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Eur J Nucl Med Mol Imaging. 2016 Mar;43(3):537-47. doi: 10.1007/s00259-015-3209-0. Epub 2015 Oct 12.

PET imaging evaluation of [(18)F]DBT-10, a novel radioligand specific to α7 nicotinic acetylcholine receptors, in nonhuman primates.

Author information

  • 1PET Center, Yale University, 801 Howard Ave, PO Box 208048, New Haven, CT, 06520-8048, USA. ansel.hillmer@yale.edu.
  • 2PET Center, Yale University, 801 Howard Ave, PO Box 208048, New Haven, CT, 06520-8048, USA.
  • 3Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf, Permoserstraße 15, 04318, Leipzig, Germany.

Abstract

PURPOSE:

Positron emission tomography (PET) radioligands specific to α7 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 α7-nAChR-specific radioligand, 7-(1,4-diazabicyclo[3.2.2]nonan-4-yl)-2-[(18)F]-fluorodibenzo[b,d]thiophene 5,5-dioxide ([(18)F]DBT-10), in nonhuman primates.

METHODS:

[(18)F]DBT-10 was produced via nucleophilic substitution of the nitro-precursor. Four Macaca mulatta subjects were imaged with [(18)F]DBT-10 PET, with measurement of [(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 α7-nAChR-specific ligand ASEM were also acquired to assess dose-dependent blockade of [(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 T/f P).

RESULTS:

[(18)F]DBT-10 was produced within 90 min at high specific activities of 428 ± 436 GBq/μmol at end of synthesis. Metabolism of [(18)F]DBT-10 varied across subjects, stabilizing by 120 min post-injection at parent fractions of 15-55%. Uptake of [(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 [(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 T/f P values were 193-376 ml/cm(3) across regions, with regional rank order of thalamus > frontal cortex > striatum > hippocampus > occipital cortex > cerebellum > pons. Dose-dependent blockade of [(18)F]DBT-10 binding by structural analog ASEM was observed throughout the brain, and occupancy plots yielded a V ND/f P estimate of 20 ± 16 ml/cm(3).

CONCLUSION:

These results demonstrate suitable kinetic properties of [(18)F]DBT-10 for in vivo quantification of α7-nAChR binding in nonhuman primates.

KEYWORDS:

Alpha 7; Nicotine; Nicotinic acetylcholine receptor; PET

PMID:
26455500
PMCID:
PMC4733418
[Available on 2017-03-01]
DOI:
10.1007/s00259-015-3209-0
[PubMed - indexed for MEDLINE]
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