Publications by authors named "Lee Josephson"

143 Publications

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

ACS Chem Neurosci 2021 03 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 annihilation localization by nanoscale magnetization.

Sci Rep 2020 11 20;10(1):20262. Epub 2020 Nov 20.

Faculty of Science, School of Physics, The University of Sydney, Sydney, NSW, Australia.

In positron emission tomography (PET), the finite range over which positrons travel before annihilating with an electron places a fundamental physical limit on the spatial resolution of PET images. After annihilation, the photon pair detected by the PET instrumentation is emitted from a location that is different from the positron-emitting source, resulting in image blurring. Here, we report on the localization of positron range, and hence annihilation quanta, by strong nanoscale magnetization of superparamagnetic iron oxide nanoparticles (SPIONs) in PET-MRI. We found that positron annihilations localize within a region of interest by up to 60% more when SPIONs are present (with [Fe] = 3 mM) compared to when they are not. The resulting full width at half maximum of the PET scans showed the spatial resolution improved by up to [Formula: see text] 30%. We also found evidence suggesting that the radiolabeled SPIONs produced up to a six-fold increase in ortho-positronium. These results may also have implications for emerging cancer theranostic strategies, where charged particles are used as therapeutic as well as diagnostic agents and improved dose localization within a tumor is a determinant of better treatment outcomes.
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http://dx.doi.org/10.1038/s41598-020-76980-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7680104PMC
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
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8027431PMC
March 2021

Synthesis and preliminary evaluation of 4-hydroxy-6-(3-[C]methoxyphenethyl)pyridazin-3(2H)-one, a C-labeled d-amino acid oxidase (DAAO) inhibitor for PET imaging.

Bioorg Med Chem Lett 2020 08 9;30(16):127326. Epub 2020 Jun 9.

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

Selective DAAO inhibitors have demonstrated promising therapeutic effects in clinical studies, including clinically alleviating symptoms of schizophrenic patients and ameliorating cognitive function in Alzheimer's patients with early phase. Herein we report the synthesis and preliminary evaluation of a C-labeled positron emission tomography ligand based on a DAAO inhibitor, DAO-1903 (8). C-Isotopologue of 8 was prepared in high radiochemical yield with high radiochemical purity (>99%) and high molar activity (>37 GBq/µmol). In vitro autoradiography studies indicated that the ligand possessed high in vitro specific binding to DAAO, while in vivo dynamic PET studies demonstrated that [C]8 failed to cross the blood-brain barrier possibly due to moderate brain efflux mechanism. Further chemical scaffold optimization is necessary to overcome limited brain permeability and improve specific binding.
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http://dx.doi.org/10.1016/j.bmcl.2020.127326DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7363051PMC
August 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

A Radio-Nano-Platform for T1/T2 Dual-Mode PET-MR Imaging.

Int J Nanomedicine 2020 24;15:1253-1266. Epub 2020 Feb 24.

Faculty of Science, School of Physics, The University of Sydney, Sydney, NSW, Australia.

Purpose: This study aimed to develop a chelate-free radiolabeled nanoparticle platform for simultaneous positron emission tomography (PET) and magnetic resonance (MR) imaging that provides contrast-enhanced diagnostic imaging and significant image quality gain by integrating the high spatial resolution of MR with the high sensitivity of PET.

Methods: A commercially available super-paramagnetic iron oxide nanoparticle (SPION) (Feraheme, FH) was labeled with the [Zr]Zr using a novel chelate-free radiolabeling technique, heat-induced radiolabeling (HIR). Radiochemical yield (RCY) and purity (RCP) were measured using size exclusion chromatography (SEC) and radio-thin layer chromatography (radio-TLC). Characterization of the non-radioactive isotope Zr-labeled FH was performed by transmission electron microscopy (TEM). Simultaneous PET-MR phantom imaging was performed with different Zr-FH concentrations. The MR quantitative image analysis determined the contrast-enhancing properties of FH. The signal-to-noise ratio (SNR) and full-width half-maximum (FWHM) of the line spread function (LSF) were calculated before and after co-registering the PET and MR image data.

