benzofurans and 2--iodospiperone

The regional brain distribution and pharmacological specificity of three high affinity tracers for the dopamine (DA) D2 receptor: [123I]IBF, [123I]epidepride, and [123I]2'-ISP were assessed by SPECT imaging of non-human primates. The ratios of striatal-to-occipital activities at the time of peak striatal uptake were 2.2, 6.3 and 1.7, respectively. From the peak striatal activities, washout rates were 33, 4 and 16%/h for [123I]IBF, [123I]epidepride and [123I]2'-ISP, respectively. The reversibility of the striatal uptake of all three agents was demonstrated by the rapid displacement induced by the dopamine D2 selective antipsychotic agent raclopride, which increased washout rates to 96, 58 and 43%/h. The administration of d-amphetamine, which induces release of dopamine, had no noticeable effect on [123I]epidepride but increased the washout rate of [123I]IBF. These results suggest that, among these three agents, [123I]epidepride is the superior tracer for in vivo displacement studies because of its slow washout and high target-to-background ratios. However, for tracer kinetic modeling, [123I]IBF may be the superior agent because of its early time of peak uptake and its higher target-to-background ratios than [123I]2'-ISP.

Topics: Animals; Benzamides; Benzofurans; Brain; Contrast Media; Dextroamphetamine; Dopamine Agents; Female; Iodine Radioisotopes; Papio; Pyrrolidines; Raclopride; Receptors, Dopamine D2; Ritanserin; Salicylamides; Serotonin Antagonists; Spiperone; Tissue Distribution; Tomography, Emission-Computed, Single-Photon

The pharmacokinetics of three radioiodinated high affinity dopamine D2 receptor binding ligands-two benzamide neuroleptics (IBF and epidepride) and the butyrophenone neuroleptic analog 2'-iodospiperone (2'-ISP)-were measured in nonhuman primates. [123I]IBF and [123I]epidepride were prepared by iododestannylation of the corresponding tributylstannyl derivative, whereas [123I]2'-ISP was labeled by (NH4)2SO4 mediated iodide for bromide exchange starting from 2'-bromospiperone. Labeled products were purified by HPLC and were obtained in > 93% radiochemical purity and > 7000 Ci/mmol sp. act. After i.v. injection in baboons, serial arterial plasma samples were extracted with ethyl acetate (IBF and epidepride) or denatured with methanol (2'-ISP) and analyzed by HPLC. For IBF, plasma levels of parent compound dropped to 50% of the plasma activity within 20 min post injection and the major radiometabolite was lipophilic. For epidepride, it took 30-40 min for parent content to reach 50% and the major radiometabolite was polar. For 2'-ISP, parent composition dropped to 60% after about 15 min. Arterial input curves for IBF and epidepride fit three-exponential models with terminal half-life of 54-76 and 50-59 min, respectively. Whole body images were acquired using the conjugate counting method. The distribution of all three agents was qualitatively similar, with major excretion through the hepatobiliary route. Peak whole brain uptake, observed within 20 min for all three tracers, was estimated as 7% injected dose for [123I]IBF, 8% for [123I]epidepride and 5% for [123I]2'-ISP.

Topics: Animals; Antipsychotic Agents; Autoradiography; Benzamides; Benzofurans; Brain; Chlorocebus aethiops; Chromatography, High Pressure Liquid; Female; Iodine Radioisotopes; Male; Papio; Pyrrolidines; Receptors, Dopamine D2; Spiperone; Tissue Distribution