Synthesis and Pharmacological Evaluation of [11C]4-Methoxy- N-[2-(thiophen-2-yl)imidazo[1,2- a]pyridin-3-yl]benzamide as a Brain Penetrant PET Ligand Selective for the δ-Subunit-Containing γ-Aminobutyric Acid Type A Receptors

Abstract

The α_4/6βδ-containing GABA_A receptors are involved in a number of brain diseases. Despite the potential of a δ-selective imaging agent, no PET radioligand is currently available for in vivo imaging. Here, we report the characterization of DS2OMe (1) as a candidate radiotracer, ¹¹C-labeling, and subsequent evaluation of [¹¹C]DS2OMe in a domestic pig as a PET radioligand for visualization of the δ-containing GABA_A receptors.

Figure 1

Chemical structures of GABA, the orthosteric agonist THIP/gaboxadol, and the two PAMs, DS2 and DS2OMe (1).

Scheme 1. Synthesis of [¹¹C]1

Figure 2

Concentration–response curves of the modulation of GABA EC₂₀ by 1 at α₆β₂δ and α₆β₂γ_2s receptors and DS2 at α₆β₂δ receptors, tested in the FMP assay. Data are shown as mean reSD of a single representative experiment performed with three technical triplicates. Two additional experiments gave similar results; data are summarized in Table 1.

Figure 3

(A) PET images of the pig brain in the transverse, sagittal, and coronal planes (left to right). (B) Time–activity curves of [¹¹C]1 in the indicated regions of the pig brain. (C) Time–activity curves of [¹¹C]1 in the thalamus and cerebellum at the baseline (closed symbols) and after administration of 2.1 mg/kg unlabeled 1 (coadministrated with the tracer, open symbols). SUV: standardized uptake value. Tha: thalamus, Str: striatum, Ctx: cortex, Cb: cerebellum.