Preclinical Evaluation of Dihydropyrazole-Cored Positron Emission Tomography (PET) Ligands for Imaging of Receptor-Interacting Serine/Threonine Protein Kinase 1 (RIPK1) in the Brain.

Receptor-interacting serine/threonine protein kinase 1 (RIPK1) has emerged as an important regulator of pathologic cell death and inflammation and is implicated in the pathologies of various central nervous system diseases. In this study, we reported the development of three potent dihydropyrazole-cored RIPK1 positron emission tomography (PET) ligands [F]-. Among these, [F] showed specific binding to RIPK1 in mouse brain sections through autoradiography and exhibited favorable brain kinetics in mice, characterized by a high initial uptake (brain = 4.

Structure-based discovery of a 4,5-Dihydropyrazole-cored PET ligand for imaging of receptor-interacting serine/threonine-protein kinase 1 (RIPK1) in the brain.

Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) regulates programmed cell death and inflammation, contributing to a wide range of human pathologies, including inflammatory disorders, neurodegenerative conditions, and cancer. Despite this, no RIPK1 positron emission tomography (PET) ligand with significant in vivo specificity has been reported to date. In this work, we designed and synthesized a new family of dihydropyrazole-cored ligands suitable for F-labeling at the late stage.

Imaging Cholinergic Receptors in the Brain by Positron Emission Tomography.

Cholinergic receptors represent a promising class of diagnostic and therapeutic targets due to their significant involvement in cognitive decline associated with neurological disorders and neurodegenerative diseases as well as cardiovascular impairment. Positron emission tomography (PET) is a noninvasive molecular imaging tool that has helped to shed light on the roles these receptors play in disease development and their diverse functions throughout the central nervous system (CNS). In recent years, there has been a notable advancement in the development of PET probes targeting cholinergic receptors.

F-Labeled o‑aminopyridyl alkynyl radioligands targeting colony-stimulating factor 1 receptor for neuroinflammation imaging.

We report the design, synthesis and evaluation of five o‑aminopyridyl alkynyl derivatives as colony-stimulating factor 1 receptor (CSF-1R) ligands. Compounds 4 and 5 with the fluoroethoxy group at the meta- or para-position of the phenyl ring possessed nanomolar inhibitory potency against CSF-1R with IC values of 7.6 nM and 2.

D-π-A-Based Trisubstituted Alkenes as Environmentally Sensitive Fluorescent Probes to Detect Lewy Pathologies.

Lewy pathologies, which mainly consist of insoluble α-synuclein (α-syn) aggregates, are the hallmarks of Parkinson's disease and many other neurodegenerative diseases termed "synucleinopathies". Detection of Lewy pathologies with optical methods is of interest for preclinical studies, while the α-syn fluorescent probe is still in great demand. By rational design, we obtained a series of D-π-A-based trisubstituted alkenes with acceptable optical properties and high binding affinities to α-syn fibrils.

Imaging Leucine-Rich Repeat Kinase 2 In Vivo with F-Labeled Positron Emission Tomography Ligand.

Leucine-rich repeat kinase 2 (LRRK2) has been demonstrated to be closely involved in the pathogenesis of Parkinson's disease (PD), and pharmacological blockade of LRRK2 represents a new opportunity for therapeutical treatment of PD and other related neurodegenerative conditions. The development of an LRRK2-specific positron emission tomography (PET) ligand would enable a target occupancy study in vivo and greatly facilitate LRRK2 drug discovery and clinical translation as well as provide a molecular imaging tool for studying physiopathological changes in neurodegenerative diseases. In this work, we present the design and development of compound (PF-06455943) as a promising PET radioligand through a PET-specific structure-activity relationship optimization, followed by comprehensive pharmacology and ADME/neuroPK characterization.

Rational design of molecular rotor-based fluorescent probes with bi-aromatic rings for efficient in vivo detection of amyloid-β plaques in Alzheimer's disease.

The presence of Aβ plaques in the brain is a hallmark of Alzheimer's disease. Here, we designed and synthesized a series of molecular rotors with various bi-aromatic rings and investigated their applications as near-infrared (NIR) probes for Aβ plaques. We found that the interaction with Aβ aggregates hindered the rotational freedom of the molecular rotors, which brought about a noticeable enhancement in fluorescence intensity.

Positron Emission Tomography (PET) Imaging Tracers for Serotonin Receptors.

Serotonin (5-hydroxytryptamine, 5-HT) and 5-HT receptors (5-HTRs) have crucial roles in various neuropsychiatric disorders and neurodegenerative diseases, making them attractive diagnostic and therapeutic targets. Positron emission tomography (PET) is a noninvasive nuclear molecular imaging technique and is an essential tool in clinical diagnosis and drug discovery. In this context, numerous PET ligands have been developed for "visualizing" 5-HTRs in the brain and translated into human use to study disease mechanisms and/or support drug development.

