PET measurement of "GABA shift" in the rat brain: A preclinical application of bolus plus constant infusion paradigm of [18F]flumazenil

Wook Kim; Hyun Soo Park; Byung Seok Moon; Byung Chul Lee; Sang Eun Kim

doi:10.1016/j.nucmedbio.2016.11.003

PET measurement of "GABA shift" in the rat brain: A preclinical application of bolus plus constant infusion paradigm of [¹⁸F]flumazenil

Nucl Med Biol. 2017 Feb:45:30-34. doi: 10.1016/j.nucmedbio.2016.11.003. Epub 2016 Nov 4.

Authors

Wook Kim¹, Hyun Soo Park², Byung Seok Moon³, Byung Chul Lee², Sang Eun Kim⁴

Affiliations

¹ Department of Transdisciplinary Studies, Graduate School of Convergence Science and Technology, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul 151-742, South Korea.
² Department of Nuclear Medicine, Seoul National University College of Medicine, Seoul National University Bundang Hospital, 300 Gumi-dong, Bundang-gu, Seongnam 463-707, South Korea; Advanced Institutes of Convergence Technology, 864-1, Iui-dong, Yeongtong-gu, Suwon 443-270, South Korea.
³ Department of Nuclear Medicine, Seoul National University College of Medicine, Seoul National University Bundang Hospital, 300 Gumi-dong, Bundang-gu, Seongnam 463-707, South Korea.
⁴ Department of Transdisciplinary Studies, Graduate School of Convergence Science and Technology, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul 151-742, South Korea; Department of Nuclear Medicine, Seoul National University College of Medicine, Seoul National University Bundang Hospital, 300 Gumi-dong, Bundang-gu, Seongnam 463-707, South Korea; Advanced Institutes of Convergence Technology, 864-1, Iui-dong, Yeongtong-gu, Suwon 443-270, South Korea. Electronic address: kse@snu.ac.kr.

PMID: 27886620
DOI: 10.1016/j.nucmedbio.2016.11.003

Abstract

Introduction: We measured the tiagabine-induced enhancement of the GABA_A receptor's affinity for benzodiazepine ligands ("GABA shift") using [¹⁸F]flumazenil (FMZ) PET with preclinical application of bolus plus constant infusion (B/I). Differences in quantified results of [¹⁸F]FMZ binding were compared to that of [¹⁸F]FMZ PET with single bolus injection (SB).

Materials and methods: Sprague-Dawley rats underwent [¹⁸F]FMZ PET scans with B/I, which consisted of baseline and "GABA shift" sessions in a scan, or scans with SB one week apart. Tiagabine (10mg/kg) was intravenously injected after the baseline session. [¹⁸F]FMZ binding potentials (BP_ND) were calculated using an equilibrium ratio method and a modeling method for B/I and SB, respectively. Regional brain BP_ND changes (%) before and after the tiagabine treatment were also calculated.

Results: In PET studies with B/I (K_bol=20min), [¹⁸F]FMZ distribution in the various cortical and subcortical regions rapidly reached equilibrium. After the tiagabine treatment, [¹⁸F]FMZ BP_ND were substantially increased across the regions of interest (the frontal cortex, hippocampus, thalamus, and striatum), ranging from 3% to 7% BP_ND change (B/I) and 6-14% BP_ND change (SB), respectively. In PET studies with SB, a statistically significant increase of [¹⁸F]FMZ BP_ND was found only in the striatum, due to the greater inter-individual variance compared to those with B/I.

Conclusions: Data demonstrated that an [¹⁸F]FMZ PET study with B/I (K_bol=20min) is both reliable and sensitive for the assessment of altered GABA_A receptor function induced by tiagabine treatment in the rat brain. These results may help to improve the efficiency of the development of new GABA-targeting drugs in the preclinical stage using [¹⁸F]FMZ PET.

Keywords: Bolus plus constant infusion; GABA shift; PET; [(18)F]flumazenil.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Benzodiazepines / metabolism
Brain / diagnostic imaging
Brain / metabolism
Flumazenil / administration & dosage*
Fluorine Radioisotopes*
Injections
Male
Positron-Emission Tomography*
Rats
Rats, Sprague-Dawley
Receptors, GABA-A / metabolism*

Substances

Fluorine Radioisotopes
Receptors, GABA-A
Benzodiazepines
Flumazenil