Publications by authors named "Steven H Liang"

88 Publications

Evaluation of [H]CPPC as a Tool Radioligand for CSF-1R.

ACS Chem Neurosci 2021 Mar 5;12(6):998-1006. Epub 2021 Mar 5.

Azrieli Centre for Neuro-Radiochemistry, Brain Health Imaging Centre, Centre for Addiction and Mental Health (CAMH), Toronto, ON M5T 1R8, Canada.

Microglia play a role in several central nervous system (CNS) diseases and are a highly sought target for positron emission tomography (PET) imaging and therapeutic intervention. 5-Cyano--(4-(4-[C]methylpiperazin-1-yl)-2-(piperidin-1-yl)phenyl)furan-2-carboxamide ([C]CPPC) is a radiopharmaceutical designed to selectively target microglia macrophage colony stimulating factor-1 receptor (CSF-1R) in the CNS. Herein, we report the first preclinical evaluation of [H]CPPC using radioligand binding methods for the evaluation of putative CSF-1R inhibitors in rodent models of neuroinflammation. The distribution of [H]CPPC by autoradiography did not align with 18 kDa translocator protein (TSPO) distribution using [H]PBR28 and IBA-1 staining for microglia. In the CNS, [H]CPPC had considerable nonspecific binding, as indicated by a low displacement of the tritiated ligand by unlabeled CPPC and the known CSF1R inhibitors BLZ-945 and PLX3397. Spleen was identified as a tissue that provided an adequate signal-to-noise ratio to enable screening with [H]CPPC and a library of 20 novel PLX3397 derivatives. However, unlabeled CPPC lacked selectivity and showed off-target binding to a substantial number of kinase targets (204 out of 403 tested) at a concentration relevant to radioligand binding assays (10 μM). These findings suggest that, while [H]CPPC may have utility as a radioligand tool for the evaluation of peripheral targets and screening of CSF-1R inhibitors, it may have limited utility as an CNS imaging probe on the basis of the current evaluation.
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http://dx.doi.org/10.1021/acschemneuro.0c00802DOI Listing
March 2021

Recent developments on PET radiotracers for TSPO and their applications in neuroimaging.

Acta Pharm Sin B 2021 Feb 25;11(2):373-393. Epub 2020 Aug 25.

Division of Nuclear Medicine and Molecular Imaging, Massachusetts General Hospital & Department of Radiology, Harvard Medical School, Boston, MA 02114, USA.

The 18 kDa translocator protein (TSPO), previously known as the peripheral benzodiazepine receptor, is predominately localized to the outer mitochondrial membrane in steroidogenic cells. Brain TSPO expression is relatively low under physiological conditions, but is upregulated in response to glial cell activation. As the primary index of neuroinflammation, TSPO is implicated in the pathogenesis and progression of numerous neuropsychiatric disorders and neurodegenerative diseases, including Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD), multiple sclerosis (MS), major depressive disorder (MDD) and obsessive compulsive disorder (OCD). In this context, numerous TSPO-targeted positron emission tomography (PET) tracers have been developed. Among them, several radioligands have advanced to clinical research studies. In this review, we will overview the recent development of TSPO PET tracers, focusing on the radioligand design, radioisotope labeling, pharmacokinetics, and PET imaging evaluation. Additionally, we will consider current limitations, as well as translational potential for future application of TSPO radiopharmaceuticals. This review aims to not only present the challenges in current TSPO PET imaging, but to also provide a new perspective on TSPO targeted PET tracer discovery efforts. Addressing these challenges will facilitate the translation of TSPO in clinical studies of neuroinflammation associated with central nervous system diseases.
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http://dx.doi.org/10.1016/j.apsb.2020.08.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7893127PMC
February 2021

Positron Emission Tomography Imaging of the Endocannabinoid System: Opportunities and Challenges in Radiotracer Development.

J Med Chem 2021 01 30;64(1):123-149. Epub 2020 Dec 30.

Division of Nuclear Medicine and Molecular Imaging, Massachusetts General Hospital, and Department of Radiology, Harvard Medical School, Boston, Massachusetts 02114, United States.

The endocannabinoid system (ECS) is involved in a wide range of biological functions and comprises cannabinoid receptors and enzymes responsible for endocannabinoid synthesis and degradation. Over the past 2 decades, significant advances toward developing drugs and positron emission tomography (PET) tracers targeting different components of the ECS have been made. Herein, we summarized the recent development of PET tracers for imaging cannabinoid receptors 1 (CB1R) and 2 (CB2R) as well as the key enzymes monoacylglycerol lipase (MAGL) and fatty acid amide hydrolase (FAAH), particularly focusing on PET neuroimaging applications. State-of-the-art PET tracers for the ECS will be reviewed including their chemical design, pharmacological properties, radiolabeling, as well as preclinical and human PET imaging. In addition, this review addresses the current challenges for ECS PET biomarker development and highlights the important role of PET ligands to study disease pathophysiology as well as to facilitate drug discovery.
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http://dx.doi.org/10.1021/acs.jmedchem.0c01459DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7877880PMC
January 2021

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

Theranostics 2020 14;10(24):11178-11196. Epub 2020 Sep 14.

