Synthesis and pharmacokinetic study of a 11C-labeled cholesterol 24-hydroxylase inhibitor using 'in-loop' [11C]CO2 fixation method.
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ABSTRACT:
SUBMITTER: Chen Z
PROVIDER: S-EPMC7196435 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundThe ?-amyloid radiotracer [11C] PiB is extensively used for the Positron Emission Tomography (PET) diagnosis of Alzheimer's Disease and related dementias. For clinical use, [11C] PiB is produced using the 11C-methylation method ([11C] Methyl iodide or [11C] methyl triflate as 11C-methylation agents), which represents the most employed 11C-labelling strategy for the synthesis of 11C-radiopharmaceuticals. Recently, the use of direct [11C]CO2 fixation for the syntheses of 11C-tracers has gained interest in the radiochemical community due to its importance in terms of radiochemical versatility and for permitting the direct employment of the cyclotron-produced precursor [11C]CO2. This paper presents an optimised alternative one-pot methodology of [11C]CO2 fixation-reduction for the rapid synthesis of [11C] PiB using an automated commercial platform and its quality control.Results[11C] PiB was obtained from a (25.9?±?13.2)% (Average?±?Variation Coefficient, n?=?3) (end of synthesis, decay corrected) radiochemical yield from trapped [11C]CO2 after 1?min of labelling time using PhSiH3 / TBAF as the fixation-reduction system in Diglyme at 150?°C. The radiochemical purity was higher than 95% in all cases, and the molar activity was (61.4?±?1.6) GBq/?mol. The radiochemical yield and activity (EOS) of formulated [11C] PiB from cyclotron-produced [11C]CO2 was (14.8?±?12.1)%, decay corrected) and 9.88?GBq (± 6.0%), respectively. These are higher values compared to that of the 11C-methylation method with [11C]CH3OTf (~?8.3%).ConclusionsThe viability of the system PhSiH3 / TBAF to efficiently promote the radiosynthesis of [11C] PiB via direct [11C]CO2 fixation-reduction has been demonstrated. [11C] PiB was obtained through a fully automated radiosynthesis with a satisfactory yield, purity and molar activity. According to the results, the one-pot methodology employed could reliably yield sufficiently high tracer amounts for preclinical and clinical use.
| S-EPMC6635575 | biostudies-literature
Project description:Cholesterol 24-hydroxylase is a highly conserved cytochrome P450 that is responsible for the majority of cholesterol turnover in the vertebrate central nervous system. The enzyme is expressed in neurons, including hippocampal and cortical neurons that are important for learning and memory formation. Disruption of the cholesterol 24-hydroxylase gene in the mouse reduces both cholesterol turnover and synthesis in the brain but does not alter steady-state levels of cholesterol in the tissue. The decline in synthesis reduces the flow of metabolites through the cholesterol biosynthetic pathway, of which one, geranylgeraniol diphosphate, is required for learning in the whole animal and for synaptic plasticity in vitro. This review focuses on how the link between cholesterol metabolism and higher-order brain function was experimentally established.
| S-EPMC2837268 | biostudies-literature
Project description:ObjectiveThe formation of 24S-hydroxycholesterol is a brain-specific mechanism of cholesterol catabolism catalyzed by cholesterol 24-hydroxylase (CYP46A1, also known as CH24H). CH24H has been implicated in various biological mechanisms, whereas pharmacological lowering of 24S-hydroxycholesterol has not been fully studied. Soticlestat is a novel small-molecule inhibitor of CH24H. Its therapeutic potential was previously identified in a mouse model with an epileptic phenotype. In the present study, the anticonvulsive property of soticlestat was characterized in rodent models of epilepsy that have long been used to identify antiseizure medications.MethodsThe anticonvulsive property of soticlestat was investigated in maximal electroshock seizures (MES), pentylenetetrazol (PTZ) acute seizures, 6-Hz psychomotor seizures, audiogenic seizures, amygdala kindling, PTZ kindling, and corneal kindling models. Soticlestat was characterized in a PTZ kindling model under steady-state pharmacokinetics to relate its anticonvulsive effects to pharmacodynamics.ResultsAmong models of acutely evoked seizures, whereas anticonvulsive effects of soticlestat were identified in Frings mice, a genetic model of audiogenic seizures, it was found ineffective in MES, acute PTZ seizures, and 6-Hz seizures. The protective effects of soticlestat against audiogenic seizures increased with repetitive dosing. Soticlestat was also tested in models of progressive seizure severity. Soticlestat treatment delayed kindling acquisition, whereas fully kindled animals were not protected. Importantly, soticlestat suppressed the progression of seizure severity in correlation with 24S-hydroxycholesterol lowering in the brain, suggesting that 24S-hydroxycholesterol can be aggressively reduced to produce more potent effects on seizure development in kindling acquisition.SignificanceThe data collectively suggest that soticlestat can ameliorate seizure symptoms through a mechanism distinct from conventional antiseizure medications. With its novel mechanism of action, soticlestat could constitute a novel class of antiseizure medications for treatment of intractable epilepsy disorders such as developmental and epileptic encephalopathy.
