Kinetic Analysis of the Metabotropic Glutamate Subtype 5 Tracer [¹⁸F]FPEB in Bolus and Bolus-Plus-Constant-Infusion Studies in Humans

Abstract

[ 18 F]FPEB is a positron emission tomography tracer which, in preclinical studies, has shown high specificity and selectivity toward the metabotropic glutamate receptor 5 (mGluR5). It possesses the potential to be used in human studies to evaluate mGluR5 function in a range of neuropsychiatric disorders, such as anxiety and Fragile X syndrome. To define optimal scan methodology, healthy human subjects were scanned for 6 hours following either a bolus injection (n ¼ 5) or bolus-plus-constant-infusion (n ¼ 5) of [ 18 F]FPEB. Arterial blood samples were collected and parent fraction measured by high-performance liquid chromatography (HPLC) to determine the metabolite-corrected plasma input function. Time activity curves were extracted from 13 regions and fitted by various models to estimate V T and BP ND . [ 18 F]FPEB was well fitted by the two-tissue compartment model, MA1 (t* ¼ 30), and MRTM (using cerebellum white matter as a reference). Highest V T values were observed in the anterior cingulate and caudate, and lowest V T values were observed in the cerebellum and pallidum. For kinetic modeling studies, V T and BP ND were estimated from bolus or bolus-plus-constant-infusion scans as short as 90 minutes. Bolus-plus-constant-infusion of [ 18 F]FPEB reduced intersubject variability in V T and allowed equilibrium analysis to be completed with a 30-minute scan, acquired 90-120 minutes after the start of injection.

Altered metabotropic glutamate receptor 5 markers in PTSD: In vivo and postmortem evidence

“…[ 18 F]FPEB was administered i.v. as bolus plus infusion for 120 min, with a K bol of 190 min (19,76). Based on previous studies showing that equilibrium was reached at 60 min, emission data were acquired 90-120 min after the start of injection on the high-resolution research tomograph (Siemens/CTI), which has intrinsic spatial resolution of ∼2.5 mm FWHM.…”

“…Given the lack of a reference region for mGluR5 targets (78), V T (ratio of radioligand concentration in ROI to the concentration in plasma at equilibrium) was used as the outcome measure. V T was estimated by the equilibrium analysis method described previously (76) and a venous plasma input function (19).…”

Radiation Dosimetry of18F-FPEB in Humans

“…To minimize the radiation dose received by human subjects, it is recommended that bladder voiding be done at 1 or 1.5 h after bolus administration of 18 F-FPEB, which significantly lowers both the urinary bladder wall and the effective doses. Previous studies indicate that 1.5 h of imaging after bolus injection of 18 F-FPEB should allow quantitation of mGluR5 levels in all brain regions; for such studies, urinary voiding at the end of the imaging study is recommended (14,15).…”

“…It has a high affinity (0.11-0.15 nM) for the mGluR5 and nearly optimal lipophilicity for imaging, with a logP of 2.8 (13). Initial human imaging studies have shown high contrast between regions rich in mGluR5 levels, such as the anterior cingulated, and regions with low levels, such as the cerebellum and pons, as well as the ability to estimate regional receptor levels using both bolus administration with 2-tissue-compartment modeling and bolus-infusion administration (14,15). Given the importance of the mGluR5 in several disease states and its promise as a PET radioligand for studies of mGluR5, we undertook studies of human radiation dosimetry of 18 F-FPEB.…”

Preclinical Evaluation and Quantification of 18F-FPEB as a Radioligand for PET Imaging of the Metabotropic Glutamate Receptor 5

“…The radioactivity concentration in each brain region was normalized to the injected dose and body weight and expressed as standardized uptake value. Receptor occupancy was calculated with the Michaelis-Menten equation (12), using the free fraction of 18 F-FPEB determined in humans (13).…”