Division of Nuclear Medicine and Molecular Imaging, Massachusetts General Hospital & Department of Radiology, Harvard Medical School, Boston, MA, 02114, USA.

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. A focused small molecule library of mGlu 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 NAMs, among which compounds and were selected as PET ligand candidates. Autoradiography in SD rat brain sections was used to confirm the binding specificity and selectivity of [C] and [C] towards mGlu. binding specificity was then studied by PET imaging. Whole body biodistribution study and radiometabolite analysis were conducted to demonstrate the pharmacokinetic properties of [C] as most promising PET mGlu PET ligand. mGlu NAMs were synthesized in 14%-20% yields in five steps. NAMs and were selected to be the most promising ligands due to their high affinity in GIRK dose-response assays. [C] and [C] displayed similar heterogeneous distribution by autoradiography, consistent with mGlu expression in the brain. While PET imaging study showed good brain permeability for both tracers, compound [C] demonstrated superior binding specificity compared to [C]. Further radiometabolite analysis of [C] showed excellent stability in the brain. Compound exhibited high affinity and excellent subtype selectivity, which was then evaluated by autoradiography and PET imaging study after labeling with carbon-11. Ligand [C], which we named [C]MG2-1904, demonstrated high brain uptake and excellent / specific binding towards mGlu with high metabolic stability in the brain. As proof-of-concept, our preliminary work demonstrated a successful example of visualizing mGlu derived from NAMs, which represents a promising chemotype for further development and optimization aimed for clinical translation.
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http://dx.doi.org/10.7150/thno.42587DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7532674PMC
September 2020

Identification and Development of a New Positron Emission Tomography Ligand 4-(2-Fluoro-4-[C]methoxyphenyl)-5-((1-methyl-1-pyrazol-3-yl)methoxy)picolinamide for Imaging Metabotropic Glutamate Receptor Subtype 2 (mGlu).

J Med Chem 2020 10 22;63(20):11469-11483. Epub 2020 Sep 22.

Department of Advanced Nuclear Medicine Sciences, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, 4-9-1 Anagawa, Inage-ku, Chiba 263-8555, Japan.

Metabotropic glutamate receptor 2 (mGlu) is a known target for treating several central nervous system (CNS) disorders. To develop a viable positron emission tomography (PET) ligand for mGlu, we identified new candidates - that are potent negative allosteric modulators (NAMs) of mGlu. Among these candidates, 4-(2-fluoro-4-methoxyphenyl)-5-((1-methyl-1-pyrazol-3-yl)methoxy)picolinamide (, also named as [C]MG2-1812) exhibited high potency, high subtype selectivity, and favorable lipophilicity. Compound was labeled with positron-emitting carbon-11 (C) to obtain [C] in high radiochemical yield and high molar activity by -[C]methylation of the phenol precursor with [C]CHI. autoradiography with [C] showed heterogeneous radioactive accumulation in the brain tissue sections, ranked in the order: cortex > striatum > hippocampus > cerebellum ≫ thalamus > pons. PET study of [C] indicated specific binding of mGlu in the rat brain. Based on the [C] scaffold, further optimization for new candidates is underway to identify a more suitable ligand for imaging mGlu.
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http://dx.doi.org/10.1021/acs.jmedchem.9b01991DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7892210PMC
October 2020

Synthesis and preliminary evaluation of a novel positron emission tomography (PET) ligand for imaging fatty acid amide hydrolase (FAAH).

Bioorg Med Chem Lett 2020 11 27;30(21):127513. Epub 2020 Aug 27.

Center of Cyclotron and PET Radiopharmaceuticals, Department of Nuclear Medicine and PET/CT-MRI Center, The First Affiliated Hospital of Jinan University, Guangzhou 510630, China. Electronic address:

Fatty acid amide hydrolase (FAAH) exerts its main function in the catabolism of the endogenous chemical messenger anandamide (AEA), thus modulating the endocannabinoid (eCB) pathway. Inhibition of FAAH may serve as an effective strategy to relieve anxiety and possibly other central nervous system (CNS)-related disorders. Positron emission tomography (PET) would facilitate us to better understand the relationship between FAAH in certain disease conditions, and accelerate clinical translation of FAAH inhibitors by providing in vivo quantitative information. So far, most PET tracers show irreversible binding patterns with FAAH, which would result in complicated quantitative processes. Herein, we have identified a new FAAH inhibitor (1-((1-methyl-1H-indol-2-yl)methyl)piperidin-4-yl)(oxazol-2-yl)methanone (8) which inhibits the hydrolysis of AEA in the brain with high potency (IC value 11 nM at a substrate concentration of 0.5 µM), and without showing time-dependency. The PET tracer [C]8 (also called [C]FAAH-1906) was successfully radiolabeled with [C]MeI in 17 ± 6% decay-corrected radiochemical yield (n = 7) with >74.0 GBq/μmol (2 Ci/μmol) molar activity and >99% radiochemical purity. Ex vivo biodistribution and blocking studies of [C]8 in normal mice were also conducted, indicating good brain penetration, high brain target selectivity, and modest to excellent target selectivity in peripheral tissues. Thus, [C]8 is a potentially useful PET ligand with enzyme inhibitory and target binding properties consistent with a reversible mode of action.
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http://dx.doi.org/10.1016/j.bmcl.2020.127513DOI Listing
November 2020

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

Acta Pharmacol Sin 2021 Mar 13;42(3):491-498. Epub 2020 Jul 13.

