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PET imaging evaluation of [^sup 18^F]DBT-10, a novel radioligand specific to [alpha]^sub 7^ nicotinic acetylcholine receptors, in nonhuman primates

Purpose Positron emission tomography (PET) radioligands specific to [alpha]^sub 7^ nicotinic acetylcholine receptors (nAChRs) afford in vivo imaging of this receptor for neuropathologies such as Alzheimer's disease, schizophrenia, and substance abuse. This work aims to characterize the kinetic prope... Full description

Journal Title: European journal of nuclear medicine and molecular imaging 2016-03-01, Vol.43 (3), p.537
Main Author: Ansel T Hillmer
Other Authors: Ming-Qiang Zheng , Songye Li , Matthias Scheunemann , Shu-fei Lin , Daniel Holden , David Labaree , Jim Ropchan , Rodrigo Teodoro , Winnie Deuther-Conrad , Richard E Carson , Peter Brust , Yiyun Huang
Format: Electronic Article Electronic Article
Language: English
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Publisher: Heidelberg: Springer Nature B.V
ID: ISSN: 1619-7070
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title: PET imaging evaluation of [^sup 18^F]DBT-10, a novel radioligand specific to [alpha]^sub 7^ nicotinic acetylcholine receptors, in nonhuman primates
format: Article
creator:
  • Ansel T Hillmer
  • Ming-Qiang Zheng
  • Songye Li
  • Matthias Scheunemann
  • Shu-fei Lin
  • Daniel Holden
  • David Labaree
  • Jim Ropchan
  • Rodrigo Teodoro
  • Winnie Deuther-Conrad
  • Richard E Carson
  • Peter Brust
  • Yiyun Huang
subjects:
  • Medical imaging
  • Nicotine
  • Primates
  • Tomography
ispartof: European journal of nuclear medicine and molecular imaging, 2016-03-01, Vol.43 (3), p.537
description: Purpose Positron emission tomography (PET) radioligands specific to [alpha]^sub 7^ nicotinic acetylcholine receptors (nAChRs) afford in vivo imaging of this receptor for neuropathologies such as Alzheimer's disease, schizophrenia, and substance abuse. This work aims to characterize the kinetic properties of an [alpha]^sub 7^-nAChR-specific radioligand, 7-(1,4-diazabicyclo[3.2.2]nonan-4-yl)-2-[^sup 18^F]-fluorodibenzo[b,d]thiophene 5,5-dioxide ([^sup 18^F]DBT-10), in nonhuman primates. Methods [^sup 18^F]DBT-10 was produced via nucleophilic substitution of the nitro-precursor. Four Macaca mulatta subjects were imaged with [^sup 18^F]DBT-10 PET, with measurement of [^sup 18^F]DBT-10 parent concentrations and metabolism in arterial plasma. Baseline PET scans were acquired for all subjects. Following one scan, ex vivo analysis of brain tissue was performed to inspect for radiolabeled metabolites in brain. Three blocking scans with 0.69 and 1.24 mg/kg of the [alpha]^sub 7^-nAChR-specific ligand ASEM were also acquired to assess dose-dependent blockade of [^sup 18^F]DBT-10 binding. Kinetic analysis of PET data was performed using the metabolite-corrected input function to calculate the parent fraction corrected total distribution volume (V ^sub T^/f ^sub P^). Results [^sup 18^F]DBT-10 was produced within 90 min at high specific activities of 428±436 GBq/[mu]mol at end of synthesis. Metabolism of [^sup 18^F]DBT-10 varied across subjects, stabilizing by 120 min post-injection at parent fractions of 15-55 %. Uptake of [^sup 18^F]DBT-10 in brain occurred rapidly, reaching peak standardized uptake values (SUVs) of 2.9-3.7 within 30 min. The plasma-free fraction was 18.8±3.4 %. No evidence for radiolabeled [^sup 18^F]DBT-10 metabolites was found in ex vivo brain tissue samples. Kinetic analysis of PET data was best described by the two-tissue compartment model. Estimated V ^sub T^/f ^sub P^ values were 193-376 ml/cm^sup 3^ across regions, with regional rank order of thalamus>frontal cortex>striatum>hippocampus>occipital cortex>cerebellum>pons. Dose-dependent blockade of [^sup 18^F]DBT-10 binding by structural analog ASEM was observed throughout the brain, and occupancy plots yielded a V ^sub ND^/f ^sub P^ estimate of 20±16 ml/cm^sup 3^. Conclusion These results demonstrate suitable kinetic properties of [^sup 18^F]DBT-10 for in vivo quantification of [alpha]^sub 7^-nAChR binding in nonhuman primates.
