Chapter 20: Acetylcholine transporter — vesamicol receptor pharmacology and structure

Parsons, Stanley M.; Bahr, Ben A.; Rogers, Gary A.; Clarkson, Edward D.; Noremberg, Krystyna; Hicks, Barry W.

doi:10.1016/s0079-6123(08)62396-1

Cited by 21 publications

(10 citation statements)

References 25 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The tissue with the lowest expression, colliculus, is set to one, and the remaining tissues are expressed relatively to that as fold increase addition four conserved aspartate (D) residues in TM1, 6, 10, and 11. In SLC18A1-2, the aspartate residues in TM1 (D33), 10 (D400), and 11 (D427) are thought to be critical for substrate recognition and transport (Parsons et al 1993;Merickel et al 1995Merickel et al , 1997Steiner-Mordoch et al 1996). The aspartates in TM10 (D398) and 11 (D425) of SLC18A3 appear to be equally important for acetylcholine recognition and transport, while those in TM4 (D193) and TM10 (D398) are critical for vesamicol binding (Kim et al 1999;Parsons et al 1993).…”

Section: Displays Two Putative Motifs [K/s] W[a/g]pp[l/q]er[s/g][r/qmentioning

confidence: 99%

“…In SLC18A1-2, the aspartate residues in TM1 (D33), 10 (D400), and 11 (D427) are thought to be critical for substrate recognition and transport (Parsons et al 1993;Merickel et al 1995Merickel et al , 1997Steiner-Mordoch et al 1996). The aspartates in TM10 (D398) and 11 (D425) of SLC18A3 appear to be equally important for acetylcholine recognition and transport, while those in TM4 (D193) and TM10 (D398) are critical for vesamicol binding (Kim et al 1999;Parsons et al 1993). None of the conserved motifs or residues mentioned above is seen in C6ORF192, and this may indicate that this protein has different substrates for transport or cell localization than the other transporter members.…”

Section: Displays Two Putative Motifs [K/s] W[a/g]pp[l/q]er[s/g][r/qmentioning

confidence: 99%

See 1 more Smart Citation

C6ORF192 Forms a Unique Evolutionary Branch Among Solute Carriers (SLC16, SLC17, and SLC18) and Is Abundantly Expressed in Several Brain Regions

2009

View full text Add to dashboard Cite

About one third of all known human proteins are membrane proteins, which constitute several large families. The solute carriers with over 300 known members are probably the second largest family with additional members frequently being identified. We recently found a new putative solute carrier, C6ORF192, belonging to the major facilitator superfamily type of proteins. The gene is evolutionary highly conserved with a single copy present in each of the genomes from mouse, rat, chicken, zebrafish, tetraodon, Caenorhabditis elegans, and Drosophila melanogaster. C6ORF192 forms a novel evolutionary branch of solute carriers and is most closely related to the solute carrier families 16, 17, and 18, all members of the major facilitator superfamily. Ten of the 25 members of these families show amino acid identity with C6ORF192 ranging from 21% to 27%. C6ORF192 differs however, structurally from these families and does not share key motifs in the transmembrane domains. Expression profiling by quantitative real-time polymerase chain reaction and in situ hybridization showed that C6ORF192 transcript can be detected in several tissues, both in the central nervous system and the periphery.

show abstract

Section: Displays Two Putative Motifs [K/s] W[a/g]pp[l/q]er[s/g][r/qmentioning

confidence: 99%

Section: Displays Two Putative Motifs [K/s] W[a/g]pp[l/q]er[s/g][r/qmentioning

confidence: 99%

C6ORF192 Forms a Unique Evolutionary Branch Among Solute Carriers (SLC16, SLC17, and SLC18) and Is Abundantly Expressed in Several Brain Regions

2009

View full text Add to dashboard Cite

show abstract

“…Hexabutylditin, toluene, reflux Pd(PPh 3 ) 4 striatum, frontal cortex and hippocampus (Figure 3) for the vesamicol pre-treated rats group compared to the control group. These results confirmed the specific and selective binding of IBVM to the VAChT.…”

Section: Resultsmentioning

confidence: 98%

“…The aqueous layer was separated, alkalinized (pH ¼ 9) with 3 N NaOH and extracted with CH 2 Cl 2 (3 Â 30 ml). The organic extracts were dried over anhydrous MgSO 4 and concentrated under reduced pressure to afford 86% (184 mg, 0.705 mmol) of (R; R)-3. General procedure for preparation of ( AE )-6 and ( AE )-7…”

Section: Resolution Of 4-hydroxy-3-(n-phenylpiperazinyl)piperidine [(mentioning

confidence: 99%

“…The most suitable method for this type of exploration consists of SPECT or PET imaging using specific tracers of the molecular targets labelled with g or bþ emitters. For this aim, several labelled vesamicol derivatives have been developed, [2][3][4] such as (À)-5-iodobenzovesamicol (IBVM) ( Figure 1) which has been used in humans volunteers 5 and subjects suffering from Alzheimer's or Parkinson's disease. 6 Examples of additional vesamicol derivatives that have been proposed are meta-iodobenzyltrozamicol (MIBT) 7 and DRC140 8 ( Figure 1).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Synthesis and ex vivo evaluation of aza‐trozamicol analogs as SPECT radiotracers for exploration of the vesicular acetylcholine transporter