Results: High RCY (92%) and RCP (98%) of the [Zr]Zr-FH product was achieved. TEM analysis confirmed the Zr atoms adsorption onto the SPION surface (≈ 10% average radial increase). Simultaneous PET-MR scans confirmed the capability of the [Zr]Zr-FH nano-platform for this multi-modal imaging technique. Relative contrast image analysis showed that [Zr]Zr-FH can act as a dual-mode T1/T2 contrast agent. For co-registered PET-MR images, higher spatial resolution (FWHM enhancement ≈ 3) and SNR (enhancement ≈ 8) was achieved at a clinical dose of radio-isotope and Fe.

Conclusion: Our results demonstrate FH is a highly suitable SPION-based platform for chelate-free labeling of PET tracers for hybrid PET-MR. The high RCY and RCP confirmed the robustness of the chelate-free HIR technique. An overall image quality gain was achieved compared to PET- or MR-alone imaging with a relatively low dosage of [Zr]Zr-FH. Additionally, FH is suitable as a dual-mode T1/T2 MR image contrast agent.
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http://dx.doi.org/10.2147/IJN.S241971DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7049573PMC
June 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

A Chelate-Free Nano-Platform for Incorporation of Diagnostic and Therapeutic Isotopes.

Int J Nanomedicine 2020 7;15:31-47. Epub 2020 Jan 7.

Gordon Center for Medical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States.

Purpose: Using our chelate-free, heat-induced radiolabeling (HIR) method, we show that a wide range of metals, including those with radioactive isotopologues used for diagnostic imaging and radionuclide therapy, bind to the Feraheme (FH) nanoparticle (NP), a drug approved for the treatment of iron anemia.

Material And Methods: FH NPs were heated (120°C) with nonradioactive metals, the resulting metal-FH NPs were characterized by inductively coupled plasma mass spectrometry (ICP-MS), dynamic light scattering (DLS), and r and r relaxivities obtained by nuclear magnetic relaxation spectrometry (NMRS). In addition, the HIR method was performed with [Y]Y, [Lu]Lu, and [Cu]Cu, the latter with an HIR technique optimized for this isotope. Optimization included modifying reaction time, temperature, and vortex technique. Radiochemical yield (RCY) and purity (RCP) were measured using size exclusion chromatography (SEC) and thin-layer chromatography (TLC).

Results: With ICP-MS, metals incorporated into FH at high efficiency were bismuth, indium, yttrium, lutetium, samarium, terbium and europium (>75% @ 120 C). Incorporation occurred with a small (less than 20%) but statistically significant increases in size and the r relaxivity. An improved HIR technique (faster heating rate and improved vortexing) was developed specifically for copper and used with the HIR technique and [Cu]Cu. Using SEC and TLC analyses with [Y]Y, [Lu]Lu and [Cu]Cu, RCYs were greater than 85% and RCPs were greater than 95% in all cases.

Conclusion: The chelate-free HIR technique for binding metals to FH NPs has been extended to a range of metals with radioisotopes used in therapeutic and diagnostic applications. Cations with f-orbital electrons, more empty d-orbitals, larger radii, and higher positive charges achieved higher values of RCY and RCP in the HIR reaction. The ability to use a simple heating step to bind a wide range of metals to the FH NP, a widely available approved drug, may allow this NP to become a platform for obtaining radiolabeled nanoparticles in many settings.
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http://dx.doi.org/10.2147/IJN.S227931DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6954846PMC
May 2020

A Novel Dual Fluorochrome Near-Infrared Imaging Probe for Potential Alzheimer's Enzyme Biomarkers-BACE1 and Cathepsin D.

Molecules 2020 Jan 9;25(2). Epub 2020 Jan 9.

Neurochemistry Laboratory, Department of Psychiatry, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA.