language: eng
source:
identifier: ISSN: 1619-7070
fulltext: no_fulltext
issn:
  • 1619-7070
  • 1619-7089
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titlePET imaging evaluation of [^sup 18^F]DBT-10, a novel radioligand specific to [alpha]^sub 7^ nicotinic acetylcholine receptors, in nonhuman primates
creatorAnsel T Hillmer ; Ming-Qiang Zheng ; Songye Li ; Matthias Scheunemann ; Shu-fei Lin ; Daniel Holden ; David Labaree ; Jim Ropchan ; Rodrigo Teodoro ; Winnie Deuther-Conrad ; Richard E Carson ; Peter Brust ; Yiyun Huang
creatorcontribAnsel T Hillmer ; Ming-Qiang Zheng ; Songye Li ; Matthias Scheunemann ; Shu-fei Lin ; Daniel Holden ; David Labaree ; Jim Ropchan ; Rodrigo Teodoro ; Winnie Deuther-Conrad ; Richard E Carson ; Peter Brust ; Yiyun Huang
descriptionPurpose Positron emission tomography (PET) radioligands specific to [alpha]^sub 7^ nicotinic acetylcholine receptors (nAChRs) afford in vivo imaging of this receptor for neuropathologies such as Alzheimer's disease, schizophrenia, and substance abuse. This work aims to characterize the kinetic properties of an [alpha]^sub 7^-nAChR-specific radioligand, 7-(1,4-diazabicyclo[3.2.2]nonan-4-yl)-2-[^sup 18^F]-fluorodibenzo[b,d]thiophene 5,5-dioxide ([^sup 18^F]DBT-10), in nonhuman primates. Methods [^sup 18^F]DBT-10 was produced via nucleophilic substitution of the nitro-precursor. Four Macaca mulatta subjects were imaged with [^sup 18^F]DBT-10 PET, with measurement of [^sup 18^F]DBT-10 parent concentrations and metabolism in arterial plasma. Baseline PET scans were acquired for all subjects. Following one scan, ex vivo analysis of brain tissue was performed to inspect for radiolabeled metabolites in brain. Three blocking scans with 0.69 and 1.24 mg/kg of the [alpha]^sub 7^-nAChR-specific ligand ASEM were also acquired to assess dose-dependent blockade of [^sup 18^F]DBT-10 binding. Kinetic analysis of PET data was performed using the metabolite-corrected input function to calculate the parent fraction corrected total distribution volume (V ^sub T^/f ^sub P^). Results [^sup 18^F]DBT-10 was produced within 90 min at high specific activities of 428±436 GBq/[mu]mol at end of synthesis. Metabolism of [^sup 18^F]DBT-10 varied across subjects, stabilizing by 120 min post-injection at parent fractions of 15-55 %. Uptake of [^sup 18^F]DBT-10 in brain occurred rapidly, reaching peak standardized uptake values (SUVs) of 2.9-3.7 within 30 min. The plasma-free fraction was 18.8±3.4 %. No evidence for radiolabeled [^sup 18^F]DBT-10 metabolites was found in ex vivo brain tissue samples. Kinetic analysis of PET data was best described by the two-tissue compartment model. Estimated V ^sub T^/f ^sub P^ values were 193-376 ml/cm^sup 3^ across regions, with regional rank order of thalamus>frontal cortex>striatum>hippocampus>occipital cortex>cerebellum>pons. Dose-dependent blockade of [^sup 18^F]DBT-10 binding by structural analog ASEM was observed throughout the brain, and occupancy plots yielded a V ^sub ND^/f ^sub P^ estimate of 20±16 ml/cm^sup 3^. Conclusion These results demonstrate suitable kinetic properties of [^sup 18^F]DBT-10 for in vivo quantification of [alpha]^sub 7^-nAChR binding in nonhuman primates.
