Trial Summary
What is the purpose of this trial?The purpose of this research is to measure the extent of inflammation in the brain between different groups of participants using a radioactive tracer called \[18F\]NOS. A radioactive tracer is a type of imaging drug that is labeled with a radioactive tag and injected into the body. This study will see how the tracer is taken up in the brain using an imaging scan called Positron Emission Tomography / Computed Tomography (PET/CT).
Participants will undergo approximately 60 minutes of dynamic scanning of the brain starting at approximately the time of injection of \[18F\]NOS.
Participants are required to have a brain MRI performed within 1 year prior to study enrollment, or if the subject has not had a brain MRI that is deemed acceptable for use for this study they will be asked to undergo a research brain MRI after they have consented for this study.
Is the drug used in the [18F]NOS PET/CT Scan for Neuroinflammation a promising treatment?Yes, the drug used in the [18F]NOS PET/CT Scan for Neuroinflammation is promising because it helps measure neuroinflammation, which is important for understanding diseases like Parkinson's. It provides a non-invasive way to see inflammation in the brain, which can help in studying and potentially treating these conditions.69101213
What safety data exists for [18F]NOS PET/CT Scan for Neuroinflammation?The provided research does not contain specific safety data for [18F]NOS or its variants like [18F]6-(2-fluoropropyl)-4-methylpyridin-2-amine, [18F]iNOS-9, FNOS, or 18F-NOS. The studies focus on different PET tracers and their applications, such as [18F]-FNM for NMDA receptors, 18F-FMISO for hypoxic tissue, [18F]AFA for NMDA receptor imaging, [18F]PBR111 for neuroinflammation, and [(18)F]FPEB for mGluR5 imaging. None of these studies provide safety data relevant to [18F]NOS.3481114
What data supports the idea that [18F]NOS PET/CT Scan for Neuroinflammation is an effective treatment?The available research does not provide specific data supporting the effectiveness of [18F]NOS PET/CT Scan for Neuroinflammation as a treatment. Instead, the studies focus on using similar compounds to detect hypoxic (low oxygen) tissues in tumors and brain conditions. These compounds are used to visualize areas with low oxygen, which can help in understanding certain diseases, but they are not treatments themselves. Therefore, there is no direct evidence from the provided information that [18F]NOS is an effective treatment for neuroinflammation.12578
Do I have to stop taking my current medications for the trial?The trial requires participants with HIV to stay on a stable ART regimen and those with OUD to be on a stable dosage of OUD treatment for at least four weeks before screening. Other medications are not specified, so check with the study team for details.
Eligibility Criteria
This trial is for adults aged 18-65 with or without HIV and opioid use disorder (OUD). Participants must have stable health conditions, including a controlled viral load if HIV positive, and be on consistent OUD treatment if applicable. Pregnant or breastfeeding women, individuals over 350 lb, those with claustrophobia affecting scans, MRI contraindications like incompatible metal in the body, significant organ dysfunction, epilepsy/seizure disorders, severe head trauma history, certain psychiatric disorders including schizophrenia or active major depression with suicidal ideation are excluded.Exclusion Criteria
My organs are not working properly.
I am not pregnant or breastfeeding.
I have a history of epilepsy or seizures.
I drink 15 or more alcoholic drinks weekly.
Treatment Details
The study tests how a radioactive tracer called [18F]NOS behaves in the brain to measure inflammation levels using PET/CT imaging. It involves an injection of [18F]NOS followed by about an hour-long dynamic brain scan. The research includes people both with and without HIV/OUD to compare results across different health statuses.