Department of Radiology, Division of Nuclear Medicine and Molecular Imaging Massachusetts General Hospital and Harvard Medical School, 55 Fruit Street, Boston, MA, 02114, USA.

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. Two PET ligands, namely [C]31 and [C]37 (also called N2B-1810 and N2B-1903, respectively) were labeled with [C]CHI in good radiochemical yields (decay-corrected 28% and 32% relative to starting [C]CO, respectively), high radiochemical purity (>99%) and high molar activity (>74 GBq/μmol). In particular, PET ligand [C]31 demonstrated moderate specific binding to GluN2B subtype by in vitro autoradiography studies. However, because in vivo PET imaging studies showed limited brain uptake of [C]31 (up to 0.5 SUV), further medicinal chemistry and ADME optimization are necessary for this chemotype attributed to low binding specificity and rapid metabolism in vivo.
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http://dx.doi.org/10.1038/s41401-020-0456-9DOI Listing
March 2021

Fifty Years of Radiopharmaceuticals.

J Nucl Med Technol 2020 06;48(Suppl 1):34S-39S

Molecular Imaging Core, Department of Diagnostic Imaging, St. Jude Children's Research Hospital, Memphis, Tennessee; and.

To celebrate the 50th anniversary of the founding of the SNMMI Technologist Section in 1970, the Radiopharmaceutical Sciences Council board of directors is pleased to contribute to this celebratory supplement of the with a perspective highlighting major developments in the radiopharmaceutical sciences that have occurred in the last 50 years.
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June 2020

Classics in Neuroimaging: Imaging the Endocannabinoid Pathway with PET.

ACS Chem Neurosci 2020 07 19;11(13):1855-1862. Epub 2020 Jun 19.

Azrieli Centre for Neuro-Radiochemistry, Brain Health Imaging Centre, Centre for Addiction and Mental Health (CAMH), Toronto, Ontario M5T-1R8, Canada.

This Viewpoint aims to highlight positron emission tomography (PET) research studies that have shaped our understanding of the endocannabinoid system (ECS) through radiopharmaceutical targeting of cannabinoid receptors 1 and 2 (CB and CB), and the enzyme fatty acid amide hydrolase (FAAH), in several brain health illnesses including addiction, schizophrenia, eating disorders, and post-traumatic stress disorder. Advances in radiochemistry, including C-carbonylation and radiofluorination of nonactivated aromatic rings, are accelerating the translation of radiotracers with optimal kinetics, bringing us closer to clinical PET research studies to image the enzyme monoacylglycerol lipase (MAGL) and enabling the imaging of unexplored targets in the ECS.
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http://dx.doi.org/10.1021/acschemneuro.0c00305DOI Listing
July 2020

Marriage of black phosphorus and Cu as effective photothermal agents for PET-guided combination cancer therapy.

Nat Commun 2020 06 8;11(1):2778. Epub 2020 Jun 8.

Department of Advanced Nuclear Medicine Sciences, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba, 2638555, Japan.

The use of photothermal agents (PTAs) in cancer photothermal therapy (PTT) has shown promising results in clinical studies. The rapid degradation of PTAs may address safety concerns but usually limits the photothermal stability required for efficacious treatment. Conversely, PTAs with high photothermal stability usually degrade slowly. The solutions that address the balance between the high photothermal stability and rapid degradation of PTAs are rare. Here, we report that the inherent Cu-capturing ability of black phosphorus (BP) can accelerate the degradation of BP, while also enhancing photothermal stability. The incorporation of Cu into BP@Cu nanostructures further enables chemodynamic therapy (CDT)-enhanced PTT. Moreover, by employing Cu, positron emission tomography (PET) imaging can be achieved for in vivo real-time and quantitative tracking. Therefore, our study not only introduces an "ideal" PTA that bypasses the limitations of PTAs, but also provides the proof-of-concept application of BP-based materials in PET-guided, CDT-enhanced combination cancer therapy.
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http://dx.doi.org/10.1038/s41467-020-16513-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7280494PMC
June 2020

Glucose Metabolism on Tumor Plasticity, Diagnosis, and Treatment.

Front Oncol 2020 6;10:317. Epub 2020 Mar 6.

Department of Thoracic Surgery, Beijing Sijitan Hospital, Capital Medical University, Beijing, China.

