopamine Antagonists - pharmacokinetics Dose-Response Relationship, Drug d‐amphetamine Fundamental and applied biological sciences. Psychology Male Molecular and cellular biology Monoamines receptors (catecholamine, serotonine, histamine, acetylcholine) naphthoxazine derivatives Neurology Neurotransmitters Oxazines - metabolism Oxazines - pharmacokinetics Positron-Emission Tomography - methods Presynaptic Terminals - drug effects Presynaptic Terminals - metabolism raclopride Raclopride - metabolism Receptors, Dopamine D2 - drug effects Receptors, Dopamine D2 - metabolism Synaptic Transmission - drug effects Synaptic Transmission - physiology Tomography Vertebrates: nervous system and sense organs Central nervous system d-amphetamine Modeling Encephalon raclopride Specificity Endogenous D2 receptors Antagonist Fissipedia Carnivora Dopamine Basal ganglion Corpus striatum Catecholamine Uptake Vertebrata Sensitivity Mammalia D2 Dopamine receptor naphthoxazine derivatives Cat Neurotransmitter Positron Emission tomography
ISSN:	0022-3042, 1471-4159
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Zusammenfassung:	[11C]‐(+)‐PHNO (4‐propyl‐9‐hydroxynaphthoxazine) is a new agonist radioligand that provides a unique opportunity to measure the high‐affinity states of the D2 receptors (D2‐high) using positron emission tomography (PET). Here we report on the distribution, displaceablity, specificity and modeling of [11C]‐(+)‐PHNO and compare it with the well characterized antagonist D2 radioligand, [11C]raclopride, in cat. [11C]‐(+)‐PHNO displayed high uptake in striatum with a mean striatal binding potential (BP) of 3.95 ± 0.85. Pre‐treatment with specific D1 (SCH23390), D2 (raclopride, haloperidol) and D3 receptor (SB‐277011) antagonists indicated that [11C]‐(+)‐PHNO binding in striatum is specific to D2 receptors. Within‐subject comparisons showed that [11C]‐(+)‐PHNO BP in striatum was almost 2.5‐fold higher than that measured with [11C]‐(–)‐NPA ([11C]‐(–)‐N‐propyl‐norapomorphine). Comparison of the dose‐effect of amphetamine (0.1, 0.5 and 2 mg/kg; i.v.) showed that [11C]‐(+)‐PHNO was more sensitive to the dopamine releasing effect of amphetamine than [11C]raclopride. Amphetamine induced up to 83 ± 4% inhibition of [11C]‐(+)‐PHNO BP and only up to 56 ± 8% inhibition of [11C]raclopride BP. Scatchard analyses of [11C]‐(+)‐PHNO and [11C]raclopride bindings in two cats showed that the Bmax obtained with the agonist (29.6 and 32.9 pmol/mL) equalled that obtained with the antagonist (30.6 and 33.4 pmol/mL). The high penetration of [11C]‐(+)‐PHNO in brain, its high signal‐to‐noise ratio, its favorable in vivo kinetics and its high sensitivity to amphetamine shows that [11C]‐(+)‐PHNO has highly suitable characteristics for probing the D2‐high with PET.
Bibliographie:	SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 14
ISSN:	0022-3042 1471-4159
DOI:	10.1111/j.1471-4159.2006.03840.x