Publications by authors named "Neil Vasdev"

129 Publications

Radiofluorination of oxazole-carboxamides for preclinical PET neuroimaging of GSK-3.

J Fluor Chem 2021 May 21;245. Epub 2021 Feb 21.

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

Glycogen synthase kinase 3 (GSK-3) is an enzyme that is dysregulated in oncology neurodegeneration, neuroinflammation and several mental health illnesses. As such, GSK-3 is a long-sought after target for positron emission tomography (PET) imaging and therapeutic intervention. Herein, we report on the development and radiofluorination of two oxazole-4-carboxamides, including one bearing a non-activated aromatic ring. Both compounds demonstrated excellent selectivity in a kinase screen and inhibit GSK-3 with high affinity. [F]OCM-49 was synthesized from [F]fluoride using a copper-mediated reaction of an aryl boronic acid precursor, while [F]OCM-50 used a trimethylammonium triflate precursor, and both radiotracers were translated for preclinical PET imaging in rodents. Due to superior radiochemical yields and brain uptake (peak standardized uptake value of ~2.0), [F]OCM-50 was further evaluated in non-human primate and also showed good brain uptake and rapid clearance. Further studies to consider clinical translation of both radiotracers are underway.
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http://dx.doi.org/10.1016/j.jfluchem.2021.109760DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8034590PMC
May 2021

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

Preclinical Evaluation of TSPO and MAO-B PET Radiotracers in an LPS Model of Neuroinflammation.

PET Clin 2021 Apr;16(2):233-247

Department of Psychiatry, Brain Health Imaging Centre, Azrieli Centre for Neuro-Radiochemistry, Centre for Addiction and Mental Health, University of Toronto, 250 College Street, Room PET G2, Toronto, Ontario M5T 1R8, Canada. Electronic address:

Discovery of novel PET radiotracers targeting neuroinflammation (microglia and astrocytes) is actively pursued. Employing a lipopolysaccharide (LPS) rat model, this longitudinal study evaluated the translocator protein 18-kDa radiotracer [F]FEPPA (primarily microglia) and monoamine oxidase B radiotracers [C]L-deprenyl and [C]SL25.1188 (astrocytes preferred). Increased [F]FEPPA binding peaked at 1 week in LPS-injected striatum whereas increased lazabemide-sensitive [C]L-deprenyl binding developed later. No increase in radiotracer uptake was observed for [C]SL25.1188. The unilateral intrastriatal LPS rat model may serve as a useful tool for benchmarking PET tracers targeted toward distinct phases of neuroinflammatory reactions involving both microglia and astrocytes.
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http://dx.doi.org/10.1016/j.cpet.2020.12.003DOI Listing
April 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

Radiosynthesis, and Evaluation of [F]CBD-2115 as a First-in-Class Radiotracer for Imaging 4R-Tauopathies.

ACS Chem Neurosci 2021 02 26;12(4):596-602. Epub 2021 Jan 26.

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

CBD-2115 was selected from a library of 148 compounds based on a pyridinyl-indole scaffold as a first-in-class 4R-tau radiotracer. In vitro binding assays showed [H]CBD-2115 had a value of 6.9 nM and a nominal of 500 nM in 4R-tau expressing P301L transgenic mouse tissue. In binding assays with human brain tissue homogenates, [H]CBD-2115 has a higher affinity (4.9 nM) for progressive supranuclear palsy specific 4R-tau deposits than [H]flortaucipir (45 nM) or [H]MK-6240 (>50 nM). [F]CBD-2115 was reliably synthesized (3-11% radiochemical yield with molar activity of 27-111 GBq/μmol and >97% radiochemical purity). Dynamic PET imaging was conducted in mice, rats, and nonhuman primates, and all species showed initial brain uptake of 0.5-0.65 standardized uptake value with fast clearance from normal tissues. [H]CBD-2115 could be a useful lead radioligand for further research in 4R-tauopathies, and PET radiotracer development will focus on improving brain uptake and binding affinity.
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http://dx.doi.org/10.1021/acschemneuro.0c00801DOI Listing
February 2021

A Workshop on Cognitive Aging and Impairment in the 9/11-Exposed Population.

Int J Environ Res Public Health 2021 01 14;18(2). Epub 2021 Jan 14.

World Trade Center Health Program, Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health, Washington, DC 20201, USA.

