Effect of reduction in endogenous dopamine on extrastriatal binding of [11C]FLB 457 in rat brain -: An ex vivo study

Carbon-11 labeled FLB 457 has been used successfully as a selective, high affinity PET ligand for the quantification of extrastriatal D-2-like receptors in man. This study was carried out in rats to investigate regional values for maximal binding and ED50 (a measure of apparent K-d) for the radioligand in vivo in control animals and in a group pretreated with the neuronal impulse flow inhibitor, gamma-butyrolactone. The aims were to obtain further information regarding the specific activity needed to ensure tracer kinetics and to investigate baseline occupancy by dopamine (DA), each relevant to optimal clinical use of the radioligand. Regional B-max values were consistent with the distribution of D-2-like receptors in rat brain. Of interest, 60% of the binding in cerebellum, often used as a low-binding "reference region" for PET quantification, was saturable, with B-max only 2- to 3-fold less than that in neocortex, hippocampus, and thalamus. ED50 values were in the range 2-3 nmol/kg, confirming minimal receptor occupancy by the tracer in human PET, using high but achievable specific activities. In the majority of extrastriatal tissues, reduction in synaptic DA did not significantly decrease the apparent Kd, except in cortical regions, where the extent of the effect suggested a low (similar to 10%), but measurable baseline receptor occupancy by DA.