PET Radioligands for Rheumatoid Arthritis
Recruiting in Palo Alto (17 mi)
Overseen byRobert B Innis, M.D.
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 1
Recruiting
Sponsor: National Institute of Mental Health (NIMH)
Must not be taking: NSAIDs, Probenecid
Disqualifiers: HIV, Cardiovascular disease, Pregnancy, others
No Placebo Group
Trial Summary
What is the purpose of this trial?Background:
Inflammation plays a significant role in various disorders that involve neurodegeneration or autoimmune reaction as one of their mechanisms. PET scans can help detect inflammation. Two new drugs may create better PET images.
Objective:
To see if the drug \[11C\]MC1 can help image inflammation.
Eligibility:
People ages 18 and older with rheumatoid arthritis or idiopathic inflammatory myopathy (IIM).
Healthy volunteers enrolled in protocol 01-M-0254 or 17-M-0181 are also needed.
Design:
Healthy participants will be screened under protocol 01-M-0254 or 17-M-0181.
Participants with arthritis or IIM will have a screening visit. This will include:
Medical history
Physical exam
Blood and urine tests
Possible CT or X-ray: A machine will take pictures of the body.
Healthy participants will have 1 or 2 visits. They may have urine tests. They may take the drug celecoxib by mouth. They will have a PET scan. A small amount of one or both study drugs will be injected through a catheter: A needle will guide a thin plastic tube into an arm vein. Another catheter will draw blood. They will like on a bed that slides into a machine. Their vital signs and heart activity will be measured.
Participants with arthritis will have up to 2 visits after screening. They may take celecoxib and have PET scans.
Participants with IIM will have up to 3 visits after screening. At 1 or 2 visits, they will take celecoxib and have PET scans. They will have 1 visit where they have an MRI: They will lie on a table that slides into a machine. The machine takes pictures of the body.
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Will I have to stop taking my current medications?
The trial requires that participants stop taking non-steroidal anti-inflammatory drugs (NSAIDs) or willow bark tea for two weeks before the PET scan. Other medications are not specifically mentioned, so it's best to discuss your current medications with the trial team.
What evidence supports the effectiveness of the drug celecoxib in treating rheumatoid arthritis?
Celecoxib, a COX-2 inhibitor, has been shown in studies to be effective in reducing pain and improving physical function in patients with rheumatoid arthritis, with similar efficacy to other nonsteroidal anti-inflammatory drugs (NSAIDs) but with fewer gastrointestinal side effects.
12345Is [11C]celecoxib safe for use in humans?
Studies in baboons suggest that [11C]celecoxib is safe at certain doses, with the liver and gallbladder being the primary organs affected. The maximum safe dose for humans is estimated to be 1110 MBq, which is within research safety limits.
12346How does the drug used in the PET Radioligands for Rheumatoid Arthritis trial differ from other treatments for this condition?
The drug in this trial uses PET imaging to target COX-2, an enzyme involved in inflammation, allowing for precise visualization of inflammation in rheumatoid arthritis. This approach is unique because it combines imaging with treatment, potentially offering more targeted therapy compared to traditional anti-inflammatory drugs.
12678Eligibility Criteria
Adults over 18 with rheumatoid arthritis or idiopathic inflammatory myopathy (IIM), and healthy adults enrolled in specific protocols, can join this trial. Participants must be able to perform all study procedures and provide consent. Women should not plan to become pregnant soon. NSAIDs use is a disqualifier, along with certain medical conditions.Inclusion Criteria
I am over 18, can follow the study plan, agree to participate, and if female, not planning to get pregnant soon.
I am an adult with RA, can follow the study plan, and not planning to get pregnant soon.
I am over 18, healthy, can follow the study plan, and if female, not planning to get pregnant soon.
Exclusion Criteria
I haven't taken NSAIDs or willow bark tea for two weeks before a PET scan.
Unable to travel to NIH, recent exposure to radiation related to research, inability to lie flat on camera bed for at least two hours, current pregnancy or breastfeeding, substance use disorder or alcohol use disorder, NIMH employees and staff or immediate family member of NIMH employee/staff.
People with certain medical conditions that prevent them from having an MRI scan.
+2 more
Participant Groups
The trial tests if two new drugs, [11C]ER176 and [11C]MC1, improve PET scan imaging of inflammation in patients with arthritis or IIM compared to healthy volunteers. It involves taking celecoxib orally, undergoing PET scans, and possibly CT scans or MRIs.