The terrorist attacks on 11 September 2001 potentially exposed more than 400,000 responders, workers, and residents to psychological and physical stressors, and numerous hazardous pollutants. In 2011, the World Trade Center Health Program (WTCHP) was mandated to monitor and treat persons with 9/11-related adverse health conditions and conduct research on physical and mental health conditions related to the attacks. Emerging evidence suggests that persons exposed to 9/11 may be at increased risk of developing mild cognitive impairment. To investigate further, the WTCHP convened a scientific workshop that examined the natural history of cognitive aging and impairment, biomarkers in the pathway of neurodegenerative diseases, the neuropathological changes associated with hazardous exposures, and the evidence of cognitive decline and impairment in the 9/11-exposed population. Invited participants included scientists actively involved in health-effects research of 9/11-exposed persons and other at-risk populations. Attendees shared relevant research results from their respective programs and discussed several options for enhancements to research and surveillance activities, including the development of a multi-institutional collaborative research network. The goal of this report is to outline the meeting's agenda and provide an overview of the presentation materials and group discussion.
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http://dx.doi.org/10.3390/ijerph18020681DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7830144PMC
January 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

On the consensus nomenclature rules for radiopharmaceutical chemistry - Reconsideration of radiochemical conversion.

Nucl Med Biol 2021 02 18;93:19-21. Epub 2020 Nov 18.

Department of Chemistry, Hunter College of the City University of New York, New York, NY, USA; Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Radiochemical conversion is an important term to be included in the "Consensus nomenclature rules for radiopharmaceutical chemistry". Radiochemical conversion should be used to define reaction efficiency by measuring the transformation of components in a crude reaction mixture at a given time, whereas radiochemical yield is better suited to define the efficiency of an entire reaction process including, for example, separation, isolation, filtration, and formulation.
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http://dx.doi.org/10.1016/j.nucmedbio.2020.11.003DOI Listing
February 2021

Repurposing [C]PS13 for PET imaging of cyclooxygenase-1 (COX-1) in ovarian cancer xenograft mouse models.

J Nucl Med 2020 Sep 25. Epub 2020 Sep 25.

Centre for Addiction and Mental Health, Canada.

Cyclooxygenase-1 (COX-1), a biomarker for neuroinflammation, is implicated in ovarian cancer (OvCa) progression and prognosis. This study considered the repurposing of [C]PS13, a COX-1 PET neuroimaging radiopharmaceutical, in OvCa xenograft mouse models. [C]PS13 was evaluated in ICRscid mice with s.c. or i.p. human OVCAR-3 OvCa xenografts by dynamic PET/MR imaging, ex vivo biodistribution and radiometabolite analysis of plasma and tumor. OVCAR-3 xenografts were well visualized with [C]PS13 in xenograft mouse models. Time-activity curves revealed steady tumor radioactivity accumulation that plateaued from 40-60 min, and was significantly reduced by pre-treatment with ketoprofen (3.56 ± 0.81 and 1.30 ± 0.18 %ID/g, respectively, = 0.01). Radiometabolite analysis showed that intact [C]PS13 accounted for >80% of radioactivity in the tumor, with <20% in plasma, at 40 min post-injection. [C]PS13 shows promise for PET imaging COX-1 in OvCa and rapid translation for clinical cancer research should be considered.
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http://dx.doi.org/10.2967/jnumed.120.249367DOI Listing
September 2020

Radionuclide Imaging for Neuroscience: Current Opinion and Future Directions.

Mol Imaging 2020 Jan-Dec;19:1536012120936397

Azrieli Centre for Neuro-Radiochemistry, Brain Health Imaging Centre, 7978Centre for Addiction and Mental Health, Toronto, Ontario, Canada.

This meeting report summarizes a Consultants Meeting that was held at International Atomic Energy Agency headquarters in Vienna to provide an update on radionuclide imaging for neuroscience applications.
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http://dx.doi.org/10.1177/1536012120936397DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7493278PMC
September 2020

Radiosynthesis of a Bruton's tyrosine kinase inhibitor, [ C]Tolebrutinib, via palladium-NiXantphos-mediated carbonylation.

J Labelled Comp Radiopharm 2020 09 13;63(11):482-487. Epub 2020 Aug 13.

Azrieli Centre for Neuro-Radiochemistry, Brain Health Imaging Centre, Centre for Addiction and Mental Health & Department of Psychiatry, University of Toronto, Ontario, Canada.