| S-EPMC9311151 | biostudies-literature
Project description:The turnover of cholesterol in the brain is thought to occur via conversion of excess cholesterol into 24S-hydroxycholesterol, an oxysterol that is readily secreted from the central nervous system into the plasma. To gain molecular insight into this pathway of cholesterol metabolism, we used expression cloning to isolate cDNAs that encode murine and human cholesterol 24-hydroxylases. DNA sequence analysis indicates that both proteins are localized to the endoplasmic reticulum, share 95% identity, and represent a new cytochrome P450 subfamily (CYP46). When transfected into cultured cells, the cDNAs produce an enzymatic activity that converts cholesterol into 24S-hydroxycholesterol, and to a lesser extent, 25-hydroxycholesterol. The cholesterol 24-hydroxylase gene contains 15 exons and is located on human chromosome 14q32.1. Cholesterol 24-hydroxylase is expressed predominantly in the brain as judged by RNA and protein blotting. In situ mRNA hybridization and immunohistochemistry localize the expression of this P450 to neurons in multiple subregions of the brain. The concentrations of 24S-hydroxycholesterol in serum are low in newborn mice, reach a peak between postnatal days 12 and 15, and thereafter decline to baseline levels. In contrast, cholesterol 24-hydroxylase protein is first detected in the brain of mice at birth and continues to accumulate with age. We conclude that the cloned cDNAs encode cholesterol 24-hydroxylases that synthesize oxysterols in neurons of the brain and that secretion of 24S-hydroxycholesterol from this tissue in the mouse is developmentally regulated.
| S-EPMC22064 | biostudies-literature
Project description:Oxysterols are oxidised forms of cholesterol or its precursors. In this study we utilised the cholesterol 24-hydroxylase knockout mouse (Cyp46a1-/-) to study the sterol and oxysterol content of brain. Despite a great reduction in the abundance of 24S-hydroxycholesterol, the dominant metabolite of cholesterol in wild type brain, no other cholesterol metabolite was found to quantitatively replace this oxysterol in the Cyp46a1-/- mouse. Only minor amounts of other side-chain oxysterols including 22R-, 24R-, 25- and (25R),26-hydroxycholesterols were detected. In line with earlier studies, levels of cholesterol were similar in Cyp46a1-/- and wild type animals. However, the level of the cholesterol precursor, desomsterol, and its parallel metabolite formed via a shut of the mevalonate pathway, 24S,25-epoxycholesterol, were reduced in the Cyp46a1-/- mouse. The reduction in abundance of 24S,25-epoxycholesterol is interesting in light of a recent report indicating that this oxysterol promotes dopaminergic neurogenesis.
| S-EPMC4000437 | biostudies-literature
Project description:The compound La24Ru11 (tetra-cosa-lanthanum undeca-ruthenium) crystallizes in a Ce24Co11-type structure. The non-centrosymmetric crystal structure (space group P63 mc) contains RuLa6 trigonal prisms, La6 octa-hedra and LaRu4 tetra-hedra and is closely related to that of Ce23Ni7Mg4. This communication highlights the crystal-chemical similarities and points out the differences between the two structures. All of the tested crystals were inversion twins.
| S-EPMC7405562 | biostudies-literature
Project description:Cholesterol 24-hydroxylase catalyzes the conversion of cholesterol to 24-hydroxycholesterol, which is a major pathway for cholesterol elimination from the brain, since 24-hydroxycholesterol can readily cross the blood brain barrier. The present study aimed to elucidate the distribution of cholesterol 24-hydroxylase in the monkey brain.The distribution of cholesterol 24-hydroxylase in the monkey brain was examined using Western blot and immunohistochemistry methods, and was observed under light microscopy and electron microscopy.High levels of cholesterol 24-hydroxylase were observed in projection neurons and neuropil in structures derived from telencephalon, including the cerebral neocortex, hippocampus, amygdala, nucleus basalis of Meynert, and striatum. Electron microscopy revealed that the enzyme was localized in the axon terminals. One the other hand, cholesterol 24-hydroxylase was expressed at a lower level in the thalamus, globus pallidus and brainstem.The high level of cholesterol 24-hydroxylase in the telencephalon possibly reflects a high rate of cholesterol turnover in this part of brain.
| S-EPMC5560299 | biostudies-other
Project description:The development of a novel electrochemical methodology to generate carbon-11 carbon monoxide ([11C]CO) from cyclotron-produced carbon-11 carbon dioxide ([11C]CO2) using Ni(cyclam) and Zn(cyclen) complexes is described. This methodology allows up to 10% yields of [11C]CO from [11C]CO2. Produced [11C]CO was subsequently converted to [11C]N-benzylbenzamide under mild conditions with a radiochemical purity (RCP) of >98%.
| S-EPMC5633808 | biostudies-literature
Project description:BackgroundCarbon-11 labeled L-methionine (11C-MET) is a popular tracer used in the clinic for imaging brain tumors with positron emission tomography. However, the stability of 11C-MET in its final formulation is not well documented in literature. Recently, we observed fast degradation of HPLC-purified 11C-MET over time, and systematic investigation was conducted to identify the cause.ResultsIn this study, we verified the degraded product as 11C-labeled methionine sulfoxide (11C-METSO). To minimize oxidation, ascorbate (100 ppm) was added to the HPLC eluant, and the resulting HPLC-purified 11C-MET was stable in the final formulation solution without noticeable degradation for up to 1 h after the end of synthesis.ConclusionsOur data suggest that to minimize degradation, ascorbate can be added to the 11C-MET formulation solution especially if it is not administered into patients soon after the end of synthesis.
| S-EPMC5824703 | biostudies-literature
Project description:We describe the development of a new methodology focusing on 11C-labeling of sulfonyl carbamates in a multicomponent reaction comprised of a sulfonyl azide, an alkyl alcohol, and [11C]CO. A number of 11C-labeled sulfonyl carbamates were synthesized and isolated, and the developed methodology was then applied in the preparation of a biologically active molecule. The target compound was obtained in 24±10 % isolated radiochemical yield and was evaluated for binding properties in a tumor cell assay; in vivo biodistribution and imaging studies were also performed. This represents the first successful radiolabeling of a non-peptide angiotensin II receptor subtype 2 agonist, C21, currently in clinical trials for the treatment of idiopathic pulmonary fibrosis.
| S-EPMC5167284 | biostudies-literature