Quantification of nicotinic acetylcholine receptors in the human brain with PET: bolus plus infusion administration of 2-[18F]F-A85380

Abstract

Quantitative analysis of most positron emission tomography (PET) data requires arterial blood sampling and dynamic scanning when the radioligand is administered as a bolus injection. Less invasive studies can be accomplished if the radioligand is administered as a bolus plus constant infusion (B/I). The purpose of the current study was to evaluate a B/I paradigm for quantifying high affinity nicotinic acetylcholine receptors (nAChRs) with PET and 2-[(18)F]F-A85380 (2FA). Seven volunteers underwent a study in which 2FA was administered as a bolus injection and another study in which the 2FA was administered by B/I (Kbolus=500 min). We evaluated the feasibility of using scans of a 2 h duration starting 6 h after the start of the 2FA administration and data from venous blood. Radioactivity in the brain and in arterial and venous plasma reached steady state by 6 h. Volumes of distribution (V(T)) calculated from the ratio of radioactivity in the brain areas of interest to the radioactivity corresponding to unbound, unmetabolized 2FA in venous plasma at steady state in the B/I studies were very similar to those calculated from time activity curves of unbound, unmetabolized 2FA in arterial plasma and regional brain radioactivity from 8-h dynamic scans after bolus administration of 2FA. The results of repeated PET studies with 2FA showed a high reproducibility of V(T) measurements. We conclude that B/I methodology will be useful for clinical and research studies of brain nAChRs.

Figure 1

Panel A Time activity curves (TACs) from bolus study of a representative volunteer. Panel B Predicted TACs (dashed lines) for B/I study if Kbolus = 500 min. Panel C TACs from the B/I study on the same volunteer. Curves are provided for thalamus (blue), pons (yellow), midbrain (pink), cerebellum (aqua), frontal cortex (brown), putamen (green), corpus callosum (gray), and radioactivity corresponding to unmetabolized 2FA in blood plasma (red). Radioactivity values are given as standard uptake values (SUV).

Figure 2

Time course of arterial and venous plasma radioactivity during B/I studies (data are given as mean ± SEM, n = 5). (A) Radioactivity corresponding to unmetabolized 2FA expressed as a percent of total plasma radioactivity (open squares = arterial plasma, filled squares = venous plasma). The insert shows the unmetabolized 2FA in arterial (white bars) and venous plasma (black bars) at 6.5 h after start of 2FA injection, expressed as a percent of total plasma radioactivity for each of five participants (#1, #2, #3, #4 and #5). Values given are the average of the last seven blood samples collected (5–8 h after the start of 2FA administration). (B) Total arterial (open circles) and venous (filled circles) plasma radioactivity along with radioactivity corresponding to unbound unmetabolized 2FA in arterial (open squares) and venous (filled squares) plasma, expressed as standard uptake values (SUV) from the same five B/I studies shown in Figure 2A. The insert shows the average concentration of unbound unmetabolized 2FA in arterial (white bars) and venous (black bars) plasma expressed as SUV for each of five participants (#1, #2, #3, #4 and #5). Values given are the average of the last 7 blood draws (5–8 h after the start of 2FA administration).

Figure 3

Comparison of plasma radioactivity after bolus and B/I administration of 2FA (mean ± SEM, n = 7). Time course of total radioactivity (circles) and radioactivity corresponding to unbound unmetabolized 2FA (squares) in B/I study (venous plasma, open symbols) and bolus study (arterial plasma, filled symbols).

Figure 4

Radioactivity in various brain regions given as mean ± SEM of standard uptake values (SUV) obtained from 6 to 8 h after the start of 2FA administration. White bars and black bars represent data from the bolus studies (n = 7) and from the B/I studies (same n=7), respectively. Abbreviations: CC – corpus callosum, frcx – frontal cortex, cb - cerebellum, midbr – midbrain, pons – pons, put- putamen and th – thalamus, pl tot – total radioactivity in arterial (bolus study) or venous plasma (B/I study), 2FA free – unbound, unmetabolized 2FA in arterial (bolus study) and venous plasma (B/I study).

Figure 5

Time required for plasma or tissue radioactivity to reach steady state. Values are expressed as percent of average of values obtained from 7–8 h after the start of the B/I administration of 2FA Data are given as mean ± SEM for n = 7.

Figure 6

Comparison of the total volume of distribution (V_T, mean ± SEM) in various brain regions. Data were acquired from seven volunteers in a B/I study and the same volunteers in a bolus study. V_T from the bolus administration studies were calculated by the one tissue compartment model (white bars), two tissue compartment model (diagonally striped bars), and Logan graphical analysis (horizontally striped bars), all using the arterial input function. V_T from the B/I studies (black bars) were calculated as a ratio of radioactivity in each brain region at steady state to the radioactivity corresponding to unbound, unmetabolized 2FA in venous plasma at steady state. The abbreviations are as in Fig.4. See Table 1 for comparisons of data from B/I study and bolus study for each participant..

Figure 7

Images from a representative volunteer (nonsmoker). Top panel – MRI scans, Middle panel - parametric maps of total volumes of distribution (V_T) from the bolus plus infusion study (B/I) using 2FA concentrations from venous plasma, Bottom panel – fused MRI and V_T images.

Figure 8

Average parametric maps (n = 7) of total volume of distribution (V_T) obtained by different methods. Average parametric maps in each row are shown in axial, saggital and coronal planes (from left to right) at the level of the thalamus. From top to bottom: bolus/infusion study (B/I), bolus study using classic Logan analysis, bolus study using MA1 analysis, difference between the B/I map and classic Logan analysis map of bolus study and between the B/I map and the MA1 analysis map of the bolus study. The insert provides the mean (± SEM, n = 7) V_T values for the entire brain for the B/I study, the bolus study with Logan analysis and the bolus study with Ichise analysis. Note that the scale for the difference maps is expanded.

Figure 9

Scatter plots comparing values for V_T from each voxel from averaged images (see Figure 8). (A) Averaged parametric maps from bolus plus constant infusion study (B/I) vs. averaged parametric maps from bolus study with classic Logan analysis (Logan). The slope of the line is 0.93. (B) Averaged parametric maps from bolus study with MA1 (Ichise) analysis. The slope of the line is 1.01