Kinetic analysis in healthy humans of a novel positron emission tomography radioligand to image the peripheral benzodiazepine receptor, a potential biomarker for inflammation

Abstract

The peripheral benzodiazepine receptor (PBR) is upregulated on activated microglia and macrophages and thereby is a useful biomarker of inflammation. We developed a novel PET radioligand, [ 11 C]PBR28, that was able to image and quantify PBRs in healthy monkeys and in a rat model of stroke. The objective of this study was to evaluate the ability of [ 11 C]PBR28 to quantify PBRs in brain of healthy human subjects. Twelve subjects had PET scans of 120 to 180 min duration as well as serial sampling of arterial plasma to measure the concentration of unchanged parent radioligand. One-and two-tissue compartmental analyses were performed. To obtain stable estimates of distribution volume, which is a summation of B max /K D and nondisplaceable activity, 90 min of brain imaging was required. Distribution volumes in human were only ∼5% of those in monkey. This comparatively low amount of receptor binding required a two-rather than a one-compartment model, suggesting that nonspecific binding was a sizeable percentage compared to specific binding. The time-activity curves in two of the twelve subjects appeared as if they had no PBR binding -i.e., rapid peak of uptake and fast washout from brain. The cause(s) of these unusual findings are unknown, but both subjects were also found to lack binding to PBRs in peripheral organs such as lung and kidney. In conclusion, with the exception of those subjects who appeared to have no PBR binding, [ 11 C]PBR28 is a promising ligand to quantify PBRs and localize inflammation associated with increased densities of PBRs.

Determination of [11C]PBR28 Binding Potential in vivo: A First Human TSPO Blocking Study

“…19 For each ROI examined, the V T was estimated from the rate constants as described previously. 20 Model fitting and parameter estimation was performed using software implemented in Matlab R2008b (The MathWorks, Natick, MA, USA).…”

Kinetic Modeling without Accounting for the Vascular Component Impairs the Quantification of [11C]PBR28 Brain PET Data

“…The threshold corresponds to the average value plus three times the standard deviation reported in the literature for [ 11 C]PBR28 data. 22 In addition, we discarded V T values with a CV higher than 50% in order to eliminate unreliable estimates. The statistical difference of the estimated V T values obtained with 2CTM and 2TCM-1K was assessed by using a one-sample t-test (Po0.05).…”

Translocator Protein (18 kDa) Polymorphism (rs6971) Explains in-vivo Brain Binding Affinity of the PET Radioligand [18F]-FEPPA

“…The deficiencies of [ 11 C]-PK11195 coupled with the recognized importance of TSPO imaging have fueled considerable efforts to develop radiotracers with greater sensitivity to detect TSPO binding (James et al, 2006;Okubo et al, 2004). While [ 11 C]-PBR28 (Fujita et al, 2008) and [ 11 C]-DPA713 (Boutin et al, 2007) circumvent many of the deficiencies of [ 11 C]-PK11195, both are radiolabeled with the short-lived carbon-11, rendering unsuitable for wide-spread dissemination. The advantages of fluorine-18-labeled radiotracer are several; improved targetry means that [ 18 F]-fluoride can now be produced by low/medium energy cyclotrons in large quantities, the imaging quality of this radionuclide are superior to carbon-11, and most importantly the longer half-life (t 1/2 E 109 minutes), allows shipment to imaging sites distant from the site of production, which is particularly useful for clinical applications.…”