Bruton's tyrosine kinase (BTK) is a key component in the B-cell receptor signaling pathway and is consequently a target for in vivo imaging of B-cell malignancies as well as in multiple sclerosis (MS) with positron emission tomography (PET). A recent Phase 2b study with Sanofi's BTK inhibitor, Tolebrutinib (also known as [a.k.a.] SAR442168, PRN2246, or BTK'168) showed significantly reduced disease activity associated with MS. Herein, we report the radiosynthesis of [ C]Tolebrutinib ([ C]5) as a potential PET imaging agent for BTK. The N-[ C]acrylamide moiety of [ C]5 was labeled by C-carbonylation starting from [ C]CO, iodoethylene, and the secondary amine precursor via a novel palladium-NiXantphos-mediated carbonylation protocol, and the synthesis was fully automated using a commercial carbon-11 synthesis platform (TracerMaker™, Scansys Laboratorieteknik). [ C]5 was obtained in a decay-corrected radiochemical yield of 37 ± 2% (n = 5, relative to starting [ C]CO activity) in >99% radiochemical purity, with an average molar activity of 45 GBq/μmol (1200 mCi/μmol). We envision that this methodology will be generally applicable for the syntheses of labeled N-acrylamides.
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http://dx.doi.org/10.1002/jlcr.3872DOI Listing
September 2020

Classics in Neuroimaging: Development of Positron Emission Tomography Tracers for Imaging the GABAergic Pathway.

ACS Chem Neurosci 2020 07 24;11(14):2039-2044. Epub 2020 Jun 24.

Azrieli Centre for Neuro-Radiochemistry, Brain Health Imaging Centre, Centre for Addiction and Mental Health & Department of Psychiatry, University of Toronto, Toronto, Ontario M5T-1R8, Canada.

Advances in drug discovery and diverse radiochemical methodologies have led to the discovery of novel positron emission tomography (PET) radiotracers used to image the GABAergic system, shaping our fundamental understanding of a variety of brain health illnesses, including epilepsy, stroke, cerebral palsy, schizophrenia, autism, Alzheimer's disease, and addictions. In this Viewpoint, we review the state-of-the art of PET imaging with radiotracers that target the GABA-benzodiazepine receptor complex, challenges and opportunities for imaging GABA receptors and GABA transporters, and highlight an ongoing need to develop more sensitive radiotracers for imaging GABA release in the central nervous system.
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http://dx.doi.org/10.1021/acschemneuro.0c00343DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7982716PMC
July 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

Synthesis, in vitro and in vivo evaluation of C-O-methylated arylpiperazines as potential serotonin 1A (5-HT) receptor antagonist radiotracers.

EJNMMI Radiopharm Chem 2020 May 19;5(1):13. Epub 2020 May 19.

Molecular Imaging and Neuropathology Division, New York State Psychiatric Institute, New York, USA.

Background: Serotonin 1A (5-HT) receptors are implicated in the pathogenesis of several psychiatric and neurodegenerative disorders motivating the development of suitable radiotracers for in vivo positron emission tomography (PET) neuroimaging. The gold standard PET imaging agent for this target is [carbonyl-C]WAY-100635, labeled via a technically challenging multi-step reaction that has limited its widespread use. While several antagonist and agonist-based PET radiotracers for 5-HT receptors have been developed, their clinical translation has been hindered by methodological challenges and/or and non-specific binding. As a result, there is continued interest in the development of new and more selective 5-HT PET tracers having a relatively easier and reliable radiosynthesis process for routine production and with favorable metabolism to facilitate tracer-kinetic modeling. The purpose of the current study was to develop and characterize a radioligand with suitable characteristics for imaging 5-HT receptors in the brain. The current study reports the in vitro characterization and radiosyntheses of three candidate 5-HT receptor antagonists, DF-100 (1), DF-300 (2) and DF-400 (3), to explore their suitability as potential PET radiotracers.

Results: Syntheses of 1-3 and corresponding precursors for radiolabeling were achieved from isonicotinic, picolinic acid or picolino nitrile. In vitro binding studies demonstrated nanomolar affinity of the compounds for 5-HT receptors. Binding of 1-3 for other biogenic amines, neurotransmitter receptors, and transporters was negligible with the exception of moderate affinities for α-adrenergic receptors (4-6-fold less potent than that for 5-HT receptor). Radioligands [C]1-3 were efficiently prepared by C-O-methylation of the corresponding phenolic precursor in non-decay corrected radiochemical yields of 7-11% with > 99% chemical and radiochemical purities. Dynamic PET studies in rats demonstrated negligible brain uptake of [C]1 and [C]2. In contrast, significant brain uptake of [C]3 was observed with an early peak SUV of 4-5. However, [C]3 displayed significant off-target binding attributed to α-adrenergic receptors based on regional distribution (thalamus>hippocampus) and blocking studies.

