Lena I, Ombetta J E, Chalon S, Dognon A M, Baulieu J L, Frangin Y, Garreau L, Besnard J C, Guilloteau D
Laboratoire de Biophysique Médicale et Pharmaceutique, INSERM U316, Tours-France.
Nucl Med Biol. 1995 Aug;22(6):727-36. doi: 10.1016/0969-8051(95)00019-t.
Monoamine oxidases are important in the regulation of monoaminergic neurotransmission. An increase in monoamine oxidase B (MAO B) has been observed in some neurodegenerative diseases, and therefore quantification of cerebral MAO B activity by SPECT would be useful for the diagnosis and therapeutic follow-up of these disorders. We have developed an iodinated derivative of pargyline, a selective inhibitor of MAO B, in order to explore this enzyme by SPECT. Stable bromo and iodo derivatives of pargyline were synthesized and chemically characterized. The radioiodinated ligand [125I]-2-iodopargyline was obtained with high specific activity from the bromo precursor by nucleophilic exchange. Affinity and selectivity of 2-iodopargyline were tested in vitro. Biodistribution study of [125I]-2-iodopargyline was performed in rats. Radioiodinated ligand were obtained in a no-carrier-added form. 2-iodopargyline has a higher in vitro affinity for MAO B than pargyline. However, the in vitro selectivity for MAO B was better for pargyline than for 2-iodopargyline. Ex vivo autoradiographic studies and in vivo saturation studies with selective inhibitors of MAO showed that the cerebral biodistribution of [125I]-2-iodopargyline in the rat is consistent with high level binding to MAO B sites in the pineal gland and in the thalamus. In conclusion, 2-iodopargyline preferentially binds in vivo to MAO B sites with high affinity. However, its selectivity for MAO B in rats is not very high, whereas this ligand binds to a lesser extent to MAO A. It will be then of great value to evaluate the specificity of 2-iodopargyline in humans. This new ligand labeled with 123I should therefore be a suitable tool for SPECT exploration of MAO B in the human brain.
单胺氧化酶在单胺能神经传递的调节中起着重要作用。在一些神经退行性疾病中已观察到单胺氧化酶B（MAO B）增加，因此通过SPECT定量脑MAO B活性对于这些疾病的诊断和治疗随访将是有用的。为了通过SPECT研究这种酶，我们开发了一种MAO B的选择性抑制剂——帕吉林的碘化衍生物。合成了帕吉林的稳定溴代和碘代衍生物并进行了化学表征。通过亲核交换从溴代前体中获得了具有高比活性的放射性碘标记配体[125I]-2-碘帕吉林。在体外测试了2-碘帕吉林的亲和力和选择性。在大鼠中进行了[125I]-2-碘帕吉林的生物分布研究。以无载体添加形式获得放射性碘标记配体。2-碘帕吉林在体外对MAO B的亲和力高于帕吉林。然而，帕吉林对MAO B的体外选择性优于2-碘帕吉林。用MAO选择性抑制剂进行的离体放射自显影研究和体内饱和研究表明，大鼠脑中[125I]-2-碘帕吉林的生物分布与松果体和丘脑中MAO B位点的高亲和力结合一致。总之，2-碘帕吉林在体内优先以高亲和力结合到MAO B位点。然而，其对大鼠MAO B的选择性不是很高，而这种配体与MAO A的结合程度较小。因此，评估2-碘帕吉林在人体中的特异性将具有重要价值。这种用123I标记的新配体因此应该是用于SPECT研究人脑中MAO B的合适工具。