Malignant cells support tumor proliferation and progression by adopting to metabolic changes. Tumor cells altered metabolism by increasing glucose uptake and fermentation of glucose to lactate, even in the aerobic state and the presence of functioning mitochondria. Glucose metabolism in tumor plasticity has attracted great interests by clinicians and scientists in the past decades. This review discusses the previous and emerging researches on the tumor plasticity altered by changing glucose metabolism in different cancer cells, including cancer stem cells (CSCs). In addition, we summarize the rising applications of glucose metabolism in tumor diagnosis and treatment. Our objective is to direct future investigation on this altered metabolic phenotype and its application in patient care.
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http://dx.doi.org/10.3389/fonc.2020.00317DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7069415PMC
March 2020

Visible-light induced decarboxylative coupling of redox-active esters with disulfides to construct C-S bonds.

Chem Commun (Camb) 2020 Apr;56(30):4164-4167

Key Laboratory of Tropical Medicinal Resources of Ministry of Education, Collaborative Innovation Center of Tropical Biological Resources, Hainan Normal University, Hainan, Haikou 571158, China.

A novel method has been established for the construction of C-S bonds using redox-active esters with disulfides in the presence of Ru-photoredox catalyst. This method exhibits remarkable functional group tolerance across a wide scope of substrates. Under mild conditions, a structurally diverse array of aryl alkyl sulfides is successfully and efficiently obtained through decarboxylative cross-coupling.
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http://dx.doi.org/10.1039/d0cc00451kDOI Listing
April 2020

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

Bioorg Med Chem Lett 2020 05 6;30(9):127068. Epub 2020 Mar 6.

Division of Nuclear Medicine and Molecular Imaging, Massachusetts General Hospital & Department of Radiology, Harvard Medical School, Boston, MA 02114, USA. Electronic address:

Cholesterol 24-hydroxylase, also known as CYP46A1 (EC 1.14.13.98), is a monooxygenase and a member of the cytochrome P450 family. CYP46A1 is specifically expressed in the brain where it controls cholesterol elimination by producing 24S-hydroxylcholesterol (24-HC) as the major metabolite. Modulation of CYP46A1 activity may affect Aβ deposition and p-tau accumulation by changing 24-HC formation, which thereafter serves as potential therapeutic pathway for Alzheimer's disease. In this work, we showcase the efficient synthesis and preliminary pharmacokinetic evaluation of a novel cholesterol 24-hydroxylase inhibitor 1 for use in positron emission tomography.
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http://dx.doi.org/10.1016/j.bmcl.2020.127068DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7196435PMC
May 2020

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.

Tetrahedron Lett 2020 Mar 17;61(12). Epub 2020 Jan 17.

Division of Nuclear Medicine and Molecular Imaging, Massachusetts General Hospital & Department of Radiology, Harvard Medical School, Boston, MA 02114, USA.

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. Preliminary evaluation was carried out to investigate the suitability of [C] as a potential PET probe for AMPAR imaging.
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http://dx.doi.org/10.1016/j.tetlet.2020.151635DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7062035PMC
March 2020

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

J Hepatol 2020 07 5;73(1):161-169. Epub 2020 Mar 5.

Division of Nuclear Medicine and Molecular Imaging, Department of Radiology, Massachusetts General Hospital, Boston, USA. Electronic address:

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.

Methods: PET with [F]-Alfatide, non-enhanced CT, histopathology, immunofluorescence staining, immunoblotting and gene analysis were performed to evaluate and quantify hepatic integrin αvβ3 levels and liver fibrosis progression in mouse models of fibrosis (carbon tetrachloride [CCl] and bile duct ligation [BDL]). The liver AUC divided by the blood AUC over 30 min was used as an integrin αvβ3-PET index to quantify fibrosis progression. Ex vivo analysis of frozen liver tissue from patients with fibrosis and cirrhosis verified the animal findings.

Results: Fibrotic mouse livers showed enhanced [F]-Alfatide uptake and retention compared to control livers. The radiotracer was demonstrated to bind specifically with integrin αvβ3, which is mainly expressed on aHSCs. Autoradiography and histopathology confirmed the PET imaging results. Further, the mRNA and protein level of integrin αvβ3 and its signaling complex were higher in CCl and BDL models than controls. The results obtained from analyses on human fibrotic liver sections supported the animal findings.

Conclusions: Imaging hepatic integrin αvβ3 with PET and [F]-Alfatide offers a potential non-invasive method for monitoring the progression of liver fibrosis.

Lay Summary: Integrin αvβ3 expression on activated hepatic stellate cells (aHSCs) is associated with HSC proliferation during hepatic fibrogenesis. Herein, we show that a radioactive tracer, [F]-Alfatide, binds to integrin αvβ3 with high affinity and specificity. [F]-Alfatide could thus be used as a non-invasive imaging biomarker to track hepatic fibrosis progression.
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http://dx.doi.org/10.1016/j.jhep.2020.02.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7363052PMC
July 2020

Discovery and Optimization of α-Mangostin Derivatives as Novel PDE4 Inhibitors for the Treatment of Vascular Dementia.

J Med Chem 2020 03 12;63(6):3370-3380. Epub 2020 Mar 12.

