Development of novel radiopharmaceuticals for functional imaging of sigma receptors in human brain diseases.

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Sigma receptors have been the focus of intense study because of their potential to offer new insights into the mechanism of psychoses, movement disorders, and neurodegeneration. Recently, high densities of sigma receptors have been demonstrated in several tumor-derived cell lines. SPECT and PET radiopharmaceuticals specific for sigma receptors would be of great value as diagnostic tools for movement disorders and certain psychotic illness, and for non-invasive visualization of sigma receptor expressed tumors in vivo.In the present research, novel radioiodinated ligand [^<125>I]o-BON {1-(2-[^<125>I]iodophenyl-propyl)-4-(3,4-dimethoxyphenylethyl)piperazine} was designed based on structure-activity relationship, synthesized and characterized. [^<125>I]o-BON was found to possess very high affinity and selectivity for sigma receptors.Furthermore, we investigated brain distribution of [^<125>I]o-BON and compared it with cerebral blood flow (CBF) by using rat model of middle cerebral artery (MCA) occlusion and in vitro autoradiography technique. In the region of an infarct, accumulation of [^<125>I]o-BON decreased concurrently with CBF reduction. However, an increased accumulation of [^<125>I]o-BON relative to CBF was observed in ischemic but vital regions, especially in hippocampus CA1region. These data indicate that [^<125>I]o-BON may provide functional information based on sigma receptors different from CBF, and [^<125>I]o-BON is a potentially useful radiotracer for imaging and evaluating the pathophysiology of cerebral ischemia.