A molecular imaging probe to fluorescently image the β-site of the amyloid precursor protein (APP) cleaving enzyme 1 (BACE1) and cathepsin D (CatD) enzymes associated with Alzheimer's disease (AD) was designed and synthesized. This imaging probe was built upon iron oxide nanoparticles (cross-linked dextran iron oxide nanoparticles, or CLIO). Peptide substrates containing a terminal near-infrared fluorochrome (fluorophore emitting at 775 nm for CatD or fluorophore emitting at 669 nm for BACE1) were conjugated to the CLIO nanoparticles. The CatD substrate contained a phenylalanine-phenylalanine cleavage site more specific to CatD than BACE1. The BACE1 substrate contained the sequence surrounding the leucine-asparagine cleavage site of the BACE1 found in the Swedish mutation of APP, which is more specific to BACE1 than CatD. These fluorescently-labeled peptide substrates were then conjugated to the nanoparticle. The nanoparticle probes were purified by gel filtration, and their fluorescence intensities were determined using a fluorescence plate reader. The CatD peptide substrate demonstrated a 15.5-fold increase in fluorescence when incubated with purified CatD enzyme, and the BACE1 substrate exhibited a 31.5-fold increase in fluorescence when incubated with purified BACE1 enzyme. Probe specificity was also demonstrated in the human H4 neuroglioma cells and the H4 cells stably transfected with BACE1 in which the probe monitored enzymatic cleavage. In the H4 and H4-BACE1 cells, BACE1 and active CatD activity increased, an occurrence that was reflected in enzyme expression levels as determined by immunoblotting. These results demonstrate the applicability of this probe for detecting potential Alzheimer's enzyme biomarkers.
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http://dx.doi.org/10.3390/molecules25020274DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7024167PMC
January 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

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

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

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

ChemMedChem 2019 09 22;14(17):1580-1585. Epub 2019 Aug 22.

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

Leucine-rich repeat kinase 2 (LRRK2) is a large protein involved in the pathogenesis of Parkinson's disease (PD). It has been demonstrated that PD is mainly conferred by LRRK2 mutations that bring about increased kinase activity. As a consequence, selective inhibition of LRRK2 may help to recover the normal functions of LRRK2, thereby serving as a promising alternative therapeutic target for PD treatment. The mapping of LRRK2 by positron emission tomography (PET) studies allows a thorough understanding of PD and other LRRK2-related disorders; it also helps to validate and translate novel LRRK2 inhibitors. However, no LRRK2 PET probes have yet been reported in the primary literature. Herein we present a facile synthesis and preliminary evaluation of [ C]GNE-1023 as a novel potent PET probe for LRRK2 imaging in PD. [ C]GNE-1023 was synthesized in good radiochemical yield (10 % non-decay-corrected RCY), excellent radiochemical purity (>99 %), and high molar activity (>37 GBq μmol ). Excellent in vitro binding specificity of [ C]GNE-1023 toward LRRK2 was demonstrated in cross-species studies, including rat and nonhuman primate brain tissues by autoradiography experiments. Subsequent whole-body biodistribution studies indicated limited brain uptake and urinary and hepatobiliary elimination of this radioligand. This study may pave the way for further development of a new generation of LRRK2 PET probes.
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http://dx.doi.org/10.1002/cmdc.201900321DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6726558PMC
September 2019

Author Correction: Environment-responsive nanophores for therapy and treatment monitoring via molecular MRI quenching.

Nat Commun 2019 Apr 18;10(1):1867. Epub 2019 Apr 18.

Molecular Pharmacology and Chemistry Program, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, New York, 10065, USA.

This Article contains an error in Figure 6. In panel b, the left-hand image is mistakenly described as showing fluorescence before treatment, while it in fact shows the same white light image as the right-hand panel without fluorescent overlay to better visualize the tumour location. A correct version of Figure 6b is presented in the accompanying Author Correction. The error has not been corrected in the original version of the Article.
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http://dx.doi.org/10.1038/s41467-019-09887-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6472343PMC
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

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

Synthesis and Preliminary Evaluation of C-Labeled VU0467485/AZ13713945 and Its Analogues for Imaging Muscarinic Acetylcholine Receptor Subtype 4.

ChemMedChem 2019 02 27;14(3):303-309. Epub 2018 Dec 27.

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

Muscarinic acetylcholine receptors (mAChRs) have five distinct subunits (M -M ) and are involved in the action of the neurotransmitter acetylcholine in the central and peripheral nervous system. Attributed to the promising clinical efficacy of xanomeline, an M /M -preferring agonist, in patients of schizophrenia and Alzheimer's disease, M - or M -selective mAChR modulators have been developed that target the topographically distinct allosteric sites. Herein we report the synthesis and preliminary evaluation of C-labeled positron emission tomography (PET) ligands based on a validated M R positive allosteric modulator VU0467485 (AZ13713945) to facilitate drug discovery. [ C]VU0467485 and two other ligands were prepared in high radiochemical yields (>30 %, decay-corrected) with high radiochemical purity (>99 %) and high molar activity (>74 GBq μmol ). In vitro autoradiography studies indicated that these three ligands possess moderate-to-high in vitro specific binding to M R. Nevertheless, further physiochemical property optimization is necessary to overcome the challenges associated with limited brain permeability.
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http://dx.doi.org/10.1002/cmdc.201800710DOI Listing
February 2019

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

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

Eur J Med Chem 2018 Sep 9;157:898-908. Epub 2018 Aug 9.