Conclusion: Despite efficient radiolabeling, results from PET imaging experiments limit the application of [C]3 for in vivo quantification of 5-HT receptors. Nevertheless, derivatives of compound 3 may provide a scaffold for alternative PET radiotracers with improved selectivity for 5-HT receptors or α-adrenergic receptors.
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http://dx.doi.org/10.1186/s41181-020-00096-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7237647PMC
May 2020

Translocator Protein Distribution Volume Predicts Reduction of Symptoms During Open-Label Trial of Celecoxib in Major Depressive Disorder.

Biol Psychiatry 2020 10 29;88(8):649-656. Epub 2020 Mar 29.

Brain Health Imaging Centre and Campbell Family Mental Health Research Institute, the Centre for Addiction and Mental Health, Toronto, Ontario, Canada; Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada; Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada. Electronic address:

Background: Gliosis is common among neuropsychiatric diseases, but the relationship between gliosis and response to therapeutics targeting effects of gliosis is largely unknown. Translocator protein total distribution volume (TSPO V), measured with positron emission tomography, mainly reflects gliosis in neuropsychiatric disease. Here, the primary objective was to determine whether TSPO V in the prefrontal cortex (PFC) and anterior cingulate cortex (ACC) predicts reduction of depressive symptoms following open-label celecoxib administration in treatment-resistant major depressive disorder.

Methods: A total of 41 subjects with treatment-resistant major depressive disorder underwent one [F]FEPPA positron emission tomography scan to measure PFC and ACC TSPO V. Open-label oral celecoxib (200 mg, twice daily) was administered for 8 weeks. Change in symptoms was measured with the 17-item Hamilton Depression Rating Scale (HDRS).

Results: Cumulative mean change in HDRS scores between 0 and 8 weeks of treatment was plotted against PFC and ACC TSPO V, showing a significant nonlinear relationship. At low TSPO V values, there was no reduction in HDRS scores, but as TSPO V values increased, there was a reduction in HDRS scores that then plateaued. This was modeled with a 4-parameter sigmoidal model in which PFC and ACC TSPO V accounted for 84% and 92% of the variance, respectively.

Conclusions: Celecoxib administration in the presence of gliosis labeled by TSPO V is associated with greater reduction of symptoms. Given the predictiveness of TSPO V on symptom reduction, this personalized medicine approach of matching a marker of gliosis to medication targeting effects of gliosis should be applied in early development of novel therapeutics, in particular for treatment-resistant major depressive disorder.
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http://dx.doi.org/10.1016/j.biopsych.2020.03.007DOI Listing
October 2020

Copper(I)-Mediated C-Carboxylation of (Hetero)arylstannanes.

ACS Omega 2020 Apr 2;5(14):8242-8250. Epub 2020 Apr 2.

Azrieli Centre for Neuro-Radiochemistry, Brain Health Imaging Centre, Centre for Addiction and Mental Health, 250 College Street, Toronto, ON M5T 1R8, Canada.

A novel copper-mediated carboxylation strategy of aryl- and heteroaryl-stannanes is described. The method serves as a mild (i.e., 1 atm) carboxylation method using stable carbon dioxide and is transferable as a radiosynthetic approach for carbon-11-labeled aromatic and heteroaromatic carboxylic acids using sub-stoichiometric quantities of [C]CO. The methodology was applied to the radiosynthesis of the retinoid X receptor agonist, [C]bexarotene, with a decay-corrected radiochemical yield of 32 ± 5% and molar activity of 38 ± 23 GBq/μmol ( = 3).
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http://dx.doi.org/10.1021/acsomega.0c00524DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7161067PMC
April 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

Replicating predictive serum correlates of greater translocator protein distribution volume in brain.

Neuropsychopharmacology 2020 05 4;45(6):925-931. Epub 2019 Nov 4.

Research Imaging Centre and Campbell Family Mental Health Research Institute at the Centre for Addiction and Mental Health, 250 College Street, Toronto, ON, M5T 1R8, Canada.