Discovery and development of brain-penetrant F-labeled radioligands for neuroimaging of the sigma-2 receptors.

We have discovered and synthesized a series of indole-based derivatives as novel sigma-2 ( ) receptor ligands. Two ligands with high receptor affinity and subtype selectivity were then radiolabeled with F-18 in good radiochemical yields and purities, and evaluated in rodents. In biodistribution studies in male ICR mice, radioligand [F], or 1-(4-(5,6-dimethoxyisoindolin-2-yl)butyl)-4-(2-[F]fluoroethoxy)-1-indole, was found to display high brain uptake and high brain-to-blood ratio.

[F]MAGL-4-11 positron emission tomography molecular imaging of monoacylglycerol lipase changes in preclinical liver fibrosis models.

Monoacylglycerol lipase (MAGL) is a pivotal enzyme in the endocannabinoid system, which metabolizes 2-arachidonoylglycerol (2-AG) into the proinflammatory eicosanoid precursor arachidonic acid (AA). MAGL and other endogenous cannabinoid (EC) degrading enzymes are involved in the fibrogenic signaling pathways that induce hepatic stellate cell (HSC) activation and ECM accumulation during chronic liver disease. Our group recently developed an F-labeled MAGL inhibitor ([F]MAGL-4-11) for PET imaging and demonstrated highly specific binding and .

Visualizing Tumors in Real Time: A Highly Sensitive PSMA Probe for NIR-II Imaging and Intraoperative Tumor Resection.

Owing to the complex anatomical structure, precise resection of a tumor while maintaining adjacent tissue is a challenge in radical prostatectomy for prostate cancer (PCa). Optical imaging in near-infrared window II (NIR-II) is a promising technology for intraoperative guidance, whereas there is no available probe for PCa yet. In this article, a novel probe () bearing two prostate-specific membrane antigen (PSMA) binding motifs was developed, displaying excellent optical properties (λ = 1092 nm) and ultrahigh affinity ( = 80 pM) toward PSMA.

Near-Infrared Fluorescent Probes with Rotatable Polyacetylene Chains for the Detection of Amyloid-β Plaques.

The plaques of accumulated β-amyloid (Aβ) in the parenchymal brain are accepted as an important biomarker for the early diagnosis of Alzheimer's disease (AD). Many near-infrared (NIR) probes, which were based on the D-π-A structure and bridged by conjugated double bonds, had been reported and displayed a high affinity to Aβ plaques. Considering the isomerization caused by the polyethylene chain, however, the conjugated polyacetylene chain is a better choice for developing new NIR Aβ probes.

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

Selective modulation of metabotropic glutamate receptor 2 (mGlu) 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 using positron emission tomography (PET) would allow for 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.

Synthesis and preliminary evaluation of novel C-labeled GluN2B-selective NMDA receptor negative allosteric modulators.

N-methyl-D-aspartate receptors (NMDARs) play critical roles in the physiological function of the mammalian central nervous system (CNS), including learning, memory, and synaptic plasticity, through modulating excitatory neurotransmission. Attributed to etiopathology of various CNS disorders and neurodegenerative diseases, GluN2B is one of the most well-studied subtypes in preclinical and clinical studies on NMDARs. Herein, we report the synthesis and preclinical evaluation of two C-labeled GluN2B-selective negative allosteric modulators (NAMs) containing N,N-dimethyl-2-(1H-pyrrolo[3,2-b]pyridin-1-yl)acetamides for positron emission tomography (PET) imaging.

Synthesis and evaluation of new 1-oxa-8-azaspiro[4.5]decane derivatives as candidate radioligands for sigma-1 receptors.

We report the design, synthesis, and evaluation of a series of 1-oxa-8-azaspiro[4.5]decane and 1,5-dioxa-9-azaspiro[5.5]undecane derivatives as selective σ receptor ligands.

Synthesis and pharmacokinetic study of a C-labeled cholesterol 24-hydroxylase inhibitor using 'in-loop' [C]CO fixation method.

Cholesterol 24-hydroxylase, also known as CYP46A1 (EC 1.14.13.

Radiosynthesis and preliminary evaluation of C-labeled 4-cyclopropyl-7-(3-methoxyphenoxy)-3,4-dihydro-2-benzo[] [1,2,4] thiadiazine 1,1-dioxide for PET imaging AMPA receptors.

The α-amino-3-hydroxyl-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) belong to the family of ionotropic transmembrane receptors for glutamate (iGluRs) that are implicated in the pathology of neurological disorders and neurodegenerative diseases. Inspired by a recently developed positive allosteric modulator of AMPARs, 4-cyclopropyl-7-(3-methoxyphenoxy)-3,4-dihydro-2-benzo[ ][1,2,4]thiadiazine 1,1-dioxide (; EC = 2.0 nM), we designed a new synthetic route for -protected phenolic precursor and efficiently radiolabeled a PET ligand [C] ([C]) using a modified one-pot two-step strategy in high radiochemical yield and high molar activity.