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

a-Amino-3-hydroxyl-5-methyl-4-isoxazolepropionic acid (AMPA) receptors are implicated in the pathology of neurological diseases such as epilepsy and schizophrenia. As pan antagonists for this target are often accompanied with undesired effects at high doses, one of the recent drug discovery approaches has shifted to subtype-selective AMPA receptor (AMPAR) antagonists, specifically, via modulating transmembrane AMPAR regulatory proteins (TARPs). The quantification of AMPARs by positron emission tomography (PET) would help obtain insights into disease conditions in the living brain and advance the translational development of AMPAR antagonists. Herein we report the design, synthesis and preclinical evaluation of a series of TARP γ-8 antagonists, amenable for radiolabeling, for the development of subtype-selective AMPAR PET imaging agents. Based on the pharmacology evaluation, molecular docking studies and physiochemical properties, we have identified several promising lead compounds 3, 17-19 and 21 for in vivo PET studies. All candidate compounds were labeled with [C]COCl in high radiochemical yields (13-31% RCY) and high molar activities (35-196 GBq/μmol). While tracers 30 ([C]17) &32 ([C]21) crossed the blood-brain barrier and showed heterogeneous distribution in PET studies, consistent with TARP γ-8 expression, high nonspecific binding prevented further evaluation. To our delight, tracer 31 ([C]3) showed good in vitro specific binding and characteristic high uptake in the hippocampus in rat brain tissues, which provides the guideline for further development of a new generation subtype selective TARP γ-8 dependent AMPAR tracers.
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http://dx.doi.org/10.1016/j.ejmech.2018.08.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6245653PMC
September 2018

Positron Emission Tomography (PET) Ligand Development for Ionotropic Glutamate Receptors: Challenges and Opportunities for Radiotracer Targeting N-Methyl-d-aspartate (NMDA), α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid (AMPA), and Kainate Receptors.

J Med Chem 2019 01 27;62(2):403-419. Epub 2018 Aug 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.

Ionotropic glutamate receptors (iGluRs) mediate excitatory neurotransmission within the mammalian central nervous system. iGluRs exist as three main groups: N-methyl-d-aspartate receptors (NMDARs), α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs), and kainate receptors. The past decades have witnessed a remarkable development of PET tracers targeting different iGluRs including NMDARs and AMPARs, and several of the tracers have advanced to clinical imaging studies. Here, we assess the recent development of iGluR PET probes, focusing on tracer design, brain kinetics, and performance in PET imaging studies. Furthermore, this review will not only present challenges in the tracer development but also provide novel approaches in conjunction with most recent drug discovery efforts on these iGluRs, including subtype-selective NMDAR and transmembrane AMPAR regulatory protein modulators and positive allosteric modulators (PAMs) of AMPARs. These approaches, if successful as PET tracers, may provide fundamental knowledge to understand the roles of iGluR receptors under physiological and pathological conditions.
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http://dx.doi.org/10.1021/acs.jmedchem.8b00714DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6393217PMC
January 2019

Chemistry for Positron Emission Tomography: Recent Advances in C-, F-, N-, and O-Labeling Reactions.

Angew Chem Int Ed Engl 2019 02 14;58(9):2580-2605. Epub 2019 Jan 14.

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

Positron emission tomography (PET) is a molecular imaging technology that provides quantitative information about function and metabolism in biological processes in vivo for disease diagnosis and therapy assessment. The broad application and rapid advances of PET has led to an increased demand for new radiochemical methods to synthesize highly specific molecules bearing positron-emitting radionuclides. This Review provides an overview of commonly used labeling reactions through examples of clinically relevant PET tracers and highlights the most recent developments and breakthroughs over the past decade, with a focus on C, F, N, and O.
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http://dx.doi.org/10.1002/anie.201805501DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6405341PMC
February 2019

Multiplexed Optical Imaging of Energy Substrates Reveals That Left Ventricular Hypertrophy Is Associated With Brown Adipose Tissue Activation.

