Kinetic modeling of [99mTc]TRODAT-1: a dopamine transporter imaging agent

[99mTc]Technetium[2-[[2-[[[3-(4-chlorophenyl)-8-methyl-8-azabicyclo [3.2.1] oct-2-yl]-methyl] (2-mercaptoethyl) amino] ethyl] amino] ethane-thiolato(3-)-N2,N2',S2,S2']oxo-[1R-(exo-exo)] ([99mTc] TRODAT-1) is a useful imaging agent for central nervous system dopamine transporters. The purpose of this study was to characterize the in vivo binding potential and kinetic rate constants of this agent in nonhuman primates.

A series of four SPECT scans were performed on each of two female baboons with a bolus injection of [99mTc]TRODAT-1 (717+/-78 MBq; 19.38+/-2.12 mCi). Dynamic images of the brain were acquired over 4 h using a triple-head camera equipped with fan-beam collimators. Arterial and venous blood were sampled frequently using a peristaltic pump throughout the duration of the study. Regions of interest were drawn on the corresponding MRI scan to which each functional image was coregistered. Using analytical solutions to the three-compartment model with the Levenberg-Marquardt minimization technique, each study was individually fitted to a kinetic parameter vector (method I). Additionally, within each subject, three corresponding intrasubject studies were fitted simultaneously to a single parameter vector by constraining the binding potential, distribution volume and dissociation rate constant to improve the identifiability of the parameter estimates (method II).

The results clearly indicated that [99mTc] TRODAT-1 localized in the striatum with slower washout rate than other brain regions. A maximal target/nontarget ratio of 3.5 between striatum and cerebellum was obtained. SPECT image analysis of the striatum yielded unconstrained k3/k4 values of 3.4+/-1.4, 2.4+/-0.7, 3.0+/-1.5, and 4.0+/-10.3, with respective constrained (fixed k4) values of 2.9 +/- 0.4, 2.4 +/- 0.4, 1.7+/-0.4 and 1.8+/-0.4 in one baboon using method I. With method II, the corresponding simultaneously fitted values were 2.1+/-0.3 using no constraints and 2.2+/-0.2 using a fixed k4. The second baboon had similar results.

These findings suggest that the binding potential and corresponding kinetic rate constants can be reliably estimated in nonhuman primates with dynamic SPECT imaging of the dopamine transporter using a technetium-based tropane analogue. Furthermore, method II parameter vectors compare favorably to those produced using method I based on SEEs.