Synthesis and tissue distribution of iodine-125-labeled (m-[125I]iodobenzyl)trozamicol ([125I]MIBT): potential radioligand for mapping central cholinergic innervation

Abstract

Racemic (m-iodobenzyl)trozamicol (6, MIBT), a high-affinity vesamicol receptor ligand, was radiolabeled, resolved, and evaluated in rats. Following iv injection, (+)- and (-)-[125I]MIBT achieved initial brain levels of 0.57 and 0.92% dose/g of tissue, respectively. The level of (+)-[125I]MIBT subsequently declined by 74% within 3 h, while that of (-)-[125I]MIBT remained stable for the duration. Ex vivo autoradiographic mapping of (-)-[125I]MIBT distribution in rat brain revealed a pattern which was inconsistent with central cholinergic innervation. However, high levels of (+)-[125I]MIBT were observed over the amygdala, striatum, nucleus accumbens, olfactory tubercle, and nuclei of the fifth and seventh cranial nerves, while moderate to low levels were detected within the cortex, hippocampus, and cerebellum. Thus, the distribution of (+)-[125I]MIBT parallels that of other presynaptic cholinergic markers. Co-injection of (+)-[125I]MIBT with 4-aminobenzovesamicol (2b), a potent vesamicol receptor ligand, reduced the levels of radiotracer in the striatum, cortex, and cerebellum by 58, 35, and 9%, respectively. Thus, (+)-[125I]MIBT binds to vesamicol receptors in vivo. In contrast, coadministration of (+)-[125I]MIBT with haloperidol (0.5 mumol/kg), reduced radiotracer levels in the cortex and cerebellum by 34 and 59%, respectively, while increasing the levels in the striatum by 32%. We conclude that although the distribution of (+)-[125I]MIBT qualitatively reflects cholinergic innervation, a fraction of radiotracer in the cortex and cerebellum is bound to sigma receptors.

The potential of (−)‐o‐[11C]methylvesamicol for diagnosing cholinergic deficit dementia

“…Because vesamicol was found to bind to VAChT in presynaptic cholinergic neurons with high affinity (Alter, 1988;Marien et al, 1987), many radiolabeled vesamicol analogs have been developed as radioligands for mapping presynaptic cholinergic neurons with SPECT (Efange et al, 1993;Jung et al, 1990;Shiba et al, 1995) and PET (Efange et al, 1999;Mulhollamd et al, 1998). Kawamura et al (2006) (Ishiwata et al, 2001) as a selective PET ligand for mapping the sigma-1 receptor in learning disability model monkeys produced by selectively destroying the p75NTR-positive cells in the right hemisphere of the brain affecting the cholinergic neuronal system using PET.…”

The potential ofo-bromo-trans-decalinvesamicol as a new PET ligand for vesicular acetylcholine transporter imaging

“…However, additional moderate to high affinity for sigma-1 (r 1 ) and sigma-2 (r 2 ) receptors (Efange et al, 1995) (DeGrado et al, 1994;Mulholland et al, 1998) (Jung et al, 1990;Sorger et al, 2000) and trozamicol, e.g. [ (Efange et al, 1994;Gage et al, 2000;Mach et al, 1997;Voytko et al, 2001), [ 123/125 I]MIBT (Efange et al, 1993Staley et al, 1997) (Fig. 1).…”

A tin precursor for the synthesis of no‐carrier‐added [*I]MIBG and [211At]MABG

“…24 There are a number of ways by which the tin precursor 2 can be synthesized. The synthesis of both 3-tributylstannylbenzyl alcohol 25 and 3-tributylstannylbenzylamine 10 has been reported. The tin precursor 2 could have been prepared from these by the guanidinylation methods reported.…”