1Treatment groups
Experimental Treatment
Group I: Single armExperimental Treatment2 Interventions
all groups get the same studies
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
National Institutes of Health Clinical CenterBethesda, MD
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Who Is Running the Clinical Trial?
National Institute of Mental Health (NIMH)Lead Sponsor
References
Synthesis and preliminary in vitro biological evaluation of new carbon-11-labeled celecoxib derivatives as candidate PET tracers for imaging of COX-2 expression in cancer. [2016]The enzyme cyclooxygenase-2 (COX-2) is overexpressed in a variety of malignant tumors. This study was designed to develop new radiotracers for imaging of COX-2 in cancer using biomedical imaging technique positron emission tomography (PET). Carbon-11-labeled celecoxib derivatives, [(11)C]4a-c and [(11)C]8a-d, were prepared by O-[(11)C] methylation of their corresponding precursors using [(11)C]CH(3)OTf under basic conditions and isolated by a simplified solid-phase extraction (SPE) method in 52 ± 2% (n = 5) and 57 ± 3% (n = 5) radiochemical yields based on [(11)C]CO(2) and decay corrected to end of bombardment (EOB). The overall synthesis time from EOB was 23 min, the radiochemical purity was >99%, and the specific activity at end of synthesis (EOS) was 277.5 ± 92.5 GBq/μmol (n = 5). The IC(50) values to block COX-2 for known compounds celecoxib (4d), 4a and 4c were 40, 290 and 8 nM, respectively, and preliminary findings from in vitro biological assay indicated that the synthesized new compounds 4b and 8a-d display similar strong inhibitory effectiveness in the MDA-MB-435 human cancer cell line in comparison with the parent compound 4d. These results encourage further in vivo evaluation of carbon-11-labeled celecoxib derivatives as new potential PET radiotracers for imaging of COX-2 expression in cancer.
In Vivo Brain Imaging, Biodistribution, and Radiation Dosimetry Estimation of [11C]Celecoxib, a COX-2 PET Ligand, in Nonhuman Primates. [2018]COX-2 selective inhibitors (COXIBs) are non-steroidal anti-inflammatory drugs (NSAIDs), with fewer side effects compared with non-selective NSAIDs, and are used for the treatment of arthritis, headaches, and other inflammatory diseases of the brain and peripheral tissues. Radiolabeled COXIBs may permit positron emission tomography (PET) imaging of COX-2 localization and activity in diseases, enable monitoring of inflammatory processes, and determine target occupancy of COX-2 activity by NSAIDs, thus, accelerating the development of novel CIXIBs. We synthesized [11C]celecoxib, one of the COXIBs and a prescription drug, and here report its in vivo uptake in the brain, whole body biodistribution, and radiation dosimetry in baboons using PET. Brain imaging experiments were performed in one baboon and whole body PET scans were performed in triplicates in two male baboons using an ECAT ACCEL (Siemens Medical Solutions, Inc. Knoxville) under anesthetic conditions. PET studies in baboons show that [11C]celecoxib penetrates the blood brain barrier (BBB) and accumulates in the brain, followed by a washout of radioactivity. The liver has the highest residence time and the gallbladder is the critical organ for [11C]celecoxib. Organ Level Internal Dose Assessment (OLINDA) estimates indicate that the maximum permissible single study dosage of [11C]celecoxib in humans is 1110 MBq (30 mCi) for both males and females under the 21 CFR 361.1 dose limit for research subjects.
Efficient sequential synthesis of PET Probes of the COX-2 inhibitor [11C]celecoxib and its major metabolite [11C]SC-62807 and in vivo PET evaluation. [2015]Synthesis of [(11)C]celecoxib, a selective COX-2 inhibitor, and [(11)C]SC-62807, a major metabolite of celecoxib, were achieved and the potential of these PET probes for assessing the function of drug transporter in biliary excretion was evaluated. The synthesis of [(11)C]celecoxib was achieved in one-pot by reacting [(11)C]methyl iodide with an excess of the corresponding pinacol borate precursor using Pd(2)(dba)(3), P(o-tolyl)(3), and K(2)CO(3) (1:4:9) in DMF. The radiochemical yield of [(11)C]celecoxib was 63±23% (decay-corrected, based on [(11)C]CH(3)I) (n=7) with a specific radioactivity of 83±23GBq/μmol (n=7). The average time of synthesis from end of bombardment including formulation was 30min with >99% radiochemical purity. [(11)C]SC-62807 was synthesized from [(11)C]celecoxib by further rapid oxidation in the presence of excess KMnO(4) with microwave irradiation. The radiochemical yield of [(11)C]SC-62807 was 55±9% (n=3) (decay-corrected, based on [(11)C]celecoxib) with a specific radioactivity of 39±4GBq/μmol (n=3). The average time of synthesis from [(11)C]celecoxib including formulation was 20min and the radiochemical purity was >99%. PET studies in rats and the metabolite analyzes of [(11)C]celecoxib and [(11)C]SC-62807 showed largely different excretion processes, and consequently, [(11)C]SC-62807 was rapidly excreted via hepatobiliary excretion without further metabolism. [(11)C]SC-62807 was shown to have a high potential as a PET probe for evaluating drug transporter function in biliary excretion.
