Modeling [18 F]MPPF positron emission tomography kinetics for the determination of 5-hydroxytryptamine(1A) receptor concentration with multiinjection.
The selectivity of [18F]MPPF (fluorine-18-labeled 4-(2;-methoxyphenyl)-1-[2;-(N-2"-pirydynyl)-p-fluorobenzamido]ethylpiperazine) for serotonergic 5-hydroxytryptamine(1A) (5-HT1A) receptors has been established in animals and humans. The authors quantified the parameters of ligand-receptor exchanges using a double-injection protocol. After injection of a tracer and a coinjection dose of [18F]MPPF, dynamic positron emission tomography (PET) data were acquired during a 160-minute session in five healthy males. These PET and magnetic resonance imaging data were coregistered for anatomical identification. A three-compartment model was used to determine six parameters: Fv (vascular fraction), K1, k2 (plasma/free compartment exchange rate), koff, kon/Vr (association and dissociation rate), Bmax (receptor concentration), and to deduce Kd (apparent equilibrium dissociation rate). The model was fitted with regional PET kinetics and arterial input function corrected for metabolites. Analytical distribution volume and binding potential were compared with indices generated by Logan-Patlak graphical analysis. The 5HT1A specificity for MPPF was evidenced. A Bmax of 2.9 pmol/mL and a Kd of 2.8 nmol/L were found in hippocampal regions, Kd and distribution volume in the free compartment were regionally stable, and the Logan binding potential was linearly correlated to Bmax. This study confirms the value of MPPF in the investigation of normal and pathologic systems involving the limbic network and 5-HT1A receptors. Standard values can be used for the simulation of simplified protocols.
Costes
Nicolas
N
Centre d'Exploration et de Recherche Médicales par Emission de Positons, Lyon, France. costes@cermep.fr
Merlet
Isabelle
I
Zimmer
Luc
L
Lavenne
Franck
F
Cinotti
Luc
L
Delforge
Jacques
J
Luxen
André
A
Pujol
Jean-François
JF
Le Bars
Didier
D
D000328:Adult; D000631:Aminopyridines / Q000008:administration & dosage / Q000493:pharmacokinetics*; D001812:Blood-Brain Barrier; D001921:Brain / Q000098:blood supply / Q000000981:diagnostic imaging*; D001923:Brain Chemistry; D002536:Cerebral Arteries; D005462:Fluorine Radioisotopes; D006801:Humans; D007700:Kinetics; D008297:Male; D008954:Models, Biological; D010879:Piperazines / Q000008:administration & dosage / Q000493:pharmacokinetics*; D011485:Protein Binding; D011985:Receptors, Serotonin / Q000032:analysis / Q000378:metabolism*; D044263:Receptors, Serotonin, 5-HT1; D015203:Reproducibility of Results; D012702:Serotonin Antagonists / Q000008:administration & dosage / Q000493:pharmacokinetics*; D014055:Tomography, Emission-Computed / Q000379:methods* / Q000592:standards
D000631:Aminopyridines; D005462:Fluorine Radioisotopes; D010879:Piperazines; D011985:Receptors, Serotonin; D044263:Receptors, Serotonin, 5-HT1; D012702:Serotonin Antagonists; C099463:4-(2' methoxyphenyl)-1-(2'-(N-(2''-pyridinyl)-4-fluorobenzamido)ethyl)piperazine