Greater activation of glia, a key component of neuroinflammation, is an important process to target in neuropsychiatric illnesses. However, the magnitude of gliosis varies across cases so low-cost predictors are needed to stratify subjects for clinical trials. Here, several such blood serum measures were assessed in relation to TSPO V, an index of translocator protein density, measured with positron emission tomography. Blood serum concentration of several products known to be synthesized by activated microglia (and to some extent astroglia) [prostaglandin E (PGE), prostaglandin F alpha (PGF), and tumor necrosis factor alpha (TNF)], controlled by an index of peripheral inflammation [C-reactive protein (CRP)] and TSPO V were measured in 3 cohorts: prefrontal cortex TSPO V of 20 subjects with major depressive episodes (MDEs) from major depressive disorder (MDD); and 56 subjects with treatment resistant MDEs from MDD; and dorsal caudate TSPO V of 20 subjects with obsessive-compulsive disorder. Ln(PGE/CRP) and ln(TNF/CRP) consistently correlated with TSPO V (R = 0.36 to 0.11, p = 0.0030 to p = 0.0076). Assessment of threshold serum values to predict highly elevated TSPO V, demonstrated that a positive predictive value (PPV) of 80% was possible while retaining 40% of participant samples and that receiver operating curves (ROC) ranged from 75 to 81%. Post-hoc selection of ln(CRP) was more predictive (R = 0.23 to 0.39, p = 0.0058 to p = 0.00013; ROC > 80%). Systematic assessment of selected peripheral inflammatory markers is promising for developing low cost predictors of TSPO V. Marker thresholds with high PPV will improve subject stratification for clinical trials of glial targeting therapeutics.
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http://dx.doi.org/10.1038/s41386-019-0561-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7162884PMC
May 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

Improving PET Imaging Acquisition and Analysis With Machine Learning: A Narrative Review With Focus on Alzheimer's Disease and Oncology.

Mol Imaging 2019 Jan-Dec;18:1536012119869070

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

Machine learning (ML) algorithms have found increasing utility in the medical imaging field and numerous applications in the analysis of digital biomarkers within positron emission tomography (PET) imaging have emerged. Interest in the use of artificial intelligence in PET imaging for the study of neurodegenerative diseases and oncology stems from the potential for such techniques to streamline decision support for physicians providing early and accurate diagnosis and allowing personalized treatment regimens. In this review, the use of ML to improve PET image acquisition and reconstruction is presented, along with an overview of its applications in the analysis of PET images for the study of Alzheimer's disease and oncology.
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http://dx.doi.org/10.1177/1536012119869070DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6702769PMC
June 2020

"In-loop" F-fluorination: A proof-of-concept study.

J Labelled Comp Radiopharm 2019 06;62(7):292-297

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

There is a great demand to develop more cost-efficient and robust manufacturing processes for fluorine-18 ( F) labelled compounds and radiopharmaceuticals. Herein, we present to our knowledge the first radiofluorination "in-loop," where [ F]triflyl fluoride was used as the labelling agent. Initial development of the "in-loop" [ F]fluorination method was optimized by reacting [ F]triflyl fluoride with 1,4-dinitrobenzene to form [ F]1-fluoro-4-nitrobenzene. This methodology was then applied for the syntheses of two well-known radiopharmaceuticals, namely, [ F]T807 for imaging of tau protein and [ F]FEPPA for imaging the translocator protein 18 KDa. Both radiotracers were synthesized and formulated using an automated radiosynthesis module with nondecay corrected radiochemical yields of 27% and 29% (relative [ F]F ), respectively. The overall syntheses times for [ F]T807 and [ F]FEPPA were 65 and 55 minutes, respectively. In these cases, our "in-loop" radiofluorination methodology enabled us to obtain equal or superior yields compared with conventional reactions in a vial. The radiochemical purities were more than 99%, and the molar activities were more than 350 GBq/μmol at the end-of-synthesis for both radiotracers. This novel method is simple, efficient, and allows for a reliable production of radiofluorinated compounds and radiopharmaceuticals.
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http://dx.doi.org/10.1002/jlcr.3751DOI Listing
June 2019

Synthesis and preclinical evaluation of [F]FSL25.1188, a reversible PET radioligand for monoamine oxidase-B.

Bioorg Med Chem Lett 2019 07 27;29(13):1624-1627. Epub 2019 Apr 27.

