Evaluation of N-Alkyl Derivatives of Radioiodinated Spiperone as Radioligands for in Vivo Dopamine D₂ Receptor Studies : Effects of Lipophilicity and Receptor Affinity on the in Vivo Biodistribution

抄録

A series of radioiodinated spiperone (2'-ISP) derivatives bearing amide N-alkyl substituents (N-methyl-2'-ISP, N-ethyl-2'-ISP, and N-propyl-2'-ISP) were synthesized and evaluated as potential singlet photon emission computed tomographic radiopharmaceuticals for visualizing dopaminergic receptors. The lipophilicity of these ligands (i.e., the partition coefficient for octanol-phosphate buffer) increased as the chain length increased. Investigation of blood-brain barrier permeability in rats showed a parabolic relationship between the brain uptake index and the partition coefficient.In vitro competitive binding studies showed that the relative affinity for the dopamine D₂ receptor was in te order of N-propyl-2'-ISP>2'-ISP>N-methyl-2'-ISP≈N-ethyl-2'-ISP. In vivo biodistribution studies showed that the initial brain uptake correlated fairly well with the brain uptake index and that the kinetics of the radioactivity specifically bound to the striatum were strongly influenced by the dopamine receptor binding affinity of the compounds. Thus, the in vivo behavior of these N-alkylated 2'-ISP derivatives involved a complex interplay between receptor affinity, lipophilicity, and blood-brain barrier permeability.