High-affinity dopamine D2/D3 PET radioligands 18F-fallypride and 11C-FLB457: a comparison of kinetics in extrastriatal regions using a multiple-injection protocol

Abstract

(18)F-Fallypride and (11)C-FLB457 are commonly used PET radioligands for imaging extrastriatal dopamine D(2)/D(3) receptors, but differences in their in vivo kinetics may affect the sensitivity for measuring subtle changes in receptor binding. Focusing on regions of low binding, a direct comparison of the kinetics of (18)F-fallypride and (11)C-FLB457 was made using a MI protocol. Injection protocols were designed to estimate K(1), k(2), f(ND)k(on), B(max), and k(off) in the midbrain and cortical regions of the rhesus monkey. (11)C-FLB457 cleared from the arterial plasma faster and yielded a ND space distribution volume (K(1)/k(2)) that is three times higher than (18)F-fallypride, primarily due to a slower k(2) (FAL:FLB; k(2)=0.54 min(-1):0.18 min(-1)). The dissociation rate constant, k(off), was slower for (11)C-FLB457, resulting in a lower K(Dapp) than (18)F-fallypride (FAL:FLB; 0.39 nM:0.13 nM). Specific D(2)/D(3) binding could be detected in the cerebellum for (11)C-FLB457 but not (18)F-fallypride. Both radioligands can be used to image extrastriatal D(2)/D(3) receptors, with (11)C-FLB457 providing greater sensitivity to subtle changes in low-receptor-density cortical regions and (18)F-fallypride being more sensitive to endogenous dopamine displacement in medium-to-high-receptor-density regions. In the presence of specific D(2)/D(3) binding in the cerebellum, reference region analysis methods will give a greater bias in BP(ND) with (11)C-FLB457 than with (18)F-fallypride.

Figure 1

Model input function description and fitting results. (A) The model input function used in fitting the measured input functions. (B) Fraction of the injected dose, time shifted to t=0. Each curve represents the average of all injections of a particular study. The dotted lines are for fallypride, solid lines are for FLB457. (C) The measured input function radioactivity from the M1a fallypride study (circles) and the fit of measured data, as fit with three separate input functions (dotted lines) and the sum of the three input functions (solid line). The horizontal bar indicates the time period where no blood samples were drawn due to an obstructed arterial draw line. (D) Three input functions scaled by specific activity, shown in pmol/cc (M1a fallypride). (E, F) Same as in panels C and D, but for FLB457 (M1c).

Figure 2

Representative locations of ROIs over the six regions used for analysis. ROIs are shown on a single slice (¹⁸F-fallypride, 5 to 20 mins), but were drawn on multiple adjacent slices.

Figure 3

Representative time–activity curves and model estimations. (A) A summary of model estimation and measured data for the thalamus, SN, prefrontal cortex, and temporal cortex (in M1). (B) A summary of cerebellar data fits with both 1CM and 2CM models. The 1CM is represented by a dotted line and the 2CM is shown with a solid line. The measured data have been re-binned from a 30-secs frame duration into longer frame durations for illustrative purposes only.

Figure 4

Cerebellum-to-parent plasma ratios assuming a cerebellar D₂/D₃ receptor concentration of 0.1 nmol/L. (A) Simulated cerebellum/plasma curves using FLB457 measured plasma input function; (B) curves generated using measured ¹⁸F-fallypride plasma concentration. Both fallypride-like kinetics and FLB457-like kinetics are represented using each plasma input function. Variations in k_on from the tracer's true k_on value (±50%) are shown by dotted and dashed lines. The thick solid lines indicate the kinetics parameters of FLB457, with a FLB457 input function (A) and fallypride kinetic parameters and fallypride input (B).

Figure 5

Theoretical underestimation of BP_ND using reference region methods. The series of plots are the theoretical regions of the cortex (^*, B_max=0.5 nmol/L), thalamus (○, B_max=1.5 nmol/L), and SN ( × , B_max=3.0 nmol/L). Fallypride curves are black; FLB457 curves are gray.