title: Occupancy of dopamine D2/3 receptors in rat brain by endogenous dopamine measured with the agonist positron emission tomography radioligand [11C]MNPA.
abstract: Estimates of dopamine D(2/3) receptor occupancy by endogenous dopamine using positron emission tomography (PET) in animals have varied almost threefold. This variability may have been caused by incomplete depletion of dopamine or by the use of antagonist radioligands, which appear less sensitive than agonist radioligands to changes in endogenous dopamine. PET scans were performed in rats with the agonist PET radioligand [(11)C]MNPA ([O-methyl-(11)C]2-methoxy-N-propylnorapomorphine). [(11)C]MNPA was injected as a bolus plus constant infusion to achieve steady-state concentration in the body and equilibrium receptor binding in the brain. Radioligand binding was compared at baseline and after treatment with reserpine plus alpha-methyl-para-tyrosine, which cause approximately 95% depletion of endogenous dopamine. Depletion of dopamine increased radioligand binding in striatum but had little effect in cerebellum. Striatal [(11)C]MNPA binding potential was 0.93 +/- 0.12 at baseline and increased to 1.99 +/- 0.25 after dopamine depletion. Occupancy of D(2/3) receptors by endogenous dopamine at baseline was calculated to be approximately 53%. Striatal binding was displaceable with raclopride, but not with BP 897 (a selective D(3) compound), thus confirming the D(2) receptor specificity of [(11)C]MNPA binding. Radioactivity extracted from rat brain contained only 8-10% radiometabolites and was insignificantly altered by administration of reserpine plus alpha-methyl-para-tyrosine. Hence, dopamine depletion did not increase the PET measurements via an effect on radiotracer metabolism. Our in vivo estimate of dopamine's occupancy of D(2/3) receptors at baseline is higher than that previously reported using antagonist radioligands and PET, but is similar to that reported using agonist radioligands and ex vivo measurements.
authors.affiliation: Molecular Imaging Branch, National Institute of Mental Health, Bethesda, Maryland 20892-2035, USA. nicholasseneca@mail.nih.gov
authors.forename: Nicholas
authors.initials: N
authors.lastname: Seneca
authors.forename: Sami S
authors.initials: SS
authors.lastname: Zoghbi
authors.forename: Mette
authors.initials: M
authors.lastname: Skinbjerg
authors.forename: Jeih-San
authors.initials: JS
authors.lastname: Liow
authors.forename: Jinsoo
authors.initials: J
authors.lastname: Hong
authors.forename: David R
authors.initials: DR
authors.lastname: Sibley
authors.forename: Victor W
authors.initials: VW
authors.lastname: Pike
authors.forename: Christer
authors.initials: C
authors.lastname: Halldin
authors.forename: Robert B
authors.initials: RB
authors.lastname: Innis
mesh_terms: D000818:Animals; D001058:Apomorphine / Q000031:analogs & derivatives* / Q000378:metabolism; D001921:Brain / Q000000981:diagnostic imaging* / Q000187:drug effects / Q000378:metabolism*; D002250:Carbon Radioisotopes / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism* / Q000502:physiology; D018491:Dopamine Agonists / Q000378:metabolism* / Q000494:pharmacology; D008297:Male; D049268:Positron-Emission Tomography / Q000379:methods*; D011485:Protein Binding; D019275:Radiopharmaceuticals / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017448:Receptors, Dopamine D2 / Q000819:agonists / Q000378:metabolism*; D050637:Receptors, Dopamine D3 / Q000819:agonists / Q000378:metabolism*
chemical_list: D002250:Carbon Radioisotopes; D018491:Dopamine Agonists; D019275:Radiopharmaceuticals; D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3; C064292:2-methoxy-N-n-propylnorapomorphine; D001058:Apomorphine; D004298:Dopamine