AMG 580: A Novel Small Molecule Phosphodiesterase 10A (PDE10A) Positron Emission Tomography Tracer

Abstract

Phosphodiesterase 10A (PDE10A) inhibitors have therapeutic potential for the treatment of psychiatric and neurologic disorders, such as schizophrenia and Huntington's disease. One of the key requirements for successful central nervous system drug development is to demonstrate target coverage of therapeutic candidates in brain for lead optimization in the drug discovery phase and for assisting dose selection in clinical development. Therefore, we identified AMG 580 [1-(4-(3-(4-(1H-benzo[d] imidazole-2-carbonyl)phenoxy)pyrazin-2-yl)piperidin-1-yl)-2-fluoropropan-1-one], a novel, selective small-molecule antagonist with subnanomolar affinity for rat, primate, and human PDE10A. We showed that AMG 580 is suitable as a tracer for lead optimization to determine target coverage by novel PDE10A inhibitors using triple-stage quadrupole liquid chromatography-tandem mass spectrometry technology. [ 3 H]AMG 580 bound with high affinity in a specific and saturable manner to both striatal homogenates and brain slices from rats, baboons, and human in vitro. Moreover, [18 F]AMG 580 demonstrated prominent uptake by positron emission tomography in rats, suggesting that radiolabeled AMG 580 may be suitable for further development as a noninvasive radiotracer for target coverage measurements in clinical studies. These results indicate that AMG 580 is a potential imaging biomarker for mapping PDE10A distribution and ensuring target coverage by therapeutic PDE10A inhibitors in clinical studies.

Radiosynthesis and biological evaluation of the new PDE10A radioligand [18F]AQ28A

“…In plasma, [ 18 F]AQ28A accounted for 36 ± 3% (t R = 31.0 min, n = 3) of the extraction fraction (Figure 8, bottom), which is comparable to the amount of intact radioligand found for [ 18 F]JNJ42259152 (54%, rats), 26 [ 18 F]AMG580 (~30%, baboons/rhesus monkeys), 33 and [ 18 F]MNI659 (~40%, humans). 29 Due to species-dependent differences, we hypothesize that higher amounts of intact [ 18 F]AQ28A will be detected in nonrodent species.…”

“…27,28 Furthermore, the 2- 20,[30][31][32] and recently the 1-(4-(3-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)pyrazin-2-yl) piperidin-1-yl)-2-fluoropropan-1-one [ 18 F]AMG580 was developed and tested in nonhuman primates. 33,34 We obtained an 18 F-labeled ligand from a series of (R)-6,7dimethoxy-4-(3-(quinoxalin-2-yloxy)pyrrolidin-1-yl)quinazoline (PQ-10) derivatives 35 ; however, [ 18 F]IV ( Figure 1) proved to be nonselective in vivo. 36 1-arylimidazo [1,5-a]quinoxalines were reported as a new class of compounds characterized by high inhibitory potency and selectivity for PDE10A as well as pronounced in vitro stability.…”

Automation of a Positron-emission Tomography (PET) Radiotracer Synthesis Protocol for Clinical Production

“…Using this radiosynthesizer, we have previously reported the automated synthesis of 24 different 18 F-labeled tracers and prosthetic groups 11 14 15 16 , as well as the automated enzymatic radiofluorination of biomolecules 17 , by simply changing reagents and not the configuration of the system. Others have shown the automated synthesis of [ 18 F]RO6958948 for the imaging of tau neurofibrillary tangles 18 , the automated synthesis of the prosthetic group [ 18 F]F-Py-TFP with a subsequent labeling of peptides 19 , and the automated synthesis of [ 18 F]AM580 for the imaging of phosphodiesterase 10a (PDE10A) 20 . Furthermore, several groups have shown the production of tracers suitable for clinical use, including 4-[ 18 F]Fluorobenzyl-triphenylphosphonium ([ 18 F]FBnTP) for the imaging of mitochondrial membrane potential 21 , [ 18 F]DCFPyL for the imaging of prostate-specific membrane antigen (PSMA) 22 , and [ 18 F]THK-5351 for the imaging of tau 23 .…”

The rational search for PDE10A inhibitors from Sophora�flavescens roots using pharmacophore‑ and docking‑based virtual screening

“…Phosphodiesterases (PDEs) are a family of enzymes that are able to lyse phosphodiester bonds, are expressed widely, and have demonstrable clinical significance (1,2). PDE10A has been demonstrated to be a potential target for the treatment of central nervous system (CNS) disorders (3,4). Previous studies have confirmed that PDE10A inhibitors have important biological activity in the treatment of psychosis (5)(6)(7).…”