SYNTHESIS AND TISSUE DISTRIBUTION OF (M-[I-125]IODOBENZYL)TROZAMICOL ([I-125]MIBT) - POTENTIAL RADIOLIGAND FOR MAPPING CENTRAL CHOLINERGIC INNERVATION

Racemic (m-iodobenzyl)trozamicol (6, MIBT), a high-affinity vesamicol receptor ligand, was radiolabeled, resolved, and evaluated in rats. Fo llowing iv injection, (+)- and (-)-[I-125]MIBT achieved initial brain levels of 0.57 and 0.92% dose/g of tissue, respectively. The level of (+)-[I-125]MIBT subsequently declined by 74% Within 3 h, while that of (-)-[I-125]MIBT remained stable for the duration. Ex vivo autoradiogr aphic mapping of (-)-[I-125]MIBT distribution in rat brain revealed a pattern which was inconsistent with central cholinergic innervation. H owever, high levels of (+)-[125I]MIBT were observed over the amygdala, striatum, nucleus accumbens, olfactory tubercle, and nuclei of the fi fth and seventh cranial nerves, while moderate to low levels were dete cted within the cortex, hippocampus, and cerebellum. Thus, the distrib ution of (+)-[I-125]MIBT parallels that of other presynaptic cholinerg ic markers. Co-injection of(+)-[1251]MIBT with 4-aminobenzovesamicol ( 2b), a potent vesamicol receptor ligand, reduced the levels of radiotr acer in the striatum, cortex, and cerebellum by 58, 35; and 9%, respec tively. Thus, (+)-[125I]MIBT binds to vesamicol receptors in vivo. In contrast, coadministration of (+)-[I-125]MIBT with haloperidol (0.5 mu mol/kg), reduced radiotracer levels in the cortex and cerebellum by 34 and 59 %, respectively, while increasing the levels in the striatum b y 32%. We conclude that although the distribution of (+)-[125I]MIBT qu alitatively reflects cholinergic innervation, a fraction of radiotrace r in the cortex and cerebellum is bound to a receptors.