Dataset Information

Quantification of [¹¹C]Ro15-4513 GABA_Aα5 specific binding and regional selectivity in humans.

ABSTRACT: [¹¹C]Ro15-4513 has been introduced as a positron emission tomography radioligand to image the GABA_Aα5 receptor subtype thought to be important in learning, memory and addiction. However, the in vivo selectivity of the ligand remains unknown and a full assessment of different analysis approaches has yet to be performed. Using human heterologous competition data, with [¹¹C]Ro15-4513 and the highly selective GABA_Aα5 selective negative allosteric modulator Basmisanil (RG1662), we quantify the GABA_Aα5 selectivity of [¹¹C]Ro15-4513, assess the validity of reference tissues and evaluate the performance of four different kinetic analysis methods. The results show that [¹¹C]Ro15-4513 has high but not complete selectivity for GABA_Aα5, with α5 representing around 60-70% of the specific binding in α5 rich regions. Competition data indicate that the cerebellum and pons are essentially devoid of α5 signal and might be used as reference regions under certain conditions. Off-target non-selective binding to other GABA_A subtypes means that the choice of analysis method and the interpretation of outcome measures must be considered carefully. We discuss the merits of two tissue compartmental model analyses to derive both V_T and V_S, band-pass spectral analysis for estimation of [Formula: see text] and the simplified reference tissue model for estimation of [Formula: see text].

SUBMITTER: Myers JF

PROVIDER: S-EPMC5464707 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature

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Quantification of [11C]Ro15-4513 GABAAα5 specific binding and regional selectivity in humans.

Myers Jim Fm JF Comley Robert A RA Gunn Roger N RN

Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism 20160101 6

[11C]Ro15-4513 has been introduced as a positron emission tomography radioligand to image the GABAAα5 receptor subtype thought to be important in learning, memory and addiction. However, the in vivo selectivity of the ligand remains unknown and a full assessment of different analysis approaches has yet to be performed. Using human heterologous competition data, with [11C]Ro15-4513 and the highly selective GABAAα5 selective negative allosteric modulator ...[more]

PMID: 27466376

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Project description:IntroductionAlteration of γ-aminobutyric acid "A" (GABAA) receptor-mediated neurotransmission has been associated with various neurological and psychiatric disorders. [11C]Ro15-4513 is a PET ligand with high affinity for α5-subunit-containing GABAA receptors, which are highly expressed in limbic regions of the human brain (Sur et al., 1998). We quantified the test-retest reproducibility of measures of [11C]Ro15-4513 binding derived from six different quantification methods (12 variants).MethodsFive healthy males (median age 40 years, range 38-49 years) had a 90-min PET scan on two occasions (median interval 12 days, range 11-30 days), after injection of a median dose of 441 MegaBequerels of [11C]Ro15-4513. Metabolite-corrected arterial plasma input functions (parent plasma input functions, ppIFs) were generated for all scans. We quantified regional binding using six methods (12 variants), some of which were region-based (applied to the average time-activity curve within a region) and others were voxel-based: 1) Models requiring arterial ppIFs - regional reversible compartmental models with one and two tissue compartments (2kbv and 4kbv); 2) Regional and voxelwise Logan's graphical analyses (Logan et al., 1990), which required arterial ppIFs; 3) Model-free regional and voxelwise (exponential) spectral analyses (SA; (Cunningham and Jones, 1993)), which also required arterial ppIFs; 4) methods not requiring arterial ppIFs - voxelwise standardised uptake values (Kenney et al., 1941), and regional and voxelwise simplified reference tissue models (SRTM/SRTM2) using brainstem or alternatively cerebellum as pseudo-reference regions (Lammertsma and Hume, 1996; Gunn et al., 1997). To compare the variants, we sampled the mean values of the outcome parameters within six bilateral, non-reference grey matter regions-of-interest. Reliability was quantified in terms of median absolute percentage test-retest differences (MA-TDs; preferentially low) and between-subject coefficient of variation (BS-CV, preferentially high), both compounded by the intraclass correlation coefficient (ICC). These measures were compared between variants, with particular interest in the hippocampus.ResultsTwo of the six methods (5/12 variants) yielded reproducible data (i.e. MA-TD <10%): regional SRTMs and voxelwise SRTM2s, both using either the brainstem or the cerebellum; and voxelwise SA. However, the SRTMs using the brainstem yielded a lower median BS-CV (7% for regional, 7% voxelwise) than the other variants (8-11%), resulting in lower ICCs. The median ICCs across six regions were 0.89 (interquartile range 0.75-0.90) for voxelwise SA, 0.71 (0.64-0.84) for regional SRTM-cerebellum and 0.83 (0.70-0.86) for voxelwise SRTM-cerebellum. The ICCs for the hippocampus were 0.89 for voxelwise SA, 0.95 for regional SRTM-cerebellum and 0.93 for voxelwise SRTM-cerebellum.ConclusionQuantification of [11C]Ro15-4513 binding shows very good to excellent reproducibility with SRTM and with voxelwise SA which, however, requires an arterial ppIF. Quantification in the α5 subunit-rich hippocampus is particularly reliable. The very low expression of the α5 in the cerebellum (Fritschy and Mohler, 1995; Veronese et al., 2016) and the substantial α1 subunit density in this region may hamper the application of reference tissue methods.

Dataset Information

Quantification of [¹¹C]Ro15-4513 GABA_Aα5 specific binding and regional selectivity in humans.

Publications

Quantification of [<sup>11</sup>C]Ro15-4513 GABA<sub>A</sub>α5 specific binding and regional selectivity in humans.

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