[I]-Celecoxib Analogues as SPECT Tracers of Cyclooxygenase-2 in Inflammation. [2021]We report the synthesis and evaluation of a series of iodinated celecoxib analogues as cyclooxygenase-2 (COX-2)-targeted single photon emission computerized tomography (SPECT) imaging agents for the detection of inflammation. The structure-activity relationship identified 5-(4-iodophenyl)-1-{4-(methylsulfonyl)phenyl}-3-(trifluoromethyl)-1H-pyrazole (8) as a promising compound with IC(50) values of 0.05 μM against purified COX-2 and 0.03 μM against COX-2 in activated macrophages. The arylstannane of 8 undergoes facile radio-[(123)I]-iodination upon treatment with Na(123)I/NaI and chloramine T using an EtOAc/H(2)O two-phase system. The [(123)I]-8 was produced in a radiochemical yield of 85% and a radiochemical purity of 99%. In vivo SPECT imaging demonstrated that the radiotracer was taken up by inflamed rat paws with an average 1.7-fold enrichment over contralateral noninflamed paws. This study suggests that conversion of celecoxib into its isomeric iodo-[(123)I]-analogues is a useful approach for generating novel and efficacious agents for COX-2-targeted SPECT imaging of inflammation.
Celecoxib: a review of its use in osteoarthritis, rheumatoid arthritis and acute pain. [2018]Celecoxib is a cyclo-oxygenase (COX) inhibitor that exhibits relative in vitro and ex vivo selectivity for COX-2 over COX-1. Results of randomised double-blind multicentre studies indicate that celecoxib is superior to placebo and has similar efficacy as conventional nonsteroidal anti-inflammatory drugs (NSAIDs) in improving the signs and symptoms of osteoarthritis and rheumatoid arthritis. Analgesic efficacy and improvements in functional status are apparent within 2 weeks of starting therapy and are maintained throughout treatment. Available data suggest that celecoxib has analgesic efficacy in patients with postsurgical dental pain, although this is yet to be confirmed. In patients with osteoarthritis of the knee, celecoxib 100 and 200 mg and naproxen 500 mg twice daily were similarly efficacious and superior to placebo. Once and twice daily celecoxib dosage regimens provided comparable efficacy. Improvements in physical function paralleled those in pain relief. Celecoxib also has efficacy in treating the signs and symptoms of osteoarthritis of the hip. The effects of celecoxib were not diminished in elderly patients with osteoarthritis of the hip or knee. All dosages of celecoxib (100 to 400 mg twice daily) and naproxen 500 mg twice daily produced significant anti-inflammatory and analgesic effects in patients with active rheumatoid arthritis. In patients with stable rheumatoid arthritis, celecoxib 200 mg twice daily showed sustained symptomatic improvements similar to those of twice daily slow-release diclofenac 75 mg over a 24-week period. Celecoxib was well tolerated in clinical trials. Upper gastrointestinal complications occurred in significantly fewer patients treated with twice daily celecoxib 25 to 400 mg than in those receiving comparator NSAIDs. There was no evidence of a dose relationship in endoscopic ulcer development and incidences in celecoxib and placebo recipients were lower than in those receiving twice daily naproxen 500 mg or ibuprofen 800 mg 3 times daily.