4Treatment groups
Experimental Treatment
Group I: Healthy volunteerExperimental Treatment1 Intervention
HIV-, OUD- healthy controls who have been opioid-exposed but do not have current or past OUD
Group II: HIV positive (HIV+) subjects with Opioid Use Disorder (OUD)Experimental Treatment1 Intervention
HIV positive (HIV+) subjects with Opioid Use Disorder (OUD): HIV+/OUD+
Group III: HIV negative (HIV-) subjects with OUDExperimental Treatment1 Intervention
HIV negative (HIV-) subjects with OUD: HIV-/OUD+
Group IV: HIV Positive (HIV+) subjects with OUD negativeExperimental Treatment1 Intervention
HIV+ subjects who may have been opioid-exposed but do not have current or past OUD
Find a clinic near you
Research locations nearbySelect from list below to view details:
University of PennsylvaniaPhiladelphia, PA
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Who is running the clinical trial?
University of PennsylvaniaLead Sponsor
References
Synthesis and biodistribution of 18F-labeled fluoronitroimidazoles: potential in vivo markers of hypoxic tissue. [2019]Three 18F labeled fluoronitroimidazoles have been prepared as potential in vivo markers of hypoxic cells in tumors, and ischemic areas of the heart and brain. 1-(2-Nitroimidazolyl)-3-[18F]fluoro-2-hydroxypropanol (18F]fluoro-normethoxymisonidazole) 4, 1-(2-[18F]fluoroethyl)-2-nitroimidazole 7, and 1-(2-[18F]-fluoroethyl)-2-methyl-5-nitroimidazole ([18F]fluoro-norhydroxymetronidazole) 10 were prepared in average radiochemical yields of less than 1%, 23% and 15-43% (8% at the no carrier-added level) respectively at end-of-synthesis. The in vivo biodistribution in rats was determined for each of the 18F labeled fluoronitroimidazoles. At 1 and 3 h after administration, the tissue distribution of each of the 18F labeled nitroimidzaoles was quite uniform and consistent with that of nitroimidazoles previously studied. These results suggest the need for a suitable animal model to evaluate their potential as in vivo markers of hypoxic tissue in the brain.
An efficient radiosynthesis of [18F]fluoromisonidazole. [2019]An efficient preparation of the hypoxic cell tracer [18F]3-fluoro-1-(2'-nitro-1'-imidazolyl)-2-propanol ([18F]fluoromisonidazole) is reported. This radiopharmaceutical is of interest to probe hypoxic tissue in infarcts and tumors. One-step radiolabeling and rapid protection group removal provided 55-80% yield in 50 min. The process is similar to common fluorine labeling procedures, simplifying the procedure for most laboratories, and offers an improvement over more difficult previous methods. The labeling precursor was prepared in five steps from readily available materials in a straightforward reaction scheme.
Fluorine-18 radiolabelling, biodistribution studies and preliminary PET evaluation of a new memantine derivative for imaging the NMDA receptor. [2016]A synthetic method has been established for preparing [18F]1-amino-3-fluoromethyl-5-methyl-adamantane ([18F]AFA). Biodistribution of the radiotracer in mice showed high brain uptake. The peak uptake (3.7% I.D/g organ) for the brain occurred at 30 min after injection. Accumulation of radioactivity in mouse brain was consistent with the known distribution of the NMDA receptors. The binding of [18F]AFA to the phencyclidine (PCP) binding sites of the NMDA receptor complex and the sigma recognition sites in a Rhesus monkey was also examined using positron emission tomography (PET). The regional brain distribution of [18F]AFA was changed by memantine and by (+)-MK-801, indicating competition for the same binding sites. Treatment with haloperidol caused a marked reduction of radioactivity uptake in all the brain regions examined. (-)-Butaclamol, which has pharmacological specificity for sigma sites, did not have any significant effects.