Circ Cardiovasc Imaging 2018 03;11(3):e007007

From the Cardiovascular Medicine Section, Department of Medicine, Boston University Medical Center, MA (M.P., D.C., I.L., W.S.C.); Cardiovascular Research Center (M.P., H.H.C., D.E.S.) and Martinos Center for Biomedical Imaging, Department of Radiology (M.P., H.H.C., Y.-C.I.C., C.R., L.J., D.E.S.), Massachusetts General Hospital, Boston, MA.

Background: Substrate utilization in tissues with high energetic requirements could play an important role in cardiometabolic disease. Current techniques to assess energetics are limited by high cost, low throughput, and the inability to resolve multiple readouts simultaneously. Consequently, we aimed to develop a multiplexed optical imaging platform to simultaneously assess energetics in multiple organs in a high throughput fashion.

Methods And Results: The detection of 18F-Fluordeoxyglucose uptake via Cerenkov luminescence and free fatty acid uptake with a fluorescent C free fatty acid was tested. Simultaneous uptake of these agents was measured in the myocardium, brown/white adipose tissue, and skeletal muscle in mice with/without thoracic aortic banding. Within 5 weeks of thoracic aortic banding, mice developed left ventricular hypertrophy and brown adipose tissue activation with upregulation of βAR (β adrenergic receptors) and increased natriuretic peptide receptor ratio. Imaging of brown adipose tissue 15 weeks post thoracic aortic banding revealed an increase in glucose (<0.01) and free fatty acid (<0.001) uptake versus controls and an increase in uncoupling protein-1 (<0.01). Similar but less robust changes were seen in skeletal muscle, while substrate uptake in white adipose tissue remained unchanged. Myocardial glucose uptake was increased post-thoracic aortic banding but free fatty acid uptake trended to decrease.

Conclusions: A multiplexed optical imaging technique is presented that allows substrate uptake to be simultaneously quantified in multiple tissues in a high throughput manner. The activation of brown adipose tissue occurs early in the onset of left ventricular hypertrophy, which produces tissue-specific changes in substrate uptake that may play a role in the systemic response to cardiac pressure overload.
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http://dx.doi.org/10.1161/CIRCIMAGING.117.007007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5908227PMC
March 2018

Heat-induced radiolabeling and fluorescence labeling of Feraheme nanoparticles for PET/SPECT imaging and flow cytometry.

Nat Protoc 2018 02 25;13(2):392-412. Epub 2018 Jan 25.

Gordon Center for Medical Imaging, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts, USA.

Feraheme (FH) nanoparticles (NPs) have been used extensively for treatment of iron anemia (due to their slow release of ionic iron in acidic environments). In addition, injected FH NPs are internalized by monocytes and function as MRI biomarkers for the pathological accumulation of monocytes in disease. We have recently expanded these applications by radiolabeling FH NPs for positron emission tomography (PET) or single-photon emission computed tomography (SPECT) imaging using a heat-induced radiolabeling (HIR) strategy. Imaging FH NPs using PET/SPECT has important advantages over MRI due to lower iron doses and improved quantitation of tissue NP concentrations. HIR of FH NPs leaves the physical and biological properties of the NPs unchanged and allows researchers to build on the extensive knowledge obtained about the pharmacokinetic and safety aspects of FH NPs. In this protocol, we present the step-by-step procedures for heat (120 °C)-induced bonding of three widely employed radiocations (Zr or Cu for PET, and In for SPECT) to FH NPs using a chelateless radiocation surface adsorption (RSA) approach. In addition, we describe the conversion of FH carboxyl groups into amines and their reaction with an N-hydroxysuccinimide (NHS) of a Cy5.5 fluorophore. This yields Cy5.5-FH, a fluorescent FH that enables the cells internalizing Cy5.5-FH to be examined using flow cytometry. Finally, we describe procedures for in vivo and ex vivo uptake of Cy5.5-FH by monocytes and for in vivo microPET/CT imaging of HIR-FH NPs. Synthesis of HIR-FH requires experience with working with radioactive cations and can be completed within <4 h. Synthesis of Cy5.5-FH NPs takes ∼17 h.
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http://dx.doi.org/10.1038/nprot.2017.133DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5966297PMC
February 2018

An Integrin-Targeted, Highly Diffusive Construct for Photodynamic Therapy.