Karolinska Institutet, Department of Clinical Neuroscience, Centre for Psychiatric Research, Karolinska Hospital, S-171 76 Stockholm, Sweden. Electronic address:

Carbon-11 labeled SL25.1188 is a promising reversible monoamine oxidase-B (MAO-B) radioligand that was recently translated for human positron emission tomography (PET) imaging. Herein, we report the development of a novel fluorinated derivative, namely, [F](S)-3-(6-(3-fluoropropoxy)benzo[d]isoxazol-3-yl)-5-(methoxymethyl)oxazolidin-2-one ([F]FSL25.1188; [F]6), as a candidate F-labeled MAO-B radioligand, and, its subsequent preclinical evaluation in non-human primates (NHP). [F]6 was produced and isolated (>6 GBq) with high radiochemical purity (>99%), and molar activity (>100 GBq/µmol at time of injection). Autoradiography studies conducted in post-mortem human brain sections revealed [F]6 binding in MAO-B rich regions. PET imaging study of [F]6 in NHP showed high brain uptake (SUV > 2.5) as well as a regional brain radioactivity distribution in accordance with MAO-B expression. [F]6 displayed favorable in vivo kinetics, with an early peak in the time-activity curve followed by progressive wash-out from the NHP brain. Specificity of [F]6 was investigated in a pre-treatment study with l-deprenyl (1.0 mg/kg) wherein reduced radioligand uptake was observed in all MAO-B rich regions. Results from the current preclinical investigation suggests [F]6 is a promising MAO-B PET radioligand. Further evaluation of [F]6 and structurally related F-analogs are underway to identify an optimized candidate for clinical research studies.
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http://dx.doi.org/10.1016/j.bmcl.2019.04.040DOI Listing
July 2019

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

Monoamine Oxidase B Total Distribution Volume in the Prefrontal Cortex of Major Depressive Disorder: An [11C]SL25.1188 Positron Emission Tomography Study.

JAMA Psychiatry 2019 06;76(6):634-641

Research Imaging Centre, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario, Canada.

Importance: Monoamine oxidase B (MAO-B) is an important, high-density enzyme in the brain that generates oxidative stress by hydrogen peroxide production, alters mitochondrial function, and metabolizes nonserotonergic monoamines. Recent advances in positron emission tomography radioligand development for MAO-B in humans enable highly quantitative measurement of MAO-B distribution volume (MAO-B VT), an index of MAO-B density. To date, this is the first investigation of MAO-B in the brain of major depressive disorder that evaluates regions beyond the raphe and amygdala.

Objective: To investigate whether MAO-B VT is elevated in the prefrontal cortex in major depressive episodes (MDEs) of major depressive disorder.

Design, Setting, And Participants: This case-control study was performed at a tertiary care psychiatric hospital from April 1, 2014, to August 30, 2018. Twenty patients with MDEs without current psychiatric comorbidities and 20 age-matched controls underwent carbon 11-labeled [11C]SL25.1188 positron emission tomography scanning to measure MAO-B VT. All participants were drug and medication free, nonsmoking, and otherwise healthy.

Main Outcomes And Measures: The MAO-B VT in the prefrontal cortex (PFC). The second main outcome was to evaluate the association between MAO-B VT in the PFC and duration of major depressive disorder illness.

Results: Twenty patients with MDEs (mean [SD] age, 34.2 [13.2] years; 11 women) and 20 healthy controls (mean [SD] age, 33.7 [13.1] years; 10 women) were recruited. Patients with MDEs had significantly greater MAO-B VT in the PFC (mean, 26%; analysis of variance, F1,38 = 19.6, P < .001). In individuals with MDEs, duration of illness covaried positively with MAO-B VT in the PFC (analysis of covariance, F1,18 = 15.2, P = .001), as well as most other cortex regions and the thalamus.

Conclusions And Relevance: Fifty percent (10 of 20) of patients with MDEs had MAO-B VT values in the PFC exceeding those of healthy controls. Greater MAO-B VT is an index of MAO-B overexpression, which may contribute to pathologies of mitochondrial dysfunction, elevated synthesis of neurotoxic products, and increased metabolism of nonserotonergic monoamines. Hence, this study identifies a common pathological marker associated with downstream consequences poorly targeted by the common selective serotonin reuptake inhibitor treatments. It is also recommended that the highly selective MAO-B inhibitor medications that are compatible for use with other antidepressants and have low risk for hypertensive crisis should be developed or repurposed as adjunctive treatment for MDEs.
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http://dx.doi.org/10.1001/jamapsychiatry.2019.0044DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6551845PMC
June 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

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

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

The Binding of BF-227-Like Benzoxazoles to Human α-Synuclein and Amyloid β Peptide Fibrils.

