Measuring the in Vivo Binding Parameters of [¹⁸F]-Fallypride in Monkeys Using a PET Multiple-Injection Protocol

Abstract

The goal of this work was to quantify the in vivo transport and binding parameters of [F-18]fallypride and the D2/D3 receptor density (B'max) in both the striatal (putamen, caudate, ventral striatum) and extrastriatal regions (thalamus, amygdala, cerebellum, temporal and frontal cortices) of the rhesus monkey brain. Multiple-injection PET experimental protocols with injections of radiolabeled and unlabeled doses of fallypride were used to estimate the K1, k2, kon/VR, koff and B'max kinetic parameters. The experimental design was chosen using the D-optimal criterion to maximize the precision of the estimated binding parameters for the various brain regions. There was a significant range in B'max for the putamen (27 pmol/mL), caudate (23 pmol/mL), ventral striatum (14 pmol/mL), thalamus (1.8 pmol/mL) and amygdala (0.9 pmol/mL). Significant receptor binding was also found in the cortical regions. Knowledge of these in vivo rate constants serves as a necessary step in using [F-18]fallypride PET to measure D2/D3 receptor density and drug occupancy in clinical research applications. We believe the precise parameter estimates derived from these complicated experimental protocols are necessary for proper application of drug occupancy and clinical research studies with [F-18]fallypride, which often rely on the validity of assumptions regarding the model parameters.

Measurement of 5-HT1A Receptor Density and in-vivo Binding Parameters of [18F]mefway in the Nonhuman Primate

“…C pi represents the molar concentration of mefway in the plasma (pmol/mL) and serves as the input function. For studies with multiple injections, B and F compartments are created for each injection (i) (Delforge et al, 1990;Muzic et al, 2000;Christian et al, 2004;Morris et al, 2004), as described by the differential equations:…”

“…The M-I method provides a measure of receptor density that is independent of the characteristics of the radioligand, unlike the 'binding potential' metric obtained with tracer-only PET studies, which represent a composite function of B max and ligand-receptor affinity (Innis et al, 2007). The M-I methods have also been used for the measurement of B max in the peripheral benzodiazepine (Delforge et al, 1996), badrenergic (Muzic et al, 2000;Salinas et al, 2007), dopamine transporter (Morris et al, 1996;Poyot et al, 2001), dopamine D2 (Delforge et al, 1999;Christian et al, 2004;Mauger et al, 2005;Vandehey et al, 2010), and nicotinic acetylcholine (Gallezot et al, 2008) receptor systems.…”

Amphetamine-Induced Displacement of [18F] Fallypride in Striatum and Extrastriatal Regions in Humans

“…The striatal uptakes of [ Olsson et al, 1999;Fujita et al, 1999), making estimation of striatal DA D 2 /D 3 receptor levels difficult. [ 18 F]fallypride is a benzamide with very high-affinity for DA D 2 /D 3 receptors, which has been used to visualize and quantify levels of striatal and extrastriatal DA D 2 /D 3 receptors using positron emission tomography (PET) (Mukherjee et al, 1999Rieck et al, 2004 (Mukherjee et al, 1997;Kessler et al, 1991;Olsson et al, 1999Olsson et al, , 2004Christian et al, 2004).…”

Measuring α4β2∗Nicotinic Acetylcholine Receptor Densityin Vivowith [18F]nifene PET in the Nonhuman Primate

“…A similar approach was used in experiments estimating extrastriatal D2 B max by fixing k off to the value observed in the basal ganglia. 27 Assuming a global K Dapp represents a limitation in the present results, as our group has previously shown regional K Dapp variations in experiments examining the serotonin system with MI techniques. 28 29 ), both radioligands exhibit low lipophilicity, which predicts slow diffusion rates across the BBB.…”