A Phase 1 Study of Safety, Tolerance, Pharmacokinetics and Nuclear Medicine Imaging of 123I-CMICE-013 Administered Intravenously in Healthy Adult Volunteers

The need exists for alternatives to 99mTc based perfusion radiotracers for cardiac patient management. An alternative radiotracer, I123-CMICE-013, has been developed at the Canadian Molecular Imaging Center of Excellence (C-MICE) at the University of Ottawa Heart Institute. Initial testing results in rats and pigs suggest that in addition to being a cyclotron-produced alternative to 99mTc tracers, I-123-CMICE-013 may be a superior tracer for measuring myocardial perfusion.This Phase 1 study will study the safety and tolerability, biodistribution, pharmacokinetics and radiation dosimetry, and distribution and localization of I123-CMICE-013in healthy adult volunteers.

开始日期2012-04-01

申办/合作机构

Ottawa Heart Institute Research Corp.

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100 项与 123I-CMICE-013 相关的临床结果

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100 项与 123I-CMICE-013 相关的转化医学

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100 项与 123I-CMICE-013 相关的专利（医药）

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项与 123I-CMICE-013 相关的文献（医药）

2015-05-01·Journal of Nuclear Medicine1区 · 医学

Flow-Dependent Uptake of ¹²³I-CMICE-013, a Novel SPECT Perfusion Agent, Compared with Standard Tracers

1区 · 医学

Article

作者: Ruddy, Terrence D ; Marvin, Brian ; Wells, R Glenn ; Duan, Yin ; Timmins, Rachel ; Fernando, Pasan ; Wei, Lihui ; Soueidan, Karen ; Bensimon, Corinne ; Petryk, Julia

Rotenone derivatives have shown promise in myocardial perfusion imaging (MPI). CMICE-013 is