Synthesis and preliminary biological evaluation of 3-[(18)F]fluoro-5-(2-pyridinylethynyl)benzonitrile as a PET radiotracer for imaging metabotropic glutamate receptor subtype 5. [2016]The metabotropic glutamate receptor subtype 5 (mGluR5) has been reported to be implicated in various neurological disorders in the central nervous system. To investigate physiological and pathological functions of mGluR5, noninvasive imaging in a living body with PET technology and an mGluR5-specific radiotracer is urgently needed. Here, we report the synthesis of 3-[(18)F]fluoro-5-(2-pyridinylethynyl)benzonitrile ([(18)F]FPEB) through a convenient thermal reaction as a highly specific PET radiotracer for mGluR5. The precursor and standard compounds were prepared by a coupling reaction catalyzed by palladium. Radiosynthesis of [(18)F]FPEB was performed using nitro as a leaving group replaced by [(18)F]fluoride under conventional heating condition. Biodistribution, metabolite, and microPET studies were performed using Sprague-Dawley rats. Upto 30 mCi of [(18)F]FPEB was obtained with a radiochemical yield of 5% and a specific activity of 1900 +/- 200 mCi/mumol at the end of syntheses. Biodistribution showed rapid clearance from the blood pool and fast and steady accumulation of radioactivity into the brain. Metabolite studies indicated that only 22% of [(18)F]FPEB remained in the blood system 10 min after administration, and that a metabolite existed which was much more polar than the parent tracer. MicroPET studies demonstrated that [(18)F]FPEB accumulated specifically in mGluR5-rich regions of the brain such as striatum and hippocampus, and that blockade with 2-methyl-6-(2-phenylethynyl)pyridine (MPEP) and 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine (MTEP) substantially reduced the activity uptake in these regions. Selectivity was investigated by blockage with 6-amino-N-cyclohexyl-N,3-dimethylthiazolo[3,2-a]benzimidazole-2-caroxamide (YM-298198), a specific antagonist for mGluR1. [(18)F]FPEB was prepared conveniently and showed high specificity and selectivity toward mGluR5. It possesses the potential to be used in human studies to evaluate mGluR5 functions in various neurological disorders.
[18F]EF3 is not superior to [18F]FMISO for PET-based hypoxia evaluation as measured in a rat rhabdomyosarcoma tumour model. [2021]The aim of this investigation was to quantitatively compare the novel positron emission tomography (PET) hypoxia marker 2-(2-nitroimidazol-1-yl)-N-(3[(18)F],3,3-trifluoropropyl)acetamide ([(18)F]EF3) with the reference hypoxia tracer [(18)F]fluoromisonidazole ([(18)F]FMISO).
Design and synthesis of 2-amino-4-methylpyridine analogues as inhibitors for inducible nitric oxide synthase and in vivo evaluation of [18F]6-(2-fluoropropyl)-4-methyl-pyridin-2-amine as a potential PET tracer for inducible nitric oxide synthase. [2021]A series of position-6 substituted 2-amino-4-methylpyridine analogues was synthesized and compounds 9, 18, and 20 were identified as the inhibitors with the greatest potential to serve as PET tracers for imaging inducible nitric oxide synthase (iNOS). [(18)F]9 was synthesized and evaluated in a mouse model of lipopolysaccharide (LPS)-induced iNOS activation. In vivo biodistribution studies of [(18)F]9 indicate higher tracer uptake in the lungs of the LPS-treated mice when compared to control mice. Tracer uptake at 60 min postinjection was reduced in a blocking study using a known inhibitor of iNOS. The expression of iNOS was confirmed by Western blot analysis of lung samples from the LPS-treated mice. MicroPET studies also demonstrated accumulation of radiotracer in the lungs of the LPS-treated mice. Taken collectively, these data suggest that [(18)F]9 shows favorable properties as a PET tracer to image iNOS activation with PET.
Imaging of hypoxic lesions in patients with gliomas by using positron emission tomography with 1-(2-[18F] fluoro-1-[hydroxymethyl]ethoxy)methyl-2-nitroimidazole, a new 18F-labeled 2-nitroimidazole analog. [2016]Assessment of hypoxic conditions in brain tumors is important for predicting tumor aggressiveness and treatment response. A new hypoxia imaging agent, 1-(2-[(18)F]fluoro-1-[hydroxymethyl]ethoxy)methyl-2-nitroimidazole (FRP-170), with higher image contrast and faster clearance than preexisting hypoxia tracers for PET, was used to visualize hypoxic tissues in 8 patients with glioma.
