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In Vivo Measurement of D₂ Receptor Density and Affinity for ¹⁸F-(3-N-Methyl)Benperidol in the Rat Striatum with a PET System for Small Laboratory Animals

¹ Nuklearmedizinische Klinik, Universitätsklinikum Düsseldorf, Düsseldorf, Germany
² Institut für Nuklearchemie, Forschungszentrum Jülich GmbH, Jülich, Germany

A recent investigation showed that intracerebral radioactivity concentrations can reliably be quantified in vivo with a small-animal PET device. The purpose of the current study was to investigate the binding characteristics of the D₂ receptor radioligand ¹⁸F-(3-N-methyl)benperidol (¹⁸FMB) in rat striatum by determining receptor density (B_max) and affinity (K_d) in vivo. For validation, K_d and B_max additionally were determined in vitro using storage phosphor autoradiography. Methods: Striatal radioactivity was measured with PET in 8 Sprague-Dawley rats after injection of ¹⁸FMB in increasing specific activities. Free radioligand concentrations were estimated from cortical radioactivity concentrations and were subtracted from striatal radioactivity concentrations to obtain specific binding. In vitro saturation experiments were performed on 7 further rats according to the isotopic dilution method. Specific binding was determined by both subtraction of ¹⁸FMB binding in the presence of raclopride and subtraction of cortical radioactivity concentrations from total radioligand binding. Saturation binding curves were obtained by plotting specifically bound radioligand concentrations against free radioligand concentrations and were evaluated with regression analysis. Results: PET yielded a K_d of 6.2 nmol/L and a B_max of 16 fmol/mg for the striatal D₂ receptor. In vitro, K_d and B_max amounted to 4.4 nmol/L and 84.1 fmol/mg (subtraction of ¹⁸FMB binding in the presence of raclopride), respectively, and 7.9 nmol/L and 70.1 fmol/mg (subtraction of cortical radioactivity concentrations), respectively. Conclusion: K_d values measured with PET and autoradiography agreed and corresponded to inhibition constants obtained in previous in vitro studies. B_max values lay within the same order of magnitude. The results of in vitro saturation binding analyses also agreed, irrespective of the mode of determination of free radioligand concentrations. Thus, B_max and K_d may be determined with PET in analogy to the evaluation of in vitro binding data by regression analysis of bound-versus-free ligand concentrations. Our results show that small-animal tomographs are valuable tools for the in vivo characterization of receptor radioligands as an alternative to autoradiography.

Key Words: ¹⁸F-(3-N-methyl)benperidol • dopamine D₂ receptors • animal PET • autoradiography • saturation binding analysis