Potentials and pitfalls using high affinity radioligands in PET and SPET determinations on regional drug induced D2 receptor occupancy - A simulationstudy based on experimental data

The D2 dopamine receptor density ranges from 0.2 to 40 nM among human brain regions. For high density regions radioligands like [C-11]raclopride provi de accurate and reliable estimates of the receptor density. Ir research, on neuropsychiatric disorders there is, how. ever, a growing need for quantit ative approaches that accurately measure D2 dopamine receptor occupancy ind uced by drugs or endogenous dopamine in regions with low receptor density. The new high affinity radio. ligands [C-11]FLB 457 and [I-123]epidepride ha ve beer shown to provide a signal for extrasriatal D2 dopa mine receptor po pulations in the human brain in vivo, Initial observations indicate, howeve r, that the time required to reach equilibrium is dependent on receptor den sity. Ratio analyses may thus not be readily used for comparisons among dif ferent brain regions, The aim of the present simulation study was to examin e commonly used approaches for calculation of drug induced D2 dopamine rece ptor occupancy among regions with widely different receptor density. The in . put functions and the rate constants of [C-11]FLB 457 and the reference l igand [C-11]raclopride were first used in a simulation estimating the effec t of receptor density on equilibrium time. In a second step we examined how errors produced by inaccurate determination of the binding potential param eter propagate to calculations of drug induced receptor occupancy. The simu lations showed a marked effect of receptor density on equilibrium time for [C-11]FLB 457, but not for [C-11]raclopride. For [C-11]FLB 457, a receptor den. silty above about 7 nM caused the time of equilibrium to fall beyond t ime of data acquisition (1 h). The use ol preequilibrium data caused the pe ak equilibrium and the end time ratio approaches but not the simplified ref erence tissue model (SRTM) approach to underestimate the binding potential and thus also the drug occupancy calculated for high-density regions. The s tudy supports the use of ratio and SRTM analyses in extrastriatal low-densi ty receptor regions for which the high affinity ligand [C-11]FLB 457 was de veloped, However, in high-density regions such as the human striatum simple ratio approaches cannot be validly applied, whereas the SRTM approach has higher potential to provide valid estimates. Interestingly, the results sug gest that published data on a proposed extrastriatal selectivity for the an tipsychotic drugs clozapine and olanzapine may be due to erroneous estimati ons of the binding potential when using ratio approaches. (C) 2001 Academic Press.