School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, P. R. China.

To validate PDE4 inhibitors as novel therapeutic agents against vascular dementia (VaD), 25 derivatives were discovered from the natural inhibitor α-mangostin (IC = 1.31 μM). Hit-to-lead optimization identified a novel and selective PDE4 inhibitor (IC = 17 nM), which adopted a different binding pattern from PDE4 inhibitors roflumilast and rolipram. Oral administration of at a dose of 10 mg/kg exhibited remarkable therapeutic effects in a VaD model and did not cause emesis to beagle dogs, indicating its potential as a novel anti-VaD agent.
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http://dx.doi.org/10.1021/acs.jmedchem.0c00060DOI Listing
March 2020

Revisiting the Radiosynthesis of [F]FPEB and Preliminary PET Imaging in a Mouse Model of Alzheimer's Disease.

Molecules 2020 Feb 22;25(4). Epub 2020 Feb 22.

Azrieli Centre for Neuro-Radiochemistry, Brain Health Imaging Centre, Centre for Addiction and Mental Health, Toronto, ON M5T 1R8, Canada.

[F]FPEB is a positron emission tomography (PET) radiopharmaceutical used for imaging the abundance and distribution of mGluR5 in the central nervous system (CNS). Efficient radiolabeling of the aromatic ring of [F]FPEB has been an ongoing challenge. Herein, five metal-free precursors for the radiofluorination of [F]FPEB were compared, namely, a chloro-, nitro-, sulfonium salt, and two spirocyclic iodonium ylide (SCIDY) precursors bearing a cyclopentyl (SPI5) and a new adamantyl (SPIAd) auxiliary. The chloro- and nitro-precursors resulted in a low radiochemical yield (<10% RCY), whereas both SCIDY precursors and the sulfonium salt precursor produced [F]FPEB in the highest RCYs of 25% and 36%, respectively. Preliminary PET/CT imaging studies with [F]FPEB were conducted in a transgenic model of Alzheimer's Disease (AD) using B6C3-Tg(APPswe,PSEN1dE9)85Dbo/J (APP/PS1) mice, and data were compared with age-matched wild-type (WT) B6C3F1/J control mice. In APP/PS1 mice, whole brain distribution at 5 min post-injection showed a slightly higher uptake (SUV = 4.8 ± 0.4) than in age-matched controls (SUV = 4.0 ± 0.2). Further studies to explore mGluR5 as an early biomarker for AD are underway.
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http://dx.doi.org/10.3390/molecules25040982DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7070414PMC
February 2020

Salen-based bifunctional chemosensor for copper (II) ions: Inhibition of copper-induced amyloid-β aggregation.

Anal Chim Acta 2020 Feb 12;1097:144-152. Epub 2019 Nov 12.

Molecular Imaging Laboratory, Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital and Harvard Medical School, Boston, MA, 01890, USA.

Disruption of copper homeostasis is associated with a number of severe diseases including Alzheimer's disease (AD), Parkinson's disease (PD), Wilson's disease, and Menkes syndrome. Given this association, the detection and capture of Cu in biological fluids and tissues may provide a new direction for the diagnosis and treatment of related disorders. The current analytical approaches, however, are challenging due to the high cost, complexity, and long time required to prepare and analyze samples. Here, we report a novel salen ligand, namely N,N'-(1,2-phenylene)bis(1-(1H-imidazol-4-yl)methanimine) (pimi), which can readily detect and concurrently capture Cu from aqueous as well as biological mediums. Pimi can selectively and specifically detect Cu from biofluid and cellular samples with rapid ccresponse time (<3 s) and an ultra-sensitive detecting limit (2.7 nM). More importantly, pimi showed excellent environmental tolerance and had a very wide pH range for detecting Cu in a variety of biological samples. Attributed to the strong binding affinity and selectivity towards Cu, pimi was found to capture Cu ions from Cu-Aβ complexes, thus inhibiting copper-induced aggregation of Aβ and protecting neuronal cells from the toxicity of aggregated Aβ. These results provide a compelling starting point for further fine-tuning of salen-based chemosensor for the diagnosis and treatment of diseases associated with the hyperaccumulation of copper.
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http://dx.doi.org/10.1016/j.aca.2019.10.072DOI Listing
February 2020

A concisely automated synthesis of TSPO radiotracer [ F]FDPA based on spirocyclic iodonium ylide method and validation for human use.

J Labelled Comp Radiopharm 2020 03 20;63(3):119-128. Epub 2020 Jan 20.

Division of Nuclear Medicine and Molecular Imaging, Massachusetts General Hospital & Department of Radiology, Harvard Medical School, Boston, Massachusetts.

