Quantitative PET analysis of the dopamine D2 receptor agonist radioligand 11C-(R)-2-CH3O-N-n-propylnorapomorphine in the human brain.
It has been demonstrated in vitro that the dopamine D(2) receptor has 2 interconvertible affinity states for endogenous dopamine, referred to as the high- and the low-affinity states. (11)C-(R)-2-CH(3)O-N-n-propylnorapomorphine ((11)C-MNPA) is a new agonist radioligand for in vivo imaging of the high-affinity state of dopamine D(2) receptors using PET. In the present study, the kinetics of (11)C-MNPA were examined for the first time, to our knowledge, in the human brain and analyzed using quantitative approaches with or without an arterial input function.


METHODS
A 90-min dynamic PET scan was obtained for 10 healthy men after an intravenous injection of (11)C-MNPA. The binding potential (BP(ND)) was calculated using the indirect kinetic method, a kinetic compartment analysis with a metabolite-corrected arterial input function. BP(ND) was also calculated by the simplified reference tissue model (SRTM) and transient equilibrium methods, both with the cerebellum as the reference brain region. The results of the quantitative methods were compared in a cross-validation approach.


RESULTS
The highest regional radioactivity was observed in the putamen. BP(ND) values obtained by kinetic analysis were 0.82 +/- 0.09, 0.59 +/- 0.11, and 0.28 +/- 0.06, respectively, in the putamen, caudate, and thalamus. BP(ND) values obtained by the SRTM and transient equilibrium methods were in good agreement with those obtained by the indirect kinetic method (r = 0.98 and r = 0.93, respectively). For all quantification methods, the BP(ND) values based on data acquired from 0 to 60 min were in good agreement with those based on data acquired from 0 to 90 min (r = 0.90-0.99).


CONCLUSIONS
The regional distribution of (11)C-MNPA binding was in good agreement with previous PET studies of dopamine D(2) receptors in the human brain using antagonist radioligands. The results support routine use of the SRTM and transient equilibrium methods, that is, methods that do not require an arterial input function and need a scan time of only about 60 min. (11)C-MNPA should thus be useful for clinical research on the pathophysiology of neuropsychiatric disorders and estimation of dopamine D(2) receptor occupancy by dopaminergic drugs.
Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan.
Tatsui
T
Otsuka
Hiroshi
H
Ito
Christer
C
Halldin
Hidehiko
H
Takahashi
Harumasa
H
Takano
Ryosuke
R
Arakawa
Masaki
M
Okumura
Fumitoshi
F
Kodaka
Michie
M
Miyoshi
Mizuho
M
Sekine
Chie
C
Seki
Ryuji
R
Nakao
Kazutoshi
K
Suzuki
Sjoerd
S
Finnema
Yoshio
Y
Hirayasu
Tetsuya
T
Suhara
Lars
L
Farde
D000328:Adult; D001058:Apomorphine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D001921:Brain / Q000000981:diagnostic imaging* / Q000378:metabolism*; D065127:Dopamine D2 Receptor Antagonists; D006801:Humans; D007090:Image Interpretation, Computer-Assisted / Q000379:methods; D008297:Male; D008657:Metabolic Clearance Rate; D049268:Positron-Emission Tomography / Q000379:methods; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics; D017448:Receptors, Dopamine D2 / Q000378:metabolism*; D014018:Tissue Distribution; D055815:Young Adult
D065127:Dopamine D2 Receptor Antagonists; D019275:Radiopharmaceuticals; D017448:Receptors, Dopamine D2; C009074:N-n-propylnorapomorphine; D001058:Apomorphine