Synthesis and preliminary studies of ¹¹C-labeled tetrahydro-1,7-naphthyridine-2-carboxamides for PET imaging of metabotropic glutamate receptor 2

Abstract

Selective modulation of metabotropic glutamate receptor 2 (mGlu 2 ) represents a novel therapeutic approach for treating brain disorders, including schizophrenia, depression, Parkinson's disease (PD), Alzheimer's disease (AD), drug abuse and addiction. Imaging mGlu 2 using positron emission tomography (PET) would allow for in vivo quantification under physiological and pathological conditions and facilitate drug discovery by enabling target engagement studies. In this paper, we aimed to develop a novel specific radioligand derived from negative allosteric modulators (NAMs) for PET imaging of mGlu 2 . Methods. A focused small molecule library of mGlu 2 NAMs with tetrahydro naphthyridine scaffold was synthesized for pharmacology and physicochemical evaluation. GIRK dose-response assays and CNS panel binding selectivity assays were performed to study the affinity and selectivity of mGlu 2 NAMs, among which compounds 14a and 14b were selected as PET ligand candidates. Autoradiography in SD rat brain sections was used to confirm the in vitro binding specificity and selectivity of [ 11 C] 14a and [ 11 C] 14b towards mGlu 2 . In vivo binding specificity was then studied by PET imaging. Whole body biodistribution study and radiometabolite analysis were conducted to demonstrate the pharmacokinetic properties of [ 11 C] 14b as most promising PET mGlu 2 PET ligand. Results. mGlu 2 NAMs 14a-14g were synthesized in 14%-20% yields in five steps. NAMs 14a and 14b were selected to be the most promising ligands due to their high affinity in GIRK dose-response assays. [ 11 C] 14a and [ 11 C] 14b displayed similar heterogeneous distribution by autoradiography, consistent with mGlu 2 expression in the brain. While PET imaging study showed good brain permeability for both tracers, compound [ 11 C] 14b demonstrated superior binding specificity compared to [ 11 C] 14a . Further radiometabolite analysis of [ 11 C] 14b showed excellent stability in the brain. Conclusions. Compound 14b exhibited high affinity and excellent subtype selectivity, which was then evaluated by in vitro autoradiography and in vivo PET imaging study after labeling with carbo...

Synthesis and characterization of 5-(2-fluoro-4-[11C]methoxyphenyl)-2,2-dimethyl-3,4-dihydro-2H-pyrano[2,3-b]pyridine-7-carboxamide as a PET imaging ligand for metabotropic glutamate receptor 2

“…Accumulation of [ 11 C] 13 was high at the mGluR2-rich regions of striatum, thalamus, cortex, hypothalamus, hippocampus, and cerebellum. [ 11 C] 13 showed improved brain heterogeneity compared to those of [ 11 C]MG-1904 ( 10 ) 36 and [ 11 C]MG2-1812 ( 11 ) 35 .…”

“…In the previous radiotracer synthesis, such as [ 11 C]QCA ( 7 ), the product was enriched by removing the HPLC solvents under reduced pressure. 30–31, 35–36 At the end of synthesis (EOS = 45 min), [ 11 C] 13 was obtained with a radiochemical yield of 42 ± 5% (n = 5, non-decay corrected) calculated from starting [ 11 C]CO 2 , excellent chemical and radiochemical purities (> 99%), and a high molar activity (A m ) of 212 ± 76 GBq/µmol (n = 5). As a representative 3,4-dihydro-2 H -pyrano[2,3- b ]pyridine NAM tracer, [ 11 C] 13 was characterized using in vivo PET imaging studies in rats and a non-human primate.…”

“…3. [ 11 C] 13 showed excellent brain permeability with a maximum SUV value of 3.6 at 3 min in striatum, which was higher than that of [ 11 C]MG-1904 ( 10 , SUV max = 1.7) 36 and [ 11 C]MG2-1812 ( 11 , SUV max = 1.2) 35 . [ 11 C] 13 had a satisfactory tracer kinetics with most of the radioactivity washed out at 30 min (SUV 3min /SUV 30min = 2.7).…”

“…In the previous radiotracer synthesis, such as [ 11 C]QCA (7), the product was enriched by removing the HPLC solvents under reduced pressure. [30][31][35][36] Pretreatment with both compounds were investigated using two different time points, namely, 1 min and 20 min before radioactivity. Pretreatment with 9 (0.5 mg/kg, iv.)…”

“…The recent surge on the development of mGluR2 NAMs has resulted in a number of patent applications and research publications, providing an ample reservoir of PET imaging candidates with distinct structures. For instance, the recently published NAM tracers of [ 11 C]MG- 1904 ( 10 , IC 50 = 24 nM), 36 which was selected from a series of tetrahydronaphthyridine derivatives patented by Merck in 2016, 37 and [ 11 C]MG2-1812 ( 11 , IC 50 = 21 nM), 35 which was a close analog of VU6001966 ( 9 ), 34 were brain permeable in rats.…”