IN-VIVO IMAGING OF NEUROMODULATION USING POSITRON EMISSION TOMOGRAPHY- OPTIMAL LIGAND CHARACTERISTICS AND TASK LENGTH FOR DETECTION OF ACTIVATION

Considerable evidence suggests that cognitive state affects local leve ls of neurotransmitter in the brain. We introduce a compartment model of neuroreceptor ligand kinetics to describe the effect of change in c ognitive state on positron emission tomography (PET) signal dynamics. The model is used to establish optimal experimental conditions, timing of activation, and ligand characteristics, for detecting cognitive ac tivation. The model, which follows free and bound endogenous neurotran smitter, describes the PET curve predicted for a single injection of r adioligand in the presence or absence of activation. Activation was co nceptualized as the performance of a task that raises the level of neu rotransmitter that competes for receptor sites with the radioligand. S imulating the dopamine system, for example, required making assumption s regarding the kinetic rate constants for binding/dissociation of end ogenous dopamine to/from the receptor and dopamine concentrations in t he synapse. Simulations suggest that activation of dopamine should be detectable with PET and the D2 receptor ligand [C-11]raclopride, altho ugh this ligand might not be optimal. Aspects of experimental design c an be modified to optimize the likelihood of detecting neurotransmitte r changes. The ideal radioligand for these studies should bind irrever sibly to its receptor. Furthermore, the task should commence at inject ion time and last for at least 7 minutes. Optimal task duration depend s on the dynamics of free radioligand in the tissue and can be determi ned via model simulations for any well-characterized receptor ligand. Flow effects were shown to be distinguishable from those of neurotrans mitter activation. General principles regarding desirable ligand chara cteristics and activation timing held for both the D2 receptor and the dopamine transporter site. (C) 1995 Wiley-Liss, Inc.