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0PET imaging evaluation of [^sup 18^F]DBT-10, a novel radioligand specific to [alpha]^sub 7^ nicotinic acetylcholine receptors, in nonhuman primates
1European journal of nuclear medicine and molecular imaging
descriptionPurpose Positron emission tomography (PET) radioligands specific to [alpha]^sub 7^ nicotinic acetylcholine receptors (nAChRs) afford in vivo imaging of this receptor for neuropathologies such as Alzheimer's disease, schizophrenia, and substance abuse. This work aims to characterize the kinetic properties of an [alpha]^sub 7^-nAChR-specific radioligand, 7-(1,4-diazabicyclo[3.2.2]nonan-4-yl)-2-[^sup 18^F]-fluorodibenzo[b,d]thiophene 5,5-dioxide ([^sup 18^F]DBT-10), in nonhuman primates. Methods [^sup 18^F]DBT-10 was produced via nucleophilic substitution of the nitro-precursor. Four Macaca mulatta subjects were imaged with [^sup 18^F]DBT-10 PET, with measurement of [^sup 18^F]DBT-10 parent concentrations and metabolism in arterial plasma. Baseline PET scans were acquired for all subjects. Following one scan, ex vivo analysis of brain tissue was performed to inspect for radiolabeled metabolites in brain. Three blocking scans with 0.69 and 1.24 mg/kg of the [alpha]^sub 7^-nAChR-specific ligand ASEM were also acquired to assess dose-dependent blockade of [^sup 18^F]DBT-10 binding. Kinetic analysis of PET data was performed using the metabolite-corrected input function to calculate the parent fraction corrected total distribution volume (V ^sub T^/f ^sub P^). Results [^sup 18^F]DBT-10 was produced within 90 min at high specific activities of 428±436 GBq/[mu]mol at end of synthesis. Metabolism of [^sup 18^F]DBT-10 varied across subjects, stabilizing by 120 min post-injection at parent fractions of 15-55 %. Uptake of [^sup 18^F]DBT-10 in brain occurred rapidly, reaching peak standardized uptake values (SUVs) of 2.9-3.7 within 30 min. The plasma-free fraction was 18.8±3.4 %. No evidence for radiolabeled [^sup 18^F]DBT-10 metabolites was found in ex vivo brain tissue samples. Kinetic analysis of PET data was best described by the two-tissue compartment model. Estimated V ^sub T^/f ^sub P^ values were 193-376 ml/cm^sup 3^ across regions, with regional rank order of thalamus>frontal cortex>striatum>hippocampus>occipital cortex>cerebellum>pons. Dose-dependent blockade of [^sup 18^F]DBT-10 binding by structural analog ASEM was observed throughout the brain, and occupancy plots yielded a V ^sub ND^/f ^sub P^ estimate of 20±16 ml/cm^sup 3^. Conclusion These results demonstrate suitable kinetic properties of [^sup 18^F]DBT-10 for in vivo quantification of [alpha]^sub 7^-nAChR binding in nonhuman primates.
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atitlePET imaging evaluation of [^sup 18^F]DBT-10, a novel radioligand specific to [alpha]^sub 7^ nicotinic acetylcholine receptors, in nonhuman primates
jtitleEuropean journal of nuclear medicine and molecular imaging
date2016-03-01
risdate2016
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issn1619-7070
eissn1619-7089
abstractPurpose Positron emission tomography (PET) radioligands specific to [alpha]^sub 7^ nicotinic acetylcholine receptors (nAChRs) afford in vivo imaging of this receptor for neuropathologies such as Alzheimer's disease, schizophrenia, and substance abuse. This work aims to characterize the kinetic properties of an [alpha]^sub 7^-nAChR-specific radioligand, 7-(1,4-diazabicyclo[3.2.2]nonan-4-yl)-2-[^sup 18^F]-fluorodibenzo[b,d]thiophene 5,5-dioxide ([^sup 18^F]DBT-10), in nonhuman primates. Methods [^sup 18^F]DBT-10 was produced via nucleophilic substitution of the nitro-precursor. Four Macaca mulatta subjects were imaged with [^sup 18^F]DBT-10 PET, with measurement of [^sup 18^F]DBT-10 parent concentrations and metabolism in arterial plasma. Baseline PET scans were acquired for all subjects. Following one scan, ex vivo analysis of brain tissue was performed to inspect for radiolabeled metabolites in brain. Three blocking scans with 0.69 and 1.24 mg/kg of the [alpha]^sub 7^-nAChR-specific ligand ASEM were also acquired to assess dose-dependent blockade of [^sup 18^F]DBT-10 binding. Kinetic analysis of PET data was performed using the metabolite-corrected input function to calculate the parent fraction corrected total distribution volume (V ^sub T^/f ^sub P^). Results [^sup 18^F]DBT-10 was produced within 90 min at high specific activities of 428±436 GBq/[mu]mol at end of synthesis. Metabolism of [^sup 18^F]DBT-10 varied across subjects, stabilizing by 120 min post-injection at parent fractions of 15-55 %. Uptake of [^sup 18^F]DBT-10 in brain occurred rapidly, reaching peak standardized uptake values (SUVs) of 2.9-3.7 within 30 min. The plasma-free fraction was 18.8±3.4 %. No evidence for radiolabeled [^sup 18^F]DBT-10 metabolites was found in ex vivo brain tissue samples. Kinetic analysis of PET data was best described by the two-tissue compartment model. Estimated V ^sub T^/f ^sub P^ values were 193-376 ml/cm^sup 3^ across regions, with regional rank order of thalamus>frontal cortex>striatum>hippocampus>occipital cortex>cerebellum>pons. Dose-dependent blockade of [^sup 18^F]DBT-10 binding by structural analog ASEM was observed throughout the brain, and occupancy plots yielded a V ^sub ND^/f ^sub P^ estimate of 20±16 ml/cm^sup 3^. Conclusion These results demonstrate suitable kinetic properties of [^sup 18^F]DBT-10 for in vivo quantification of [alpha]^sub 7^-nAChR binding in nonhuman primates.
copHeidelberg
pubSpringer Nature B.V
doi10.1007/s00259-015-3209-0