Sci Rep 2017 10 17;7(1):13375. Epub 2017 Oct 17.

Wellman Center for Photomedicine, Massachusetts General Hospital, Harvard Medical School, 13th St, CNY149, Charlestown, MA, 02129, USA.

Targeted antineoplastic agents show great promise in the treatment of cancer, having the ability to impart cytotoxicity only to specific tumor types. However, these therapies do not experience uniform uptake throughout tumors, leading to sub-lethal cell killing that can impart treatment resistance, and cause problematic off-target effects. Here we demonstrate a photodynamic therapy construct that integrates both a cyclic RGD moiety for integrin-targeting, as well as a 5 kDa PEG chain that passivates the construct and enables its rapid diffusion throughout tumors. PEGylation of the photosensitizer construct was found to prevent photosensitizer aggregation, boost the generation of cytotoxic reactive radical species, and enable the rapid uptake of the construct into cells throughout large (>500 µm diameter) 3D tumor spheroids. Replacing the cyclic RGD with the generic RAD peptide led to the loss of cellular uptake in 3D culture, demonstrating the specificity of the construct. Photodynamic therapy with the construct was successful in inducing cytotoxicity, which could be competitively blocked by a tenfold concentration of free cyclic RGD. This construct is a first-of-its kind theranostic that may serve as a new approach in our growing therapeutic toolbox.
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http://dx.doi.org/10.1038/s41598-017-13803-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5645319PMC
October 2017

Theranostic Nucleic Acid Binding Nanoprobe Exerts Anti-inflammatory and Cytoprotective Effects in Ischemic Injury.

Theranostics 2017 8;7(4):814-825. Epub 2017 Feb 8.

Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Harvard Medical School, Boston MA;; Cardiovascular Research Center, Massachusetts General Hospital, Harvard Medical School, Boston MA.

Extracellular nucleic acids are proinflammatory molecules that have been implicated in a diverse range of diseases. We report here the development of a multivalent nucleic acid scavenging nanoprobe, where the fluorochrome thiazole orange (TO) is conjugated to a polymeric 40 kDa dextran carrier. Dextran-TO (Dex-TO) has nanomolar affinity for mammalian and bacterial nucleic acids and attenuates the production of inflammatory cytokines from activated macrophages exposed to DNA and RNA. Mice with myocardial ischemia reperfusion that were treated with Dex-TO showed a decrease in myocardial macrophage infiltration at 24 hours (p<0.05) and a decrease in infarct size (18% ± 9%, p<0.01) on day 7. Dex-TO allows sites of injury to be identified with fluorescence imaging, while simultaneously exerting an anti-inflammatory and cytoprotective effect. Dex-TO could be of significant diagnostic and therapeutic (theranostic) utility in a broad range of conditions including ischemia, trauma, burns, sepsis and autoimmune disease.
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http://dx.doi.org/10.7150/thno.17366DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5381246PMC
October 2017

Heat-induced-radiolabeling and click chemistry: A powerful combination for generating multifunctional nanomaterials.

PLoS One 2017 22;12(2):e0172722. Epub 2017 Feb 22.

Gordon Center for Medical Imaging, Massachusetts General Hospital, Harvard Medical School, 149, 13th Street, Charlestown, Massachusetts, United States of America.

A key advantage of nanomaterials for biomedical applications is their ability to feature multiple small reporter groups (multimodality), or combinations of reporter groups and therapeutic agents (multifunctionality), while being targeted to cell surface receptors. Here a facile combination of techniques for the syntheses of multimodal, targeted nanoparticles (NPs) is presented, whereby heat-induced-radiolabeling (HIR) labels NPs with radiometals and so-called click chemistry is used to attach bioactive groups to the NP surface. Click-reactive alkyne or azide groups were first attached to the nonradioactive clinical Feraheme (FH) NPs. Resulting "Alkyne-FH" and "Azide-FH" intermediates, like the parent NP, tolerated 89Zr labeling by the HIR method previously described. Subsequently, biomolecules were quickly conjugated to the radioactive NPs by either copper-catalyzed or copper-free click reactions with high efficiency. Synthesis of the Alkyne-FH or Azide-FH intermediates, followed by HIR and then by click reactions for biomolecule attachment, provides a simple and potentially general path for the synthesis of multimodal, multifunctional, and targeted NPs for biomedical applications.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0172722PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5321420PMC
August 2017

Effects of ferumoxytol on quantitative PET measurements in simultaneous PET/MR whole-body imaging: a pilot study in a baboon model.

