Kinetic analysis in healthy humans of a novel positron emission tomography radioligand to image the peripheral benzodiazepine receptor, a potential biomarker for inflammation - PubMed (original) (raw)

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

Masahiro Fujita et al. Neuroimage. 2008.

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 approximately 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.

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Figures

Fig. 1

Fig. 1

Time course of radioactivity and images of its distribution in brain after injection of [11C]PBR28. A) Concentrations (×) of radioactivity in thalamus of a typical healthy subject - namely, one who showed binding of the radioligand. The measured data were fitted with one- and two-tissue compartment models with no constraint. The two-tissue compartment model (formula image) more closely followed the measured values than did the one-compartment model (formula image). The constrained two-tissue compartment model with a fixed value of _K_1/_k_2 (not plotted) was visually indistinguishable from the unconstrained two-compartment model. B) The transverse PET image (right) of this typical healthy subject was created by averaging all frames and scaled using %SUV. The coregistered MRI (left) of this subject identifies that the PET image was obtained at the level of the thalamus. C) Concentrations of radioactivity in thalamus (×), caudate (▲), and parietal cortex (▽) in an atypical human subjects - i.e., one who appeared to have no binding of the radioligand. The one-compartment fitting (solid line) converged but with large deviations from the observed data, and two-compartmental fitting (not plotted) did not converge.

Fig. 1

Fig. 1

Time course of radioactivity and images of its distribution in brain after injection of [11C]PBR28. A) Concentrations (×) of radioactivity in thalamus of a typical healthy subject - namely, one who showed binding of the radioligand. The measured data were fitted with one- and two-tissue compartment models with no constraint. The two-tissue compartment model (formula image) more closely followed the measured values than did the one-compartment model (formula image). The constrained two-tissue compartment model with a fixed value of _K_1/_k_2 (not plotted) was visually indistinguishable from the unconstrained two-compartment model. B) The transverse PET image (right) of this typical healthy subject was created by averaging all frames and scaled using %SUV. The coregistered MRI (left) of this subject identifies that the PET image was obtained at the level of the thalamus. C) Concentrations of radioactivity in thalamus (×), caudate (▲), and parietal cortex (▽) in an atypical human subjects - i.e., one who appeared to have no binding of the radioligand. The one-compartment fitting (solid line) converged but with large deviations from the observed data, and two-compartmental fitting (not plotted) did not converge.

Fig. 1

Fig. 1

Time course of radioactivity and images of its distribution in brain after injection of [11C]PBR28. A) Concentrations (×) of radioactivity in thalamus of a typical healthy subject - namely, one who showed binding of the radioligand. The measured data were fitted with one- and two-tissue compartment models with no constraint. The two-tissue compartment model (formula image) more closely followed the measured values than did the one-compartment model (formula image). The constrained two-tissue compartment model with a fixed value of _K_1/_k_2 (not plotted) was visually indistinguishable from the unconstrained two-compartment model. B) The transverse PET image (right) of this typical healthy subject was created by averaging all frames and scaled using %SUV. The coregistered MRI (left) of this subject identifies that the PET image was obtained at the level of the thalamus. C) Concentrations of radioactivity in thalamus (×), caudate (▲), and parietal cortex (▽) in an atypical human subjects - i.e., one who appeared to have no binding of the radioligand. The one-compartment fitting (solid line) converged but with large deviations from the observed data, and two-compartmental fitting (not plotted) did not converge.

Fig. 2

Fig. 2

Concentration of radioactivity in plasma of the typical healthy subject shown in Fig. 1A and 1B. A) Concentrations are plotted for unchanged parent radioligand [11C]PBR28 (×), total radioactivity in blood (▲), and total radioactivity in plasma (▽). The time course of [11C]PBR28 was fitted to a tri-exponential curve (formula image). Radiochromatograms of activity extracted from plasma at 6 (B) and 40 (C) min after injection of [11C]PBR28. Peak 2 was confirmed to be [11C]PBR28 based on HPLC co-elution with nonradioactive PBR28. Peak 1 was a radiometabolite with lipophilicity lower than that of [11C]PBR28. D) The percentage composition of plasma radioactivity over time is shown for [11C]PBR28 (×) and the radiometabolite (●).

Fig. 2

Fig. 2

Concentration of radioactivity in plasma of the typical healthy subject shown in Fig. 1A and 1B. A) Concentrations are plotted for unchanged parent radioligand [11C]PBR28 (×), total radioactivity in blood (▲), and total radioactivity in plasma (▽). The time course of [11C]PBR28 was fitted to a tri-exponential curve (formula image). Radiochromatograms of activity extracted from plasma at 6 (B) and 40 (C) min after injection of [11C]PBR28. Peak 2 was confirmed to be [11C]PBR28 based on HPLC co-elution with nonradioactive PBR28. Peak 1 was a radiometabolite with lipophilicity lower than that of [11C]PBR28. D) The percentage composition of plasma radioactivity over time is shown for [11C]PBR28 (×) and the radiometabolite (●).

Fig. 2

Fig. 2

Concentration of radioactivity in plasma of the typical healthy subject shown in Fig. 1A and 1B. A) Concentrations are plotted for unchanged parent radioligand [11C]PBR28 (×), total radioactivity in blood (▲), and total radioactivity in plasma (▽). The time course of [11C]PBR28 was fitted to a tri-exponential curve (formula image). Radiochromatograms of activity extracted from plasma at 6 (B) and 40 (C) min after injection of [11C]PBR28. Peak 2 was confirmed to be [11C]PBR28 based on HPLC co-elution with nonradioactive PBR28. Peak 1 was a radiometabolite with lipophilicity lower than that of [11C]PBR28. D) The percentage composition of plasma radioactivity over time is shown for [11C]PBR28 (×) and the radiometabolite (●).

Fig. 3

Fig. 3

Value of distribution volume as a function of duration for image acquisition. _V_T was calculated for thalamus (×), caudate (▲), and parietal cortex (▽) using an unconstrained two-tissue compartment model. Scans were analyzed using brain data from time 0 to the specified time on _x_-axis. _V_T was expressed as a percentage of terminal value - _i.e., V_T calculated from the entire 120-min data set. Imaging for the initial 90 min provided _V_T within 10% (dashed line) of that obtained with the full length data.

Fig. 4

Fig. 4

Reproducibility of distribution volume estimation as a function of receptor density, as simulated by increasing the value of _k_3. Simulations were performed by using average rate constants obtained in thalamus (_K_1 = 0.12 mL • cm-3 · min-1, _k_2 = 0.11 min-1, _k_3 = 0.069 min-1, and _k_4 = 0.023 min-1) and average input function, and by increasing _k_3 up to 10 times of its baseline value. The increases caused poorer reproducibility (i.e., larger %COV), but the %COV was still less than 10% for a five-fold increase in _k_3.

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