Heteroaromatic and Aniline Derivatives of Piperidines As Potent Ligands for Vesicular Acetylcholine Transporter

Li, Junfeng; Zhang, Xiang; Zhang, Zhanbin; Padakanti, Prashanth K.; Jin, Hongjun; Cui, Jinquan; Li, Aixiao; Zeng, Dexing; Rath, Nigam P.; Flores, Hubert; Perlmutter, Joel S.; Parsons, Stanley M.

doi:10.1021/jm400664x

Cited by 25 publications

(56 citation statements)

References 49 publications

(110 reference statements)

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“…The most promising ligands were radiolabeled, and we had performed preliminary evaluation in rodents and NHPs. Among these, (−)-[ 11 C] TZ659 demonstrated favorable initial results during in vivo evaluation in rats and preliminary CNS imaging studies in a male macaque [27, 28]. Here we further demonstrate in vivo binding specificity of (−)-[ 11 C] TZ659 for VAChT in healthy adult male NHPs under physiological conditions (baseline) and different pharmacological challenge conditions.…”

Section: Introductionmentioning

confidence: 64%

“…The synthesis of (−)- TZ659 and the radiolabeling of (−)-[ 11 C] TZ659 were accomplished as previously described [27]. The radiochemical yield was 40–50% (decay corrected to end of bombardment (EOB)) with a radiochemical purity > 99%, the chemical purity of > 95%, and the specific activity was >74 kBq /µmol (decay corrected to EOB).…”

Section: Methodsmentioning

confidence: 99%

“…Our group reported a number of VAChT inhibitors containing a carbonyl group attached to the 4-position of the piperidine ring and reported the structure−activity relationships of these new compounds [18, 19, 26, 27]. The most promising ligands were radiolabeled, and we had performed preliminary evaluation in rodents and NHPs.…”

Section: Introductionmentioning

confidence: 99%

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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: Introductionmentioning

confidence: 64%

Section: Methodsmentioning

confidence: 99%

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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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“…The epoxide compound 15 was synthesized as previously described. [36, 38] Commercially available (4-fluorophenyl)(piperidin-4-yl)methanone ( 16) was reacted with 15 to afford the phenol regioisomers 17a and 17b . The desired ligands 18a and 18b were obtained via O -alkylation of 17a and 17b respectively with -2-fluoroethyl tosylate.…”

Section: Resultsmentioning

confidence: 99%

“…[35-40] Evaluation of these 11 C- and 18 F-labeled radiotracers in rodents and microPET imaging studies in NHPs suggested that the radiolabeled version of several ligands ( 7-10, Figure 1 ) bound in vivo to the VAChT enriched striatal regions. [38-41] The half-life of 18 F (T 1/2 = 109.8 min) permits longer scan sessions that generate higher target-to-reference ratios; 18 F PET tracers also place fewer time constraints on tracer production. Here we further explore carbonyl-containing benzovesamicol analogues using the following strategies: 1) Incorporating PEGylated groups on the phenyl ring linked to the piperidinyl ring by the carbonyl group ( Figure 1 ), which can improve clearance kinetics by decreasing lipophilicity;[42-44] 2) Introducing a fluoroethoxy group on the tetralin moiety to further improve affinity and selectivity for VAChT versus the σ receptors; 3) Incorporating a fluorine atom to provide position(s) for 18 F radiolabeling.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and biological characterization of a promising F-18 PET tracer for vesicular acetylcholine transporter

Zhang

Jin

et al. 2015

Bioorganic & Medicinal Chemistry

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Nine fluorine-containing vesicular acetylcholine transporter (VAChT) inhibitors were synthesized and screened as potential PET tracers for imaging the VAChT. Compound 18a was one of the most promising carbonyl-containing benzovesamicol analogues; the minus enantiomer, (-)-18a displayed high potency (VAChT Ki = 0.59 ± 0.06 nM) and high selectivity for VAChT versus receptors (> 10,000-fold). The radiosynthesis of (-)-[18F]18a was accomplished by a two-step procedure with 30 – 40% radiochemical yield. Preliminary biodistribution studies of (-)-[18F]18a in adult male Sprague–Dawley rats at 5, 30, 60 and 120 min post-injection (p.i.) were promising. The total brain uptake of (-)-[18F]18a was 0.684 ID%/g at 5 min p.i. and by 120 min p.i. slowly washed out to 0.409 %ID/g.; evaluation of regional brain uptake showed stable levels of ~0.800 %ID/g from 5 to 120 min p.i in the VAChT-enriched striatal tissue of rats, indicating the tracer had crossed the blood brain barrier and was retained in the striatum. Subsequent microPET brain imaging studies of (-)-[18F]18a in nonhuman primates (NHPs) showed high striatal accumulation in the NHP brain; the standardized uptake value (SUV) for striatum reached a maximum value of 5.1 at 15 min p.i. The time-activity curve for the target striatal region displayed a slow and gradual decreasing trend 15 min after injection, while clearance of the radioactivity from the cerebellar reference region was much more rapid. Pretreatment of NHPs with 0.25 mg/kg of the VAChT inhibitor (-)-vesamicol resulted in a ~90% decrease of striatal uptake compared to baseline studies. HPLC metabolite analysis of NHP plasma revealed that (-)-[18F]18a had a good in vivo stability. Together, these preliminary results suggest (-)-[18F]18a is a promising PET tracer candidate for imaging VAChT in the brain of living subjects.

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Exploration of Sulfur‐Containing Analogues for Imaging Vesicular Acetylcholine Transporter in the Brain

et al. 2018

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Sixteen new sulfur-containing compounds targeting the vesicular acetylcholine transporter (VAChT) were synthesized and assessed for in vitro binding affinities. Enantiomers (-)-(1-(3-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)piperidin-4-yl)(4-(methylthio)phenyl)methanone [(-)-8] and (-)-(4-((2-fluoroethyl)thio)phenyl)(1-(3-hydroxy-1,2,3,4-tetrahydronaph-thalen-2-yl)piperidin-4-yl)methanone [(-)-14 a] displayed high binding affinities, with respective K values of 1.4 and 2.2 nm for human VAChT, moderate and high selectivity for human VAChT over σ (≈13-fold) and σ receptors (>420-fold). Radiosyntheses of (-)-[ C]8 and (-)-[ F]14 a were achieved using conventional methods. Ex vivo autoradiography and biodistribution studies in Sprague-Dawley rats indicated that both radiotracers have the capacity to penetrate the blood-brain barrier, with high initial brain uptake at 5 min and rapid washout. The striatal region had the highest accumulation for both radiotracers. Pretreating the rats with the VAChT ligand (-)-vesamicol decreased brain uptake for both radiotracers. Pretreating the rats with the σ ligand YUN-122 (N-(4-benzylcyclohexyl)-2-(2-fluorophenyl)acetamide) also decreased brain uptake, suggesting these two radiotracers also bind to the σ receptor in vivo. The microPET study of (-)-[ C]8 in the brain of a non-human primate showed high striatal accumulation that peaked quickly and washed out rapidly. Although preliminary results indicated these two sulfur-containing radiotracers have high binding affinities for VAChT with rapid washout kinetics from the striatum, their σ receptor binding properties limit their potential as radiotracers for quantifying VAChT in vivo.

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Heteroaromatic and Aniline Derivatives of Piperidines As Potent Ligands for Vesicular Acetylcholine Transporter

Cited by 25 publications

References 49 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

Synthesis and biological characterization of a promising F-18 PET tracer for vesicular acetylcholine transporter

Exploration of Sulfur‐Containing Analogues for Imaging Vesicular Acetylcholine Transporter in the Brain

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