Fluorine-18 labeled N,N-diethyl-2-(2-(4-(2-fluoroethoxy)phenyl)-5,7-dimethylpyrazolo[1,5-a]pyrimidin-3-yl)acetamide ([ F]FDPA) is a potent and selective radiotracer for positron-emission tomography (PET) imaging of the translocator protein 18 kDa (TSPO). Our previous in vitro and in vivo evaluations have proven that this tracer is promising for further human translation. Our study addresses the need to streamline the automatic synthesis of this radiotracer to make it more accessible for widespread clinical evaluation and application. Here, we successfully demonstrate a one-step radiolabeling of [ F]FDPA based on a novel spirocyclic iodonium ylide (SCIDY) precursor using tetra-n-butyl ammonium methanesulfonate (TBAOMs), which has demonstrated the highest radiochemical yields and molar activity from readily available [ F]fluoride ion. The nucleophilic radiofluorination was completed on a GE TRACERlab FX2 N synthesis module, and the formulated [ F]FDPA was obtained in nondecay corrected (n.d.c) radiochemical yields of 15.6 ± 4.2%, with molar activities of 529.2 ± 22.5 GBq/μmol (14.3 ± 0.6 Ci/μmol) at the end of synthesis (60 minutes, n = 3) and validated for human use. This methodology facilitates efficient synthesis of [ F]FDPA in a commercially available synthesis module, which would be broadly applicable for routine production and widespread clinical PET imaging studies.
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http://dx.doi.org/10.1002/jlcr.3824DOI Listing
March 2020

Synthesis and evaluation of 6-(C-methyl(4-(pyridin-2-yl)thiazol-2-yl)amino)benzo[d]thiazol-2(3H)-one for imaging γ-8 dependent transmembrane AMPA receptor regulatory protein by PET.

Bioorg Med Chem Lett 2020 02 17;30(4):126879. Epub 2019 Dec 17.

Department of Radiology, Division of Nuclear Medicine and Molecular Imaging, Massachusetts General Hospital, Harvard Medical School, 55 Fruit Street, Boston, MA 02114, United States. Electronic address:

Transmembrane AMPA receptor regulatory proteins (TARPs) are a recently discovered family of proteins that modulate AMPA receptors activity. Based on a potent and selective TARP subtype γ-8 antagonist, 6-(methyl(4-(pyridin-2-yl)thiazol-2-yl)amino)benzo[d]thiazol-2(3H)-one (compound 9), we perform the radiosynthesis of its C-isotopologue 1 and conduct preliminary PET evaluation to test the feasibility of imaging TARP γ-8 dependent receptors in vivo.
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http://dx.doi.org/10.1016/j.bmcl.2019.126879DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7045276PMC
February 2020

Structural Basis for Achieving GSK-3β Inhibition with High Potency, Selectivity, and Brain Exposure for Positron Emission Tomography Imaging and Drug Discovery.

J Med Chem 2019 11 21;62(21):9600-9617. Epub 2019 Oct 21.

Azrieli Centre for Neuro-Radiochemistry, Research Imaging Centre , Centre for Addiction and Mental Health , Toronto , Ontario M5T 1R8 , Canada.

Using structure-guided design, several cell based assays, and microdosed positron emission tomography (PET) imaging, we identified a series of highly potent, selective, and brain-penetrant oxazole-4-carboxamide-based inhibitors of glycogen synthase kinase-3 (GSK-3). An isotopologue of our first-generation lead, [H]PF-367, demonstrates selective and specific target engagement in vitro, irrespective of the activation state. We discovered substantial ubiquitous GSK-3-specific radioligand binding in Tg2576 Alzheimer's disease (AD), suggesting application for these compounds in AD diagnosis and identified [C]OCM-44 as our lead GSK-3 radiotracer, with optimized brain uptake by PET imaging in nonhuman primates. GSK-3β-isozyme selectivity was assessed to reveal OCM-51, the most potent (IC = 0.030 nM) and selective (>10-fold GSK-3β/GSK-3α) GSK-3β inhibitor known to date. Inhibition of CRMP2 and tau phosphorylation, as well as favorable therapeutic window against WNT/β-catenin signaling activation, was observed in cells.
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http://dx.doi.org/10.1021/acs.jmedchem.9b01030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6883410PMC
November 2019

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

J Med Chem 2019 10 26;62(19):8866-8872. Epub 2019 Sep 26.

Division of Nuclear Medicine and Molecular Imaging, Massachusetts General Hospital, and Department of Radiology, Harvard Medical School , Boston , Massachusetts 02114 , United States.

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. This work supports further development of novel F-labeled MAGL PET probes.
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http://dx.doi.org/10.1021/acs.jmedchem.9b00936DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7875603PMC
October 2019

A population stereotaxic positron emission tomography brain template for the macaque and its application to ischemic model.

Neuroimage 2019 12 5;203:116163. Epub 2019 Sep 5.

Beijing Engineering Research Center of Radiographic Techniques and Equipment, Institute of High Energy Physics, Chinese Academy of Sciences & School of Nuclear Science and Technology, University of Chinese Academy of Sciences, Beijing, 100049, China; Department of Nuclear Medicine and PET/CT-MRI Center, The First Affiliated Hospital of Jinan University & Institute of Molecular and Functional Imaging, Jinan University, Guangzhou, 510630, China; CAS Center for Excellence in Brain Science and Intelligence Technology, Shanghai, 200031, China. Electronic address:

Purpose: Positron emission tomography (PET) is a non-invasive imaging tool for the evaluation of brain function and neuronal activity in normal and diseased conditions with high sensitivity. The macaque monkey serves as a valuable model system in the field of translational medicine, for its phylogenetic proximity to man. To translation of non-human primate neuro-PET studies, an effective and objective data analysis platform for neuro-PET studies is needed.

Materials And Methods: A set of stereotaxic templates of macaque brain, namely the Institute of High Energy Physics & Jinan University Macaque Template (HJT), was constructed by iteratively registration and averaging, based on 30 healthy rhesus monkeys. A brain atlas image was created in HJT space by combining sub-anatomical regions and defining new 88 bilateral functional regions, in which a unique integer was assigned for each sub-anatomical region.

Results: The HJT comprised a structural MRI T1 weighted image (T1WI) template image, a functional FDG-PET template image, intracranial tissue segmentations accompanied with a digital macaque brain atlas image. It is compatible with various commercially available software tools, such as SPM and PMOD. Data analysis was performed on a stroke model compared with a group of healthy controls to demonstrate the usage of HJT.

Conclusion: We have constructed a stereotaxic template set of macaque brain named HJT, which standardizes macaque neuroimaging data analysis, supports novel radiotracer development and facilitates translational neuro-disorders research.
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http://dx.doi.org/10.1016/j.neuroimage.2019.116163DOI Listing
December 2019

PET/SPECT Molecular Probes for the Diagnosis and Staging of Nonalcoholic Fatty Liver Disease.

Mol Imaging 2019 Jan-Dec;18:1536012119871455

1 Division of Nuclear Medicine and Molecular Imaging, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.

Nonalcoholic fatty liver disease (NAFLD) is a significant public health challenge afflicting approximately 1 billion individuals both in the Western world and in the East world. While liver biopsy is considered as gold standard in the diagnosis and staging of liver fibrosis, noninvasive imaging technologies, including ultrasonography, computed tomography, single-photon emission computed tomography (SPECT), magnetic resonance imaging, and positron emission tomography (PET) could offer more sensitive, comprehensive, and quantitative measurement for NAFLD. In this review, we focus on recent development and applications of PET/SPECT molecular probes that enable multispatial/temporal visualization and quantification of physiopathological progress at the molecular level in the NAFLD. We shall also discuss the limitations of current radioligands and future direction for PET/SPECT probe development.
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http://dx.doi.org/10.1177/1536012119871455DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6724487PMC
June 2020

Facile F labeling of non-activated arenes via a spirocyclic iodonium(III) ylide method and its application in the synthesis of the mGluR PET radiopharmaceutical [F]FPEB.

Nat Protoc 2019 05 12;14(5):1530-1545. Epub 2019 Apr 12.

Division of Nuclear Medicine and Molecular Imaging, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.

Non-activated (electron-rich and/or sterically hindered) arenes are prevalent chemical scaffolds in pharmaceuticals and positron emission tomography (PET) diagnostics. Despite substantial efforts to develop a general method to introduce F into these moieties for molecular imaging by PET, there is an urgent and unmet need for novel radiofluorination strategies that result in sufficiently labeled tracers to enable human imaging. Herein, we describe an efficient method that relies on spirocyclic iodonium ylide (SCIDY) precursors for one-step and regioselective radiofluorination, as well as proof-of-concept translation to the radiosynthesis of a clinically useful PET tracer, 3-[F]fluoro-5-[(pyridin-3-yl)ethynyl] benzonitrile ([F]FPEB). The protocol begins with the preparation of a SCIDY precursor for FPEB, followed by radiosynthesis of [F]FPEB, by either manual operation or an automated synthesis module. [F]FPEB can be obtained in quantities >7.4 GBq (200 mCi), ready for injection (20 ± 5%, non-decay corrected), and has excellent chemical and radiochemical purity (>98%) as well as high molar activity (666 ± 51.8 GBq/μmol; 18 ± 1.4 Ci/μmol). The total time for the synthesis and purification of the corresponding labeling SCIDY precursor is 10 h. The subsequent radionuclide production, experimental setup, F labeling, and formulation of a product that is ready for injection require 2 h.
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http://dx.doi.org/10.1038/s41596-019-0149-3DOI Listing
May 2019

[ F]Ethenesulfonyl Fluoride as a Practical Radiofluoride Relay Reagent.

Chemistry 2019 Jun 9;25(32):7613-7617. Epub 2019 May 9.

Australian Nuclear Science and Technology Organisation (ANSTO), New Illawarra Rd., Lucas Heights, NSW, Australia.

Fluorine-18 is the most utilized radioisotope in positron emission tomography (PET), but the wide application of fluorine-18 radiopharmaceuticals is hindered by its challenging labelling conditions. As such, many potentially important radiotracers remain underutilized. Herein, we describe the use of [ F]ethenesulfonyl fluoride (ESF) as a novel radiofluoride relay reagent that allows radiofluorination reactions to be performed in minimally equipped satellite nuclear medicine centres. [ F]ESF has a simple and reliable production route and can be stored on inert cartridges. The cartridges can then be shipped remotely and the trapped [ F]ESF can be liberated by simple solvent elution. We have tested 18 radiolabelling precursors, inclusive of model and clinically used structures, and most precursors have demonstrated comparable radiofluorination efficiencies to those obtained using a conventionally dried [ F]fluoride source.
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http://dx.doi.org/10.1002/chem.201900930DOI Listing
June 2019

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

Chem Commun (Camb) 2019 Mar;55(25):3630-3633

Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129, USA.

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.
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http://dx.doi.org/10.1039/c8cc10166cDOI Listing
March 2019

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.

J Med Chem 2019 04 21;62(7):3336-3353. Epub 2019 Mar 21.

Division of Nuclear Medicine and Molecular Imaging, Massachusetts General Hospital & Department of Radiology , Harvard Medical School , Boston , Massachusetts 02114 , United States.

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. We developed a lead irreversible-binding MAGL inhibitor 8 and reversible-binding compounds 17 and 37, which are amenable for radiolabeling with C or F. [C]8 ([C]MAGL-2-11) exhibited high brain uptake and excellent binding specificity in the brain toward MAGL. Reversible radioligands [C]17 ([C]PAD) and [F]37 ([F]MAGL-4-11) also demonstrated excellent in vivo binding specificity toward MAGL in peripheral organs. This work may pave the way for the development of MAGL-targeted positron emission tomography tracers with tunability in reversible and irreversible binding mechanisms.
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http://dx.doi.org/10.1021/acs.jmedchem.8b01778DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6581563PMC
April 2019

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

ACS Chem Neurosci 2019 05 27;10(5):2263-2275. Epub 2019 Feb 27.

Department of Radiology, Division of Nuclear Medicine and Molecular Imaging , Massachusetts General Hospital and Harvard Medical School , 55 Fruit Street , Boston , Massachusetts 02114 , United States.

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. Herein we developed an F-labeled potent antagonist, 2-((1-(4-[F]fluoro-3-methylphenyl)-1 H-1,2,3-triazol-4-yl)methoxy)-5-methoxypyrimidine ([F]13; also called [F]N2B-0518) as a PET tracer for imaging the GluN2B subunit. The radiofluorination of [F]13 was efficiently achieved by our spirocyclic iodonium ylide (SCIDY) method. In in vitro autoradiography studies, [F]13 displayed highly region-specific binding in brain sections of rat and nonhuman primate, which was in accordance with the expression of GluN2B subunit. Ex vivo biodistribution in mice revealed that [F]13 could penetrate the blood-brain barrier with moderate brain uptake (3.60% ID/g at 2 min) and rapid washout. Altogether, this work provides a GluN2B-selective PET tracer bearing a new chemical scaffold and shows high specificity to GluN2B subunit in vitro, which may pave the way for the development of a new generation of GluN2B PET ligands.
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http://dx.doi.org/10.1021/acschemneuro.8b00591DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6727982PMC
May 2019

Recent applications of a single quadrupole mass spectrometer in C, F and radiometal chemistry.

J Fluor Chem 2018 Jun 5;210:46-55. Epub 2018 Mar 5.

Division of Nuclear Medicine and Molecular Imaging, Massachusetts General Hospital (MGH) & Department of Radiology, Harvard Medical School, Boston, Massachusetts, USA.

Mass spectrometry (MS) has longstanding applications in radiochemistry laboratories, stemming from carbon-dating. However, research on the development of radiotracers for molecular imaging with either positron emission tomography (PET) or single photon emission computed tomography has yet to take full advantage of MS. This inertia has been attributed to the relatively low concentrations of radiopharmaceutical formulations and lack of access to the required MS equipment due to the high costs for purchase and maintenance of specialized MS systems. To date, single quadrupole (SQ)-MS coupled to liquid chromatography (LC) systems is the main form of MS that has been used in radiochemistry laboratories. These LC/MS systems are primarily used for assessing the chemical purity of radiolabeling precursor or standard molecules but also have applications in the determination of metabolites. Herein, we highlight personal experiences using a compact SQ-MS in our PET radiochemistry laboratories, to monitor the small amounts of carrier observed in most radiotracer preparations, even at high molar activities. The use of a SQ-MS in the observation of the low mass associated with non-radioactive species which are formed along with the radiotracer from the trace amounts of carrier found is demonstrated. Herein, we describe a pre-concentration system to detect dilute radiopharmaceutical formulations and metabolite analyses by SQ-MS. Selected examples where SQ-MS was critical for optimization of radiochemical reactions and for unequivocal characterization of radiotracers are showcased. We also illustrate examples where SQ-MS can be applied in identification of radiometal complexes and development of a new purification methodology for Pd-catalyzed radiofluorination reactions, shedding light on the identity of metal complexes present in the labelling solution.
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http://dx.doi.org/10.1016/j.jfluchem.2018.02.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6217822PMC
June 2018