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The diaryl sulfonylurea MCC950/CRID3 is a potent NLRP3 inhibitor (IC50 = 8 nM) and, in animal models, MCC950 protects against numerous NLRP3-related neurodegenerative disorders. To ...evaluate the brain uptake and investigate target engagement of MCC950, we synthesised 11C-ureaMCC950 via carrier added 11CCO2 fixation chemistry (activity yield = 237 MBq; radiochemical purity >99%; molar activity = 7 GBq/µmol; radiochemical yield (decay-corrected from 11CCO2) = 1.1%; synthesis time from end-of-bombardment = 31 min; radiochemically stable for >1 h). Despite preclinical efficacy in neurodegeneration studies, preclinical positron emission tomography (PET) imaging studies in mouse, rat and rhesus monkey revealed poor brain uptake of low molar activity 11CMCC950 and rapid washout. In silico prediction tools suggest efflux transporter liabilities for MCC950 at microdoses, and this information should be taken into account when developing next generation NLRP3 inhibitors and/or PET radiotracers.
Naloxone (NLX) is a mu receptor antagonist used to treat acute opioid overdoses. Currently approved doses of naloxone to treat opioid overdoses are 4 mg intranasal (IN) and 2 mg intramuscular (IM). ...However, higher mu receptor occupancy (RO) may be required to treat overdoses due to more potent synthetic opioids such as fentanyl and carfentanil that have entered the illicit drug market recently. To address this need, a higher dose of NLX has been investigated in a 5 mg IM formulation called ZIMHI but, while the effects of intravenous (IV) and IN administration of NLX on the opioid mu receptor occupancy (RO) have been studied, comparatively little is known about RO for IM administration of NLX. The goal of this study was to examine the effect of IM dosing of NLX on mu RO in rhesus macaques using
Ccarfentanil positron emission tomography (PET) imaging. The lowest dose of NLX (0.06 mg/kg) approximated 51% RO. Higher doses of NLX (0.14 mg/kg, 0.28 mg/kg) resulted in higher mu RO of 70% and 75%, respectively. Plasma levels were 4.6 ng/mL, 16.8 ng/mL, and 43.4 ng/mL for the three IM doses, and a significant correlation between percent RO and plasma NLX level was observed (r = 0.80). These results suggest that higher doses of IM NLX result in higher mu RO and could be useful in combating overdoses resulting from potent synthetic opioids.
4-(18)FFluoro-m-hydroxyphenethylguanidine ((18)F4F-MHPG, (18)F1) is a new cardiac sympathetic nerve radiotracer with kinetic properties favorable for quantifying regional nerve density with PET and ...tracer kinetic analysis. An automated synthesis of (18)F1 was developed in which the intermediate 4-(18)Ffluoro-m-tyramine ((18)F16) was prepared using a diaryliodonium salt precursor for nucleophilic aromatic (18)Ffluorination. In PET imaging studies in rhesus macaque monkeys, (18)F1 demonstrated high quality cardiac images with low uptake in lungs and the liver. Compartmental modeling of (18)F1 kinetics provided net uptake rate constants Ki (mL/min/g wet), and Patlak graphical analysis of (18)F1 kinetics provided Patlak slopes Kp (mL/min/g). In pharmacological blocking studies with the norepinephrine transporter inhibitor desipramine (DMI), each of these quantitative measures declined in a dose-dependent manner with increasing DMI doses. These initial results strongly suggest that (18)F1 can provide quantitative measures of regional cardiac sympathetic nerve density in human hearts using PET.
The implication of the receptor for advanced glycation end-products (RAGE) in numerous diseases and neurodegenerative disorders makes it interesting both as a therapeutic target and as an ...inflammatory biomarker. In the context of investigating RAGE as a biomarker, there is interest in developing radiotracers that will enable quantification of RAGE using positron emission tomography (PET) imaging. We have synthesized potential small molecule radiotracers for both the intracellular (18FInRAGER) and extracellular (18FRAGER) domains of RAGE. Herein we report preclinical evaluation of both using in vitro (lead panel screens) and in vivo (rodent and nonhuman primate PET imaging) methods. Both radiotracers have high affinity for RAGE and show good brain uptake, but suffer from off-target binding. The source of the off-target PET signal is not attributable to binding to melatonin receptors, but remains unexplained. We have also investigated use of lipopolysaccharide (LPS)-treated mice as a possible animal model with upregulated RAGE for evaluation of new imaging agents. Immunoreactivity of the mouse brain sections revealed increases in RAGE in the male cohorts, but no difference in the female groups. However, it proves challenging to quantify the changes in RAGE due to off-target binding of the radiotracers. Nevertheless, they are appropriate lead scaffolds for future development of 2nd generation RAGE PET radiotracers because of their high affinity for the receptor and good CNS penetration.
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•The implication of RAGE in numerous diseases make it a therapeutic target and an imaging biomarker.•18FRAGER and 18FInRAGER are potential radiotracers for positron emission tomography (PET) imaging of RAGE.•Both radiotracers show good brain uptake but suffer from off target binding.•New radiotracers with more druglike properties and better selectivity for RAGE are needed.