EJNMMI Phys 2015 Dec 26;2(1). Epub 2015 Feb 26.

Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, 149 13th Street, Suite 2301, Charlestown, MA, 02129, USA.

Background: Simultaneous PET/MR imaging depends on MR-derived attenuation maps (mu-maps) for accurate attenuation correction of PET data. Currently, these maps are derived from gradient-echo-based MR sequences, which are sensitive to susceptibility changes. Iron oxide magnetic nanoparticles have been used in the measurement of blood volume, tumor microvasculature, tumor-associated macrophages, and characterizing lymph nodes. Our aim in this study was to assess whether the susceptibility effects associated with iron oxide nanoparticles can potentially affect measured (18)F-FDG PET standardized uptake values (SUV) through effects on MR-derived attenuation maps.

Methods: The study protocol was approved by the Institutional Animal Care and Use Committee. Using a Siemens Biograph mMR PET/MR scanner, we evaluated the effects of increasing concentrations of ferumoxytol and ferumoxytol aggregates on MR-derived mu-maps using an agarose phantom. In addition, we performed a baboon experiment evaluating the effects of a single i.v. ferumoxytol dose (10 mg/kg) on the liver, spleen, and pancreas (18)F-FDG SUV at baseline (ferumoxytol-naïve), within the first hour and at 1, 3, 5, and 11 weeks.

Results: Phantom experiments showed mu-map artifacts starting at ferumoxytol aggregate concentrations of 10 to 20 mg/kg. The in vivo baboon data demonstrated a 53% decrease of observed (18)F-FDG SUV compared to baseline within the first hour in the liver, persisting at least 11 weeks.

Conclusions: A single ferumoxytol dose can affect measured SUV for at least 3 months, which should be taken into account when administrating ferumoxytol in patients needing sequential PET/MR scans. Advances in knowledge 1. Ferumoxytol aggregates, but not ferumoxytol alone, produce significant artifacts in MR-derived attenuation correction maps at approximate clinical dose levels of 10 mg/kg. 2. When performing simultaneous whole-body (18)F-FDG PET/MR, a single dose of ferumoxytol can result in observed SUV decreases up to 53%, depending on the amount of ferumoxytol aggregates in the studied tissue. Implications for patient care Administration of a single, clinically relevant, dose of ferumoxytol can potentially result in changes in observed SUV for a prolonged period of time in the setting of simultaneous PET/MR. These potential changes should be considered in particular when administering ferumoxytol to patients with expected future PET/MR studies, as ferumoxytol-induced SUV changes might interfere with therapy assessment.
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http://dx.doi.org/10.1186/s40658-015-0109-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4544618PMC
December 2015

Heat-Induced Radiolabeling of Nanoparticles for Monocyte Tracking by PET.

Angew Chem Int Ed Engl 2015 Oct 14;54(44):13002-6. Epub 2015 Sep 14.

Center for Advanced Medical Imaging Sciences, Department of Radiology, Massachusetts General Hospital, 55 Fruit Street, Boston, MA 02114 (USA).

Heat-induced radiolabeling (HIR) yielded (89) Zr-Feraheme (FH) nanoparticles (NPs) that were used to determine NP pharmacokinetics (PK) by positron emission tomography (PET). Standard uptake values indicated a fast hepatic uptake that corresponded to blood clearance, and a second, slow uptake process by lymph nodes and spleen. By cytometry, NPs were internalized by circulating monocytes and monocytes in vitro. Using an IV injection of HIR (89) Zr-FH (rather than in vitro cell labeling), PET/PK provided a view of monocyte trafficking, a key component of the immune response.
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http://dx.doi.org/10.1002/anie.201505525DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4754124PMC
October 2015