The potential of 1H-MRS in CNS drug development

Abstract

Rationale: Proton magnetic resonance spectroscopy (¹H-MRS) is a cross-species neuroimaging technique that can measure concentrations of several brain metabolites, including glutamate and GABA. This non-invasive method has promise in developing centrally acting drugs, as it can be performed repeatedly within-subjects and be used to translate findings from the preclinical to clinical laboratory using the same imaging biomarker.

Objectives: This review focuses on the utility of single-voxel ¹H-MRS in developing novel glutamatergic or GABAergic drugs for the treatment of psychiatric disorders and includes research performed in rodent models, healthy volunteers and patient cohorts.

Results: Overall, these studies indicate that ¹H-MRS is able to detect the predicted pharmacological effects of glutamatergic or GABAergic drugs on voxel glutamate or GABA concentrations, although there is a shortage of studies examining dose-related effects. Clinical studies have applied ¹H-MRS to better understand drug therapeutic mechanisms, including the glutamatergic effects of ketamine in depression and of acamprosate in alcohol dependence. There is an emerging interest in identifying patient subgroups with 'high' or 'low' brain regional ¹H-MRS glutamate levels for more targeted drug development, which may require ancillary biomarkers to improve the accuracy of subgroup discrimination.

Conclusions: Considerations for future research include the sensitivity of single-voxel ¹H-MRS in detecting drug effects, inter-site measurement reliability and the interpretation of drug-induced changes in ¹H-MRS metabolites relative to the known pharmacological molecular mechanisms. On-going technological development, in single-voxel ¹H-MRS and in related complementary techniques, will further support applications within CNS drug discovery.

Keywords: Biomarkers; Drug development; GABA; Glutamate; Magnetic resonance spectroscopy; Psychiatry.

Fig. 1

Representative ¹H-MRS spectra from the rat (left) and human (right) medial prefrontal cortex. The images show the ¹H-MRS voxel position in each species overlaid on the corresponding anatomical MRI image. In the rat, spectra were acquired under 1.0% isoflurane anaesthesia in a 3.8 × 2.2 × 2.0-mm voxel at 7 Tesla (Agilent Technologies Inc.) using a point-resolved spin-echo sequence (PRESS) with a repetition time (TR) of 3000 ms and an echo time (TE) of 24 ms.(Vernon et al. 2015) In man, spectra were acquired in a 20 × 20 × 20-mm voxel at 3 Tesla (GE MR750, General Electric Healthcare), using a PRESS sequence with TR = 2000 ms and TE = 35 ms. Representative spectra in each species, provided using LCModel software (Provencher 1993), show peaks for choline-containing compounds (Cho), creatine (Cr), glutamate and glutamine (Glx) and N-acetylaspartate (NAA)