Fluorine-18 labeled phenethylguanidines are currently under development in our laboratory as radiotracers for quantifying regional cardiac sympathetic nerve density using PET imaging techniques. In ...this study, we report an efficient synthesis of
F-hydroxyphenethylguanidines consisting of nucleophilic aromatic
Ffluorination of a protected diaryliodonium salt precursor followed by a single deprotection step to afford the desired radiolabeled compound. This approach has been shown to reliably produce 4-
Ffluoro-m-hydroxyphenethylguanidine (
F4F-MHPG,
F1) and its structural isomer 3-
Ffluoro-p-hydroxyphenethylguanidine (
F3F-PHPG,
F2) with good radiochemical yields. Preclinical evaluations of
F2 in nonhuman primates were performed to compare its imaging properties, metabolism, and myocardial kinetics with those obtained previously with
F1. The results of these studies have demonstrated that
F2 exhibits imaging properties comparable to those of
F1. Myocardial tracer kinetic analysis of each tracer provides quantitative metrics of cardiac sympathetic nerve density. Based on these findings, first-in-human PET studies with
F1 and
F2 are currently in progress to assess their ability to accurately measure regional cardiac sympathetic denervation in patients with heart disease, with the ultimate goal of selecting a lead compound for further clinical development.
Positron emission tomography (PET) imaging of Colony Stimulating Factor 1 Receptor (CSF1R) is a new strategy for quantifying both neuroinflammation and inflammation in the periphery since CSF1R is ...expressed on microglia and macrophages. AZ683 has high affinity for CSF1R (K
= 8 nM; IC
= 6 nM) and >250-fold selectivity over 95 other kinases. In this paper, we report the radiosynthesis of
CAZ683 and initial evaluation of its use in CSF1R PET.
CAZ683 was synthesized by
C-methylation of the desmethyl precursor with
CMeOTf in 3.0% non-corrected activity yield (based upon
CMeOTf), >99% radiochemical purity and high molar activity. Preliminary PET imaging with
CAZ683 revealed low brain uptake in rodents and nonhuman primates, suggesting that imaging neuroinflammation could be challenging but that the radiopharmaceutical could still be useful for peripheral imaging of inflammation.
A new cardiac sympathetic nerve imaging agent, 18F4-fluoro-m-hydroxyphenethylguanidine (18F4F-MHPG), was synthesized and evaluated. The radiosynthetic intermediate 18F4-fluoro-m-tyramine (18F4F-MTA) ...was prepared and then sequentially reacted with cyanogen bromide and NH4Br/NH4OH to afford 18F4F-MHPG. Initial bioevaluations of 18F4F-MHPG (biodistribution studies in rats and kinetic studies in the isolated rat heart) were similar to results previously reported for the carbon-11 labeled analog 11C4F-MHPG. The neuronal uptake rate of 18F4F-MHPG into the isolated rat heart was 0.68ml/min/g wet and its retention time in sympathetic neurons was very long (T1/2 >13h). A PET imaging study in a nonhuman primate with 18F4F-MHPG provided high quality images of the heart, with heart-to-blood ratios at 80–90min after injection of 5-to-1. These initial kinetic and imaging studies of 18F4F-MHPG suggest that this radiotracer may allow for more accurate quantification of regional cardiac sympathetic nerve density than is currently possible with existing neuronal imaging agents.
Abnormally aggregated tau is the hallmark pathology of tauopathy neurodegenerative disorders and is a target for development of both diagnostic tools and therapeutic strategies across the tauopathy ...disease spectrum. Development of carbon-11- or fluorine-18-labeled radiotracers with appropriate affinity and specificity for tau would allow noninvasive quantification of tau burden using positron emission tomography (PET) imaging. We have synthesized 18Flansoprazole, 11CN-methyl lansoprazole, and 18FN-methyl lansoprazole and identified them as high affinity radiotracers for tau with low to subnanomolar binding affinities. Herein, we report radiosyntheses and extensive preclinical evaluation with the aim of selecting a lead radiotracer for translation into human PET imaging trials. We demonstrate that 18FN-methyl lansoprazole, on account of the favorable half-life of fluorine-18 and its rapid brain entry in nonhuman primates, favorable kinetics, low white matter binding, and selectivity for binding to tau over amyloid, is the lead compound for progression into clinical trials.
PD-132301, an inhibitor of sterol O-acyltransferase 1 (SOAT1; also known as acyl-coenzyme A:cholesterol acyltransferase-1, ACAT1), is under clinical investigation for numerous adrenal disorders. ...Radiolabeled SOAT1 inhibitors could support drug discovery and help diagnose SOAT1-related disorders, such as atherosclerosis. We synthesized two radiolabeled SOAT1 inhibitors, 11CPD-132301 and fluorine analogue 18F1. Rat biodistribution studies were conducted with both agents and, as the most selective tracer, 11CPD-132301 was advanced to preclinical positron emission tomography studies in (atherosclerotic) ApoE-/- mice. The uptake of 11CPD-132301 in SOAT1-rich tissue warrants further investigation into the compound as an atherosclerosis and adrenal imaging agent.
Animal Studies refers to a set of questions which take seriously the reality of animal lives, past and present, and the ways in which human societies have conceived of those lives, related to them, ...and utilized them in the production of human cultures. Scholars of the Hebrew Bible are increasingly engaging animals in their interpretive work. Such engagement is often implicit or partial, but increasingly drawing directly on the more critical aspects of Animal Studies. This article proceeds as a tour through the menagerie of the biblical canon by exploring key texts in order to describe and analyze what Animal Studies has brought to the field of Biblical Studies. Biblical texts are grouped into the following categories: animals in the narrative accounts of the Torah, legal and ritual texts concerning animals, animal metaphors in the prophets, and wisdom literature and animal life. The emergence and application of zooarchaeological research and a number of studies focusing on specific animal species will be discussed. Sustained attention will be given to two recent works which have brought Animal Studies into the fractured fold of biblical scholarship more directly. Finally, I will suggest some future directions for the study of the Hebrew Bible in light of Animal Studies.
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