Changes in apparent rates of receptor binding in the intact brain in relation to the heterogeneity of reaction environments

Neuroreceptor imaging by PET or SPECT has been widely applied in the field of neurobiology, from basic to clinical investigations, and has the potenti al to reveal the neurochemical basis of various neurological and psychiatri c diseases as well as to provide new knowledge in the field of neuropharmac ology. In contrast to the static nature of in vitro systems, neurotransmiss ion systems in the intact brain constitute part of a dynamic and communicat ing environment. Thus, it is important to develop new functional imaging me thods that reflect neural communications and the dynamism of signal transmi ssion in the living brain. In vivo receptor binding can be altered not only by competitive inhibition by endogenous neurotransmitters but by trans-syn aptic effects, and investigation of neural interactions by detection of cha nges in receptor binding therefore presents a potential method for studying this phenomenon. Recently, several PET studies on in vivo neural interacti ons using the D2 receptor ligand [C-11]-raclopride concluded that the pheno menon was mediated by changes in synaptic endogenous dopamine concentration s that compete with [C-11]-raclopride binding for neuroreceptor occupancy. However, a growing body of evidence indicates that these changes in in vivo receptor binding cannot be fully explained by competitive inhibition by en dogenous ligand, and alternative mechanisms for the interneuronal modulatio n of receptor binding are addressed. This review highlights some of the dis crepancies observed between in vitro and in vivo receptor binding studies w ith respect to a number of phenomena, including the heterogeneity of the re action field surrounding receptors. Quantitative receptor binding studies a re usually analyzed by using 'static' binding parameters, such as the B-max and K-D, which are normally determined by in vitro assays. In addition to these parameters, the apparent association and dissociation rate constants (kon, koff) play equally significant roles in receptor binding in the intac t brain is expected. The concepts of "diffusion boundary" and "reaction vol ume" are introduced, and discussions on some of the discrepancies between i n vivo and in vitro receptor binding phenomena are presented.