[F]-Alfatide PET imaging of integrin αvβ3 for the non-invasive quantification of liver fibrosis.

Background & Aims: The vitronectin receptor integrin αvβ3 drives fibrogenic activation of hepatic stellate cells (HSCs). Molecular imaging targeting the integrin αvβ3 could provide a non-invasive method for evaluating the expression and the function of the integrin αvβ3 on activated HSCs (aHSCs) in the injured liver. In this study, we sought to compare differences in the uptake of [F]-Alfatide between normal and injured liver to evaluate its utility for assessment of hepatic fibrogenesis.

Design, Synthesis, and Evaluation of F-Labeled Monoacylglycerol Lipase Inhibitors as Novel Positron Emission Tomography Probes.

Dysfunction of monoacylglycerol lipase (MAGL) is associated with several psychopathological disorders, including drug addiction and neurodegenerative diseases. Herein we design, synthesize, and evaluate several irreversible fluorine-containing MAGL inhibitors for positron emission tomography (PET) ligand development. Compound (identified from a therapeutic agent) was advanced for F-labeling via a novel spirocyclic iodonium ylide (SCIDY) strategy, which demonstrated high brain permeability and excellent specific binding.

Synthesis and Preliminary Evaluation of [ C]GNE-1023 as a Potent PET Probe for Imaging Leucine-Rich Repeat Kinase 2 (LRRK2) in Parkinson's Disease.

Leucine-rich repeat kinase 2 (LRRK2) is a large protein involved in the pathogenesis of Parkinson's disease (PD). It has been demonstrated that PD is mainly conferred by LRRK2 mutations that bring about increased kinase activity. As a consequence, selective inhibition of LRRK2 may help to recover the normal functions of LRRK2, thereby serving as a promising alternative therapeutic target for PD treatment.

Half-curcumin analogues as PET imaging probes for amyloid beta species.

In this report, we demonstrate that half-curcuminoid could be a better scaffold for PET tracer development. F-CRANAD-101 was designed and found to show significant response to both soluble and insoluble Aβs in the fluorescent spectral tests. PET imaging results indicated that 14 month and 5 month old APP/PS1 AD mice had higher signals in the brain than age-matched wild type mice.

Design, Synthesis, and Evaluation of Reversible and Irreversible Monoacylglycerol Lipase Positron Emission Tomography (PET) Tracers Using a "Tail Switching" Strategy on a Piperazinyl Azetidine Skeleton.

Monoacylglycerol lipase (MAGL) is a serine hydrolase that degrades 2-arachidonoylglycerol (2-AG) in the endocannabinoid system (eCB). Selective inhibition of MAGL has emerged as a potential therapeutic approach for the treatment of diverse pathological conditions, including chronic pain, inflammation, cancer, and neurodegeneration. Herein, we disclose a novel array of reversible and irreversible MAGL inhibitors by means of "tail switching" on a piperazinyl azetidine scaffold.

Synthesis and Preliminary Evaluations of a Triazole-Cored Antagonist as a PET Imaging Probe ([F]N2B-0518) for GluN2B Subunit in the Brain.

GluN2B is the most studied subunit of N-methyl-d-aspartate receptors (NMDARs) and implicated in the pathologies of various central nervous system disorders and neurodegenerative diseases. As pan NMDAR antagonists often produce debilitating side effects, new approaches in drug discovery have shifted to subtype-selective NMDAR modulators, especially GluN2B-selective antagonists. While positron emission tomography (PET) studies of GluN2B-selective NMDARs in the living brain would enable target engagement in drug development and improve our understanding in the NMDAR signaling pathways between normal and disease conditions, a suitable PET ligand is yet to be identified.

Synthesis, pharmacology and preclinical evaluation of C-labeled 1,3-dihydro-2H-benzo[d]imidazole-2-ones for imaging γ8-dependent transmembrane AMPA receptor regulatory protein.

a-Amino-3-hydroxyl-5-methyl-4-isoxazolepropionic acid (AMPA) receptors are implicated in the pathology of neurological diseases such as epilepsy and schizophrenia. As pan antagonists for this target are often accompanied with undesired effects at high doses, one of the recent drug discovery approaches has shifted to subtype-selective AMPA receptor (AMPAR) antagonists, specifically, via modulating transmembrane AMPAR regulatory proteins (TARPs). The quantification of AMPARs by positron emission tomography (PET) would help obtain insights into disease conditions in the living brain and advance the translational development of AMPAR antagonists.