In vitro and in vivo D2-dopamine receptor binding with [123I]S(-) iodobenzamide ([123I]IBZM) in rat and human brain.

As a promising dopamine D2-receptor imaging agent for single photon emission computerized tomography (SPECT), 123I-(-)-2-hydroxy-3-iodo-6-methoxy-N [(1-ethyl-2-pyrrolidinyl)methyl]benzamide ([123I]IBZM) has recently been synthesized in a modified way along with its precursor, S(-)BZM, and the stereoisomer R(+)BZM. The present study applied this new product to investigate in vitro and in vivo D2-receptor binding in rat brain and in postmortem human brain. In vitro saturation binding curves with [123I]IBZM for rat crude striatal membrane preparations yielded an affinity constant (Kd) of 0.28 nM confirming data in the literature. Displacement curves revealed an order of increasing potency as follows: R(+)BZM less than S(-)sulpiride = less than S(-)BZM less than S(-)IBZM. A similar order was obtained when [3H]spiperone was used as ligand. For human putamen and caudate nucleus membranes slightly higher Kd values (0.49 nM) were obtained. Rank order of displacing potency for the various drugs was similar to that found in the rat preparations. In vivo uptake of [123I]IBZM in rat brain following injection of 50 microCi (12-16 pmol) in the tail vein revealed an increase in the striatum-to-cerebellum ratio from 1.5 at 5 min to 6.9 at 2 h. The olfactory tubercle-to-cerebellum ratio was also raised from 1.6 to 3.3. Other brain regions tested failed to show statistically significant enhancements. Coinjection of 40 nmol S(-)IBZM, 4 mumol S(-)BZM or 200 nmol haloperidol displaced [123I]IBMZ when tested at 90 min. The use of 4 mumol R(+)BZM resulted in minor displacement only, demonstrating that stereospecificity of the displacement was present in vivo and in vitro. Displacements were also observed in substantia nigra and pons-medulla oblongata, but not in hippocampus or frontal and occipital cortex. The data provide the required background needed in order to initiate in vivo binding studies for D2-receptors in basal ganglia of human patients using [123I]IBZM in SPECT analyses.