Assaad

Mavel

Emond

et al. 2007

Labelled Comp Radiopharmac

View full text Add to dashboard Cite

Several vesamicol derivatives have already been proposed for SPECT exploration of the vesicular acetylcholine transporter (VAChT) which is localized on the nerve endings of cholinergic neurons which are known to degenerate in the early stages of Alzheimer's disease. However, most of these tracers have disadvantages such as in vivo non-specific binding, slow brain kinetics, or high toxicity. We present in this study the synthesis, the radiolabelling and the cerebral biodistribution in rats of two enantiomeric pairs of new trozamicol derivatives, potential imaging agents for the VAChT. Radiolabelled compounds were obtained with high purity and specific radioactivity. However, after i.v. injection in rats, they distributed homogeneously throughout the brain, in contrast to the reference compound IBVM which showed in the same experimental conditions a high striatum/cerebellum fixation ratio. These results demonstrate that these new compounds are unsuitable for the in vivo imaging of the VAChT using SPECT.

show abstract

Ex vivo and in vivo evaluation of (2R,3R)‐5‐[¹⁸F]‐fluoroethoxy‐ and fluoropropoxy‐benzovesamicol, as PET radioligands for the vesicular acetylcholine transporter

Giboureau

Emond

Fulton

et al. 2007

Synapse

View full text Add to dashboard Cite

Molecular imaging of the vesicular acetylcholine transporter (VAChT) using positron emission tomography (PET) may provide insights into early diagnosis and better understanding of Alzheimer's disease. We further characterized the VAChT ligand (2R,3R)-5-FEOBV (1) and developed new fluoropropoxy analogues. Ex vivo studies of the new nonradiolabeled analogues (2R,3R)-5-FPOBV (2) (k(D) = 0.7 nM) and (2S,3S)-5-FPOBV (3) (k(D) = 8.8 nM) were performed in rat brain and showed an enantioselective inhibition of (-)-5-[(125)I]-IBVM uptake in striatum, cortex, and hippocampus (e.g., 74% for 2 and only 54% for 3 in the cortex). Radiochemical procedures were developed to produce [(18)F]1 and [(18)F]2 as potential imaging agent for the VAChT. The radiochemistry was carried out in a one step procedure, with radiolabeling yields of 17 and 2.6% (range: 1-5.4), respectively, nondecay corrected with good specific activity: 124-338 GBq/micromol. The radiochemical purity was greater than 98%. The biological (ex vivo and in vivo) properties of these radioligands were evaluated in rats and showed a low (less then 0.1% of the injected dose) and homogeneous brain uptake. The in vivo PET study of [(18)F]2 performed in baboon also revealed rapid defluorination as the main problem. Therefore [(18)F]1 and [(18)F]2 appear to be unsuitable for in vivo imaging of the VAChT using PET.

show abstract

Chapter 20: Acetylcholine transporter — vesamicol receptor pharmacology and structure

Cited by 21 publications

References 25 publications

C6ORF192 Forms a Unique Evolutionary Branch Among Solute Carriers (SLC16, SLC17, and SLC18) and Is Abundantly Expressed in Several Brain Regions

C6ORF192 Forms a Unique Evolutionary Branch Among Solute Carriers (SLC16, SLC17, and SLC18) and Is Abundantly Expressed in Several Brain Regions

Synthesis and ex vivo evaluation of aza‐trozamicol analogs as SPECT radiotracers for exploration of the vesicular acetylcholine transporter

Ex vivo and in vivo evaluation of (2R,3R)‐5‐[¹⁸F]‐fluoroethoxy‐ and fluoropropoxy‐benzovesamicol, as PET radioligands for the vesicular acetylcholine transporter

Contact Info

Product

Resources

About

Chapter 20: Acetylcholine transporter — vesamicol receptor pharmacology and structure

Cited by 21 publications

References 25 publications

C6ORF192 Forms a Unique Evolutionary Branch Among Solute Carriers (SLC16, SLC17, and SLC18) and Is Abundantly Expressed in Several Brain Regions

C6ORF192 Forms a Unique Evolutionary Branch Among Solute Carriers (SLC16, SLC17, and SLC18) and Is Abundantly Expressed in Several Brain Regions

Synthesis and ex vivo evaluation of aza‐trozamicol analogs as SPECT radiotracers for exploration of the vesicular acetylcholine transporter

Ex vivo and in vivo evaluation of (2R,3R)‐5‐[18F]‐fluoroethoxy‐ and fluoropropoxy‐benzovesamicol, as PET radioligands for the vesicular acetylcholine transporter

Contact Info

Product

Resources

About

Ex vivo and in vivo evaluation of (2R,3R)‐5‐[¹⁸F]‐fluoroethoxy‐ and fluoropropoxy‐benzovesamicol, as PET radioligands for the vesicular acetylcholine transporter