Effects of dopamine on the in vivo binding of dopamine D2 receptor radioligands in rat striatum

The effects of moderate changes in extracellular dopamine concentrations on the in vivo binding of specific dopaminergic D2 radioligands with different affinities and kinetics were investigated in rats. Either ( 125 I)NCQ298 (Kd 5 19 pM), or ( 125 I)iodolisuride (Kd 5 0.27 nM) or ( 3 H)raclopride (Kd 5 1.5 nM) were administered intravenously (IV) to animals 1 h after the intraperitoneal (IP) injection of either a-methyl-p-tyrosine (AMPT) (250 mg/kg) or nomifensine (15 mg/kg), or saline. The kinetics of radioactivity concentration in the striatum, cerebellum, and plasma were measured for up to 4 h after ( 125 I)NCQ298 or ( 125 I)iodolisuride injection and up to 1.5 h after ( 3 H)raclopride injection. For each tracer, the striatum-to- cerebellum radioactivity concentration ratios (S/C) and the binding potential (BP), calculated as the association to dissociation binding rate constant ratios (k3/k4), were assessed and related to the changes in extracellular dopamine concentration induced by drug treatments. Results show that S/C and BP of ( 3 H)raclopride were significantly diminished by pretreatment with nomifensine, a drug that increases extracellular dopamine concentration. Nomifensine pretreatment induced no changes in the in vivo binding indexes of the high affinity ( 125 I)NCQ298 and a slight but not significant decrease of the binding indexes of ( 125 I)iodolisuride. Treatment with AMPT, which induced a 40% reduction in dopamine concentration, did not change ( 125 I)NCQ298 binding indexes but slightly increased those of ( 3 H)raclopride and ( 125 I)iodoli- suride. In conclusion, the change of dopamine concentration induces modification of radiotracer kinetics. Thus, the combined use of tracers with high and low affinities could allow us to obtain information both on receptor density and neurotransmitter release in vivo. However, as indicated by the ( 3 H)raclopride study with AMPT, small changes in the concentration of intrasynaptic dopamine cannot be easily detected. NUCL MED BIOL 26;1:91-98, 1999. © 1998 Elsevier Science Inc.