title: Positron emission tomography quantification of [11C]-(+)-PHNO binding in the human brain.
abstract: The kinetic modeling of [11C]-(+)-PHNO binding to the dopamine D2/3 receptors in six human volunteers using positron emission tomography (PET) is described. [11C]-(+)-PHNO is the first agonist radioligand for the D2/3 in humans and as expected showed high uptake in caudate, putamen, globus pallidus (GP) and ventral striatum, and low uptake in cerebellum. A two-tissue compartment model (2CM) with four parameters was necessary to adequately fit time-activity data in all regions. Although a 2CM provided an excellent estimation of total distribution volumes, which were highly correlated with those obtained with the invasive Logan approach, it provided a poor identification of the k3/k4 ratios. Coupling K1/k2 between brain regions (Method C) or fixing K1/k2 to the value obtained in cerebellum (Method D) enabled more stable estimates of k3/k4 as compared with an unconstrained 2CM. The k3/k4 obtained with Method D ranged from 0.12+/-0.03 in cerebellum to 3.93+/-0.77 in GP and were similar to those obtained when coupling K1/k2. Binding potentials (BPs) obtained using the simplified reference tissue model (BP(SRTM)) ranged from 2.08+/-0.34 in caudate to 3.55+/-0.78 in GP and were highly correlated with k3/k4 estimates obtained with Method D (r=0.98). However, BP(SRTM) were 11%+/-5% lower than values obtained with Method D. BPs derived using the noninvasive Logan approach were slightly lower but not significantly different than BP(SRTM). This study demonstrates that [11C]-(+)-PHNO can be used for the quantitative measurement of D2/3 densities and should enable further studies of potential D2/3 dysregulation in several important psychiatric and neurologic illnesses.
authors.affiliation: The Vivian Rakoff Positron Emission Tomography Unit, Centre for Addiction and Mental Health, Toronto, Ontario, Canada. nathalie.ginovart@medecine.unige.ch
authors.forename: Nathalie
authors.initials: N
authors.lastname: Ginovart
authors.forename: Matthaeus
authors.initials: M
authors.lastname: Willeit
authors.forename: Pablo
authors.initials: P
authors.lastname: Rusjan
authors.forename: Ariel
authors.initials: A
authors.lastname: Graff
authors.forename: Peter M
authors.initials: PM
authors.lastname: Bloomfield
authors.forename: Sylvain
authors.initials: S
authors.lastname: Houle
authors.forename: Shitij
authors.initials: S
authors.lastname: Kapur
authors.forename: Alan A
authors.initials: AA
authors.lastname: Wilson
mesh_terms: D000328:Adult; D000465:Algorithms; D001711:Biotransformation; D001921:Brain / Q000000981:diagnostic imaging*; D002250:Carbon Radioisotopes; D002531:Cerebellum / Q000000981:diagnostic imaging; D003198:Computer Simulation; D005260:Female; D006801:Humans; D007091:Image Processing, Computer-Assisted; D007553:Isotope Labeling; D008297:Male; D008875:Middle Aged; D015233:Models, Statistical; D017711:Nonlinear Dynamics; D010078:Oxazines / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D049268:Positron-Emission Tomography; D019275:Radiopharmaceuticals / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D017448:Receptors, Dopamine D2 / Q000378:metabolism; D050637:Receptors, Dopamine D3 / Q000378:metabolism
chemical_list: D002250:Carbon Radioisotopes; D010078:Oxazines; D019275:Radiopharmaceuticals; D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3; C042631:naxagolide