Evaluation of hypoxic tissue dynamics with 18F-FMISO PET in a rat model of permanent cerebral ischemia. [2021][¹⁸F]Fluoromisonidazole (¹⁸F-FMISO) is a nitroimidazole derivative that has been proposed as a positron emission tomography (PET) radiotracer to detect hypoxic tissue in vivo. This compound accumulates in hypoxic but viable tissue and may be a good candidate for evaluating the ischemic penumbra. We evaluated the time course of ¹⁸F-FMISO uptake using PET in a rat model of permanent cerebral ischemia and the correlation with histological changes.
Feasibility and dosimetry studies for 18F-NOS as a potential PET radiopharmaceutical for inducible nitric oxide synthase in humans. [2021]Nitric oxide (NO), the end product of the inducible form of NO synthase (iNOS), is an important mediator of a variety of inflammatory diseases. Therefore, a radiolabeled iNOS radiopharmaceutical for assessing iNOS protein concentration as a marker for its activity would be of value to the study and treatment of NO-related diseases. We recently synthesized an (18)F-radiolabeled analog of the reversible NOS inhibitor, 2-amino-4-methylpyridine ((18)F-NOS), and confirmed its utility in a murine model of lung inflammation. To determine its potential for use in humans, we measured (18)F-NOS myocardial activity in patients after orthotopic heart transplantation (OHT) and correlated it with pathologic allograft rejection, tissue iNOS levels, and calculated human radiation dosimetry.
Synthesis of a Potent Aminopyridine-Based nNOS-Inhibitor by Two Recent No-Carrier-Added (18)F-Labelling Methods. [2020]Nitric oxide (NO), an important multifunctional signaling molecule, is produced by three isoforms of NO-synthase (NOS) and has been associated with neurodegenerative disorders. Selective inhibitors of the subtypes iNOS (inducible) or nNOS (neuronal) are of great interest for decoding neurodestructive key factors, and (18)F-labelled analogues would allow investigating the NOS-function by molecular imaging with positron emission tomography. Especially, the highly selective nNOS inhibitor 6-((3-((3-fluorophenethylamino)methyl)phenoxy)methyl)-4-methylpyridin-2-amine (10) lends itself as suitable compound to be (18)F-labelled in no-carrier-added (n.c.a.) form. For preparation of the (18)F-labelled nNOS-Inhibitor [(18)F]10 a "build-up" radiosynthesis was developed based on a corresponding iodonium ylide as labelling precursor. The such activated phenethyl group of the compound was efficiently and regioselectively labelled with n.c.a. [(18)F]fluoride in 79% radiochemical yield (RCY). After conversion by reductive amination and microwave assisted displacement of the protecting groups, the desired nNOS-inhibitor was obtained in about 15% total RCY. Alternatively, for a simplified "late-stage" (18)F-labelling procedure a corresponding boronic ester precursor was synthesized and successfully used in a newer, copper(II) mediated n.c.a. (18)F-fluoro-deboroniation reaction, achieving the same total RCY. Thus, both methods proved comparatively suited to provide the highly selective NOS-inhibitor [(18)F]10 as probe for preclinical in vivo studies.
