Preclinical anaylses of [18F]cEFQ as a PET tracer for imaging metabotropic glutamate receptor type 1 (mGluR1)

Abstract

Metabotropic glutamate receptor type 1 (mGluR1) is related with various neurological and psychiatric diseases, such as anxiety, depression, epilepsy, Parkinson's disease, and neuropathic pain. Hence, mGluR1 is an important target for drug development and imaging. We synthesized [¹⁸F]cEFQ (3-ethyl-2-[¹⁸F]fluoroquinolin-6-yl cis-(4-methoxycyclohexyl)methanone) as a PET tracer for selective mGluR1 imaging and evaluated its properties in rodents. A chloroquinoline precursor was labeled by a nucleophilic substitution reaction, and the resulting [¹⁸F]cEFQ was obtained with high radiochemical purity (>99%) and specific activity (63-246 GBq/µmol). The log D value was 3.24, and the initial brain uptake at 10 min was over 4% of injected dose per gram in BALB/c mice. According to PET/CT and autoradiography in SD rats, [¹⁸F]cEFQ showed wide distribution in the whole brain and the highest uptake in the cerebellum. Pre-treatment with unlabeled cEFQ or the mGluR1-specific antagonist JNJ16259685 blocked the uptake of [¹⁸F]cEFQ. However, the uptake was not blocked by pre-treatment with the mGluR5-specific antagonist ABP688. The trans isomer [¹⁸F]tEFQ did not show high uptake in the mGluR1-rich region. [¹⁸F]cEFQ was straightforwardly prepared using a chloro-derivative precursor. Its feasibility as a specific and selective PET agent for imaging mGluR1 was proved by in vitro and in vivo experiments using rodents.

Keywords: Autoradiography; [18F]cEFQ; metabotropic glutamate receptor subtype 1 (mGluR1); positron emission tomography (PET).

Figure 1.

Structures of quinoline derivatives for studying mGluR1 (a) and radiosynthetic scheme of [¹⁸F]cEFQ and [¹⁸F]tEFQ (b).

Figure 2.

HPLC profiles of metabolites in the plasma, brain and urine of BALB/c mice. The samples were obtained at 30 min after injection of [¹⁸F]cEFQ. Metabolites 1–6 were found in the plasma sample. Metabolite 1 was not found in brain while metabolites 5 and 6 were not found in urine.

Figure 3.

PET and CT images of normal SD rat brains. PET images of [¹⁸F]cEFQ (a), [¹⁸F]tEFQ (b), [¹⁸F]cEFQ 10 min after pretreatment with 3 mg/kg cEFQ (c), [¹⁸F]cEFQ 10 min after pretreatment with 3 mg/kg JNJ16259685 (d), [¹⁸F]cEFQ 10 min after pretreatment with 3 mg/kg ABP688 (e) and CT image (f). All PET images are sum images of 2–10 min after injection.

Figure 4.

Time–activity curves of [¹⁸F]cEFQ (a), [¹⁸F]tEFQ (b), [¹⁸F]cEFQ 10 min after pretreatment with 3 mg/kg cEFQ (c), [¹⁸F]cEFQ 10 min after pretreatment with 3 mg/kg JNJ16259685 (d), and [¹⁸F]cEFQ 10 min after pretreatment with 3 mg/kg ABP688 (e) in SD rat brains. These TACs are representative results from a rat.

Figure 5.

Autoradiograms of [¹⁸F]cEFQ in the SD rat brain (a) and with co-injection of JNJ16259685 (b). Cbl, cerebellum; Hip, hippocampus; Str, striatum; Th, thalamus; Ot, olfactory tubercle; SNr, substantia nigra pars reticulata.