PET radioligands for the vesicular transporters for monoamines and acetylcholine

Kilbourn, Michael R.

doi:10.1002/jlcr.2998

Cited by 10 publications

(4 citation statements)

References 41 publications

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“…The regional TACs revealed that uptake of (−)-[ 11 C] TZ659 in the striatum, but not in the cerebellar hemispheres, was reduced following pretreatment with increasing doses of (−)-vesamicol 6 min prior to tracer injection. Initial cerebellar and striatal uptake in the blocking study was higher than the average uptake during the initial period in the baseline studies; this may result from variability associated with the scan, for example, differences in the rate of the bolus injection between studies, the minor differences in the interval between the administering the initial anesthetic and radiotracer injection, or differences in the depth of anesthesia; in addition, (−)-vesamicol that was reported to have high toxicity [44, 45], for blocking studies, another potential explanation is that the difference may be caused by a pharmacological response to the potent inhibitor (−)-vesamicol. Despite the difference seen in initial uptake, the steady state retention of the tracer in the cerebellum (after 70 min post injection of the radiotracer) did not change following pretreatment with (−)-vesamicol.…”

Section: Resultsmentioning

confidence: 99%

Kinetics modeling and occupancy studies of a novel C-11 PET tracer for VAChT in nonhuman primates

Jin

Zhang

Yue

et al. 2016

Nuclear Medicine and Biology

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Introduction Deficits in cholinergic function have been found in the aged brain and in neurodegenerative diseases including Alzheimer’s disease (AD) and Parkinson’s disease (PD). The vesicular acetylcholine transporter (VAChT) is a reliable biomarker for the cholinergic system. We previously reported the initial in vitro and ex vivo characterization of (−)-[11C]TZ659 as a VAChT specific ligand. Here, we report the in vivo specificity, tracer kinetics, and dose-occupancy studies in the nonhuman primate brain are reported. Methods MicroPET brain imaging of (−)-[11C]TZ659 was performed under baseline conditions in two male macaques. Tracer kinetic modeling was carried out using a two-tissue compartment model (2TCM) and Logan plot with arterial blood input function and using a simplified reference tissue model (SRTM) and Logan plot (LoganREF) without blood input. Specificity for VAChT was demonstrated by pretreatment with (+)-pentazocine, (−)-vesamicol, or S-(−)-eticlopride. Target occupancy (Occ) was calculated following pretreatment with escalating doses of (−)-vesamicol. Results Baseline PET imaging revealed selective retention in the striatum with rapid clearance from the cerebellar hemispheres as a reference region. Total volume of distribution (VT) values derived from both 2TCM and Logan analysis with blood input revealed ~3-fold higher levels of (−)-[11C]TZ659 in the striatum than the cerebellar hemispheres. Injection of (−)-vesamicol either as a blocking or displacing agent significantly reduced striatal uptake of (−)-[11C]TZ659. In contrast, pretreatment with the sigma-1 ligand (+)-pentazocine had no impact. Pretreatment with the S-(−)-eticlopride, a dopamine D2–like receptor antagonist, increased striatal uptake of (−)-[11C]TZ659. Striatal binding potential (BPND, range of 0.33 – 1.6 with cerebellar hemispheres as the reference region) showed good correlation (r2 = 0.97) between SRTM and LoganREF. Occupancy studies found that ~ 0.0057 mg/kg (−)-vesamicol produced 50% VAChT occupancy in the striatum. Conclusion (−)-[11C]TZ659 demonstrated specific and reversible VAChT binding and favorable pharmacokinetic properties for assessing the density of VAChT in the living brain.

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Section: Resultsmentioning

confidence: 99%

Kinetics modeling and occupancy studies of a novel C-11 PET tracer for VAChT in nonhuman primates

Jin

Zhang

Yue

et al. 2016

Nuclear Medicine and Biology

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“…Nemacol is similar in structure to Vesamicol, a canonical VAChT inhibitor 53 and both compounds likely interact with a common binding site on VAChT 31 . However, the Vesamicol scaffold has lackluster activity against nematodes, has high affinity for mammalian VAChT, and has low tolerability in rats 27 , 31 , 54 . These features likely account for a lack of interest in developing the Vesamicol scaffold as an anthelmintic.…”

Section: Discussionmentioning

confidence: 99%

Nemacol is a small molecule inhibitor of C. elegans vesicular acetylcholine transporter with anthelmintic potential

et al. 2023

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Nematode parasites of humans and livestock pose a significant burden to human health, economic development, and food security. Anthelmintic drug resistance is widespread among parasites of livestock and many nematode parasites of humans lack effective treatments. Here, we present a nitrophenyl-piperazine scaffold that induces motor defects rapidly in the model nematode Caenorhabditis elegans. We call this scaffold Nemacol and show that it inhibits the vesicular acetylcholine transporter (VAChT), a target recognized by commercial animal and crop health groups as a viable anthelmintic target. We demonstrate that it is possible to create Nemacol analogs that maintain potent in vivo activity whilst lowering their affinity to the mammalian VAChT 10-fold. We also show that Nemacol enhances the ability of the anthelmintic Ivermectin to paralyze C. elegans and the ruminant nematode parasite Haemonchus contortus. Hence, Nemacol represents a promising new anthelmintic scaffold that acts through a validated anthelmintic target.

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“…Nemacol is similar in structure to vesamicol, a canonical VAChT inhibitor 48 and both compounds likely interact with a common binding site on VAChT 32 . However, the vesamicol scaffold has lackluster activity against nematodes, has high affinity for mammalian VAChT, and has low tolerability in rats 27,32,49 . These features likely account for a lack of interest in developing the vesamicol scaffold as an anthelmintic.…”

Section: Discussionmentioning

confidence: 99%

Nemacol is a Small Molecule Inhibitor of C. elegans Vesicular Acetylcholine Transporter with Anthelmintic Potential

Harrington

Pyche

Burns

et al. 2022

Preprint

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Nematode parasites of humans and livestock pose a significant burden to human health, economic development, and food security. Anthelmintic drug resistance is widespread among parasites of livestock and many nematode parasites of humans lack effective treatments. Here, we present a nitrophenyl-piperazine scaffold that induces motor defects rapidly in the model nematode Caenorhabditis elegans. We call this scaffold Nemacol and show that it inhibits the vesicular acetylcholine transporter (VAChT), a target recognized by commercial animal and crop health groups as a viable anthelmintic target. We demonstrate that it is possible to create Nemacol analogs that maintain potent in vivo activity whilst lowering their affinity to the mammalian VAChT 10-fold. We also show that Nemacol synergizes with the anthelmintic ivermectin to kill C. elegans. Hence, Nemacol represents a promising new anthelmintic scaffold that acts through an identified viable anthelmintic target.

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PET radioligands for the vesicular transporters for monoamines and acetylcholine

Cited by 10 publications

References 41 publications

Kinetics modeling and occupancy studies of a novel C-11 PET tracer for VAChT in nonhuman primates

Kinetics modeling and occupancy studies of a novel C-11 PET tracer for VAChT in nonhuman primates

Nemacol is a small molecule inhibitor of C. elegans vesicular acetylcholine transporter with anthelmintic potential

Nemacol is a Small Molecule Inhibitor of C. elegans Vesicular Acetylcholine Transporter with Anthelmintic Potential

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