TSPO PET Using [18F]PBR111 Reveals Persistent Neuroinflammation Following Acute Diisopropylfluorophosphate Intoxication in the Rat. [2020]Acute intoxication with organophosphates (OPs) can trigger status epilepticus followed by persistent cognitive impairment and/or electroencephalographic abnormalities. Neuroinflammation is widely posited to influence these persistent neurological consequences. However, testing this hypothesis has been challenging, in part because traditional biometrics preclude longitudinal measures of neuroinflammation within the same animal. Therefore, we evaluated the performance of noninvasive positron emission tomography (PET), using the translocator protein (TSPO) radioligand [18F]PBR111 against classic histopathologic measures of neuroinflammation in a preclinical model of acute intoxication with the OP diisopropylfluorophosphate (DFP). Adult male Sprague Dawley rats administered pyridostigmine bromide (0.1 mg/kg, im) 30 min prior to administration of DFP (4 mg/kg, sc), atropine sulfate (2 mg/kg, im) and 2-pralidoxime (25 mg/kg, im) exhibited moderate-to-severe seizure behavior. TSPO PET performed prior to DFP exposure and at 3, 7, 14, 21, and 28 days postexposure revealed distinct lesions, as defined by increased standardized uptake values (SUV). Increased SUV showed high spatial correspondence to immunohistochemical evidence of neuroinflammation, which was corroborated by cytokine gene and protein expression. Regional SUV metrics varied spatiotemporally with days postexposure and correlated with the degree of neuroinflammation detected immunohistochemically. Furthermore, SUV metrics were highly correlated with seizure severity, suggesting that early termination of OP-induced seizures may be critical for attenuating subsequent neuroinflammatory responses. Normalization of SUV values to a cerebellar reference region improved correlations to all outcome measures and seizure severity. Collectively, these results establish TSPO PET using [18F]PBR111 as a robust, noninvasive tool for longitudinal monitoring of neuroinflammation following acute OP intoxication.
Automated Synthesis and Initial Evaluation of (4'-Amino-5',8'-difluoro-1'H-spiro[piperidine-4,2'-quinazolin]-1-yl)(4-[18F]fluorophenyl)methanone for PET/MR Imaging of Inducible Nitric Oxide Synthase. [2021]Label="Background">Inducible nitric oxide synthase (iNOS) plays a crucial role in neuroinflammation, especially microglial activity, and may potentially represent a useful biomarker of neuroinflammation. In this study, we carefully defined a strategic plan to develop iNOS-targeted molecular PET imaging using (4'-amino-5',8'-difluoro-1'H-spiro[piperidine-4,2'-quinazolin]-1-yl)(4-fluorophenyl)methanone ([18F]FBAT) as a tracer in a mouse model of lipopolysaccharide- (LPS-) induced brain inflammation.
[18F]NOS PET Brain Imaging Suggests Elevated Neuroinflammation in Idiopathic Parkinson's Disease. [2023]Neuroinflammation is implicated as a key pathologic mechanism in many neurodegenerative diseases and is thought to be mediated in large part by microglia, native phagocytic immune cells of the CNS. Abnormal aggregation of the protein α-synuclein after phagocytosis by microglia is one possible neuropathophysiological mechanism driving Parkinson's disease (PD). We conducted a human pilot study to evaluate the feasibility of targeting the inducible isoform of nitric oxide synthase using the [18F]NOS radiotracer to measure neuroinflammation in idiopathic PD. Ten adults consisting of 6 PD patients and 4 healthy controls (HC) underwent one hour of dynamic [18F]NOS positron emission tomography (PET) brain imaging with arterial blood sampling. We observed increased [18F]NOS whole brain distribution volume (VT) in PD patients compared to age-matched healthy controls (p < 0.008) via a 1-tissue compartment (TC) model. The rate constant K1 for transport from blood into tissue did not differ between groups (p = 0.72). These findings suggest elevated oxidative stress, a surrogate marker of inflammation, is present in early-stage idiopathic PD and indicate that [18F]NOS PET imaging is a promising, non-invasive method to measure neuroinflammation.
Pharmacological Characterization of [18F]-FNM and Evaluation of NMDA Receptors Activation in a Rat Brain Injury Model. [2023]Label="PURPOSE">NMDA receptors (NMDARs) dysfunction plays a central role in the physiopathology of psychiatric and neurodegenerative disorders whose mechanisms are still poorly understood. The development of a PET (positron emission tomography) tracer able to selectively bind to the NMDARs intra-channel PCP site may make it possible to visualize NMDARs in an open and active state. We describe the in vitro pharmacological characterization of [18F]-fluoroethylnormemantine ([18F]-FNM) and evaluate its ability to localize activated NMDA receptors in a rat preclinical model of excitotoxicity.