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

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European Journal of Nuclear Medicine and Molecular Imaging Aims and scope Submit manuscript

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-[18F]-fluorodibenzo[b,d]thiophene 5,5-dioxide ([18F]DBT-10), in nonhuman primates.

Methods

[18F]DBT-10 was produced via nucleophilic substitution of the nitro-precursor. Four Macaca mulatta subjects were imaged with [18F]DBT-10 PET, with measurement of [18F]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 [18F]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

[18F]DBT-10 was produced within 90 min at high specific activities of 428 ± 436 GBq/μmol at end of synthesis. Metabolism of [18F]DBT-10 varied across subjects, stabilizing by 120 min post-injection at parent fractions of 15–55 %. Uptake of [18F]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 [18F]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/cm3 across regions, with regional rank order of thalamus > frontal cortex > striatum > hippocampus > occipital cortex > cerebellum > pons. Dose-dependent blockade of [18F]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/cm3.

Conclusion

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

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Acknowledgments

This work was supported by NIH T32 DA022975. We thank the staff at the Yale PET Center for their expert technical assistance in support of this work. This publication was made possible by CTSA Grant Number UL1 TR000142 from the National Center for Advancing Translational Science (NCATS), a component of the National Institutes of Health (NIH). Its contents are solely the responsibility of the authors and do not necessarily represent the official view of NIH.

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Authors and Affiliations

  1. PET Center, Yale University, 801 Howard Ave, PO Box 208048, New Haven, CT, 06520-8048, USA

    Ansel T. Hillmer, Ming-Qiang Zheng, Songye Li, Shu-fei Lin, Daniel Holden, David Labaree, Jim Ropchan, Richard E. Carson & Yiyun Huang

  2. Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf, Permoserstraße 15, 04318, Leipzig, Germany

    Matthias Scheunemann, Rodrigo Teodoro, Winnie Deuther-Conrad & Peter Brust

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  1. Ansel T. Hillmer
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Correspondence to Ansel T. Hillmer.

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All applicable international, national, and institutional guidelines for the care and use of animals were followed. All procedures performed in studies involving animals were in accordance with the ethical standards of the Yale University Institutional Animal Care and Use Committee.

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Hillmer, A.T., Zheng, MQ., Li, S. et al. PET imaging evaluation of [18F]DBT-10, a novel radioligand specific to α7 nicotinic acetylcholine receptors, in nonhuman primates. Eur J Nucl Med Mol Imaging 43, 537–547 (2016). https://doi.org/10.1007/s00259-015-3209-0

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