PET measurement of D2 and S2 receptor binding of 3-N-([2?-18F]fluoroethyl)spiperone in baboon brain

Abstract

The regional pharmacokinetic behavior in baboon brain of ¹⁸F-fluoroethyl-and ¹⁸F-fluoropropylspiperone (¹⁸FESP, ¹⁸FPSP) at specific activities≥1000 Ci/mmol was studied with PET. Four hours after injection of 5–10 mCi ¹⁸FESP, uptake in striatum was 0.048%±0.005% of injected dose per cm³, which is almost the same as with ¹⁸F-and ¹¹C-methylspiperone. While ¹⁸FPSP was taken up in much smaller amounts than ¹⁸FESP, striatum to cerebellum activity ratios were quite similar for both ligands (about 9 to 10 at 4 h p.i.). Because of its higher striatal uptake, ¹⁸FESP seems to be better suited for PET. Furthermore, relative binding to S₂ receptors was much smaller for FESP: competing cold S₂ antagonists (ritanserin, ketanserin) did not alter ¹⁸FESP binding to striatum, concurrently reducing uptake in frontal cortex by only 15%–20%. With coninjection of increasing amounts of cold FESP, saturation of ¹⁸FESP binding to striatum occurred at doses exceeding 10 μg per kg. Quantitative analysis of radiolabelled ligand in arterial plasma (decrease to 8% at 4 h p.i.) demonstrated identical metabolic turnover for both ligands. Direct use of binding fractions from the saturation curve resulted in overestimation of the receptor density in striatum. Using the ¹⁸FESP plasma concentration time curve and the dynamic uptake data, k₃ of a three compartment model could be determined by non linear regression. However, dramatic changes of the dependence of k₃ on the specifically bound ligand concentration were observed even at small loading doses of FESP. Estimation of B_max yielded a D₂ receptor density of only 6 pmol per cm³ in baboon striatum.