Radiosynthesis and in vivo evaluation of [11C]MOV as a PET imaging agent for COX-2. [2019]Radiosynthesis and in vivo evaluation of [11C]4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide (methoxy analogue of valdecoxib, [11C]MOV), a COX-2 inhibitor, was conducted in rat and baboon. Synthesis of the reference standard MOV (3), and its desmethyl precursor 2 for radiolabeling were performed using 1,2-diphenylethan-1-one as the starting material in five steps with 15% overall yield. Radiosynthesis of [11C]MOV was accomplished in 40 ± 10% yield and >99% radiochemical purity by reacting the precursor 2 in dimethyl formamide (DMF) with [11C]CH3I followed by removal of the dimethoxytrityl (DMT) protective group using trifluroacetic acid. PET studies in anesthetized baboon showed very low uptake and homogeneous distribution of [11C]MOV in brain. The radioligand underwent rapid metabolism in baboon plasma. MicroPET studies in male Sprague Dawley rats revealed [11C]MOV binding in lower thorax. The tracer binding in rats was partially blocked in heart and duodenum by the administration of 1 mg/kg oral dose of COX-2 inhibitor valdecoxib.
Radiosynthesis and Preclinical Evaluation of 11C-VA426, a Cyclooxygenase-2 Selective Ligand. [2023]Cyclooxygenase-2 (COX-2) is involved in the inflammatory response, and its recurrent overexpression in cancers as well as in neurodegenerative disorders has made it an important target for therapy. For this reason, noninvasive imaging of COX-2 expression may represent an important diagnostic tool. In this work, a COX-2 inhibitor analogue, VA426 [1-(4-fluorophenyl)-3-(2-methoxyethyl)-2-methyl-5-(4-(methylsulfonil)phenyl)-1H-pyrrole], was synthesized and radiolabelled with the 11C radioisotope. The ex vivo biodistribution profile of 11C-VA426 was evaluated in the brain and periphery of healthy rats and mice and in brain and periphery of inflammation models, based on the administration of LPS. 11C-VA426 synthesis with the tBuOK base showed optimal radiochemical yield (15 ± 2%) based on triflate activity, molar activity (range 37-148 GBq/μmol), and radiochemical purity (>95%). Ex vivo biodistribution studies showed a fast uptake of radioactivity but a rapid washout, except in regions expressing COX-2 (lungs, liver, and kidney) both in rats and in mice, with maximum values at 30 and 10 minutes p.i., respectively. LPS administration did not show significant effect on radioactivity accumulation. Celecoxib competition experiments performed in rats and mice treated with LPS produced a general target unrelated reduction of radioactivity concentration in all peripheral tissues and brain areas examined. Finally, in agreement with the negative results obtained from biodistribution experiments, radiometabolites analysis revealed that 11C-VA426 is highly unstable in vivo. This study indicates that the compound 11C-VA426 is not currently suitable to be used as radiopharmaceutical for PET imaging. This family of compounds needs further implementation in order to improve in vivo stability.
General method for the (11)C-labeling of 2-arylpropionic acids and their esters: construction of a PET tracer library for a study of biological events involved in COXs expression. [2012]Cyclooxygenase (COX) is a critical enzyme in prostaglandin biosynthesis that modulates a wide range of biological functions, such as pain, fever, and so on. To perform in vivo COX imaging by positron emission tomography (PET), we developed a method to incorporate (11)C radionuclide into various 2-arylpropionic acids that have a common methylated structure, particularly among nonsteroidal anti-inflammatory drugs (NSAIDs). Thus, we developed a novel (11)C-radiolabeling methodology based on rapid C-[(11)C]methylation by the reaction of [(11)C]CH(3)I with enolate intermediates generated from the corresponding esters under basic conditions. One-pot hydrolysis of the above [(11)C]methylation products also allows the synthesis of desired (11)C-incorporated acids. We demonstrated the utility of this method in the syntheses of six PET tracers, [(11)C]Ibuprofen, [(11)C]Naproxen, [(11)C]Flurbiprofen, [(11)C]Fenoprofen, [(11)C]Ketoprofen, and [(11)C]Loxoprofen. Notably, we found that their methyl esters were particularly useful as proradiotracers for a study of neuroinflammation. The microPET studies of rats with lipopolysaccharide (LPS)-induced brain inflammation clearly showed that the radioactivity of PET tracers accumulated in the inflamed region. Among these PET tracers, the specificity of [(11)C]Ketoprofen methyl ester was demonstrated by a blocking study. Metabolite analysis in the rat brain revealed that the methyl esters were initially taken up in the brain and then underwent hydrolysis to form pharmacologically active forms of the corresponding acids. Thus, we succeeded in general (11)C-labeling of 2-arylpropionic acids and their methyl esters as PET tracers of NSAIDs to construct a potentially useful PET tracer library for in vivo imaging of inflammation involved in COXs expression.