Mol Imaging 2018 Jan-Dec;17:1536012118796297

5 Translational Imaging Engine, Eisai AiM Institute, MA, USA. Vasdev is now with Azrieli Centre for Neuro-Radiochemistry, Centre for Addiction and Mental Health and Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada.

Development of an α-synuclein (α-Syn) positron emission tomography agent for the diagnosis and evaluation of Parkinson disease therapy is a key goal of neurodegenerative disease research. BF-227 has been described as an α-Syn binder and hence was employed as a lead to generate a library of α-Syn-binding compounds. [H]BF-227 bound to α-Syn and amyloid β peptide (Aβ) fibrils with affinities (K) of 46.0 nM and 15.7 nM, respectively. Affinities of BF-227-like compounds (expressed as K) for α-Syn and Aβ fibrils were determined, along with 5 reference compounds (flutafuranol, flutemetamol, florbetapir, BF-227, and PiB). Selectivity for α-Syn binding, defined as the K(Aβ)/K(α-Syn) ratio, was 0.23 for BF-227. A similar or lower ratio was measured for analogues decorated with alkyl or oxyethylene chains attached to the oxygen at the 6 position of BF-227, suggesting a lack of involvement of the side chain in fibril binding. BF-227-like iodobenzoxazoles had lower affinities and poor α-Syn selectivity. However, BF-227-like fluorobenzoxazoles had improved α-Syn selectively having K(Aβ)/K(α-Syn) ranging from 2.2 to 5.1 with appreciable fibril affinity, although not sufficient to warrant further investigation. Compounds based on fluorobenzoxazoles might offer an approach to obtaining an α-Syn imaging agent with an appropriate affinity and selectivity.
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http://dx.doi.org/10.1177/1536012118796297DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6144582PMC
February 2019

Emerging PET Radiotracers and Targets for Imaging of Neuroinflammation in Neurodegenerative Diseases: Outlook Beyond TSPO.

Mol Imaging 2018 Jan-Dec;17:1536012118792317

1 Division of Nuclear Medicine and Molecular Imaging, Massachusetts General Hospital, Boston, MA, USA.

The dynamic and multicellular processes of neuroinflammation are mediated by the nonneuronal cells of the central nervous system, which include astrocytes and the brain's resident macrophages, microglia. Although initiation of an inflammatory response may be beneficial in response to injury of the nervous system, chronic or maladaptive neuroinflammation can have harmful outcomes in many neurological diseases. An acute neuroinflammatory response is protective when activated neuroglia facilitate tissue repair by releasing anti-inflammatory cytokines and neurotrophic factors. On the other hand, chronic neuroglial activation is a major pathological mechanism in neurodegenerative diseases, likely contributing to neuronal dysfunction, injury, and disease progression. Therefore, the development of specific and sensitive probes for positron emission tomography (PET) studies of neuroinflammation is attracting immense scientific and clinical interest. An early phase of this research emphasized PET studies of the prototypical imaging biomarker of glial activation, translocator protein-18 kDa (TSPO), which presents difficulties for quantitation and lacks absolute cellular specificity. Many alternate molecular targets present themselves for PET imaging of neuroinflammation in vivo, including enzymes, intracellular signaling molecules as well as ionotropic, G-protein coupled, and immunoglobulin receptors. We now review the lead structures in radiotracer development for PET studies of neuroinflammation targets for neurodegenerative diseases extending beyond TSPO, including glycogen synthase kinase 3, monoamine oxidase-B, reactive oxygen species, imidazoline-2 binding sites, cyclooxygenase, the phospholipase A2/arachidonic acid pathway, sphingosine-1-phosphate receptor-1, cannabinoid-2 receptor, the chemokine receptor CX3CR1, purinergic receptors: P2X and P2Y, the receptor for advanced glycation end products, Mer tyrosine kinase, and triggering receptor expressed on myeloid cells-1. We provide a brief overview of the cellular expression and function of these targets, noting their selectivity for astrocytes and/or microglia, and highlight the classes of PET radiotracers that have been investigated in early-stage preclinical or clinical research studies of neuroinflammation.
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http://dx.doi.org/10.1177/1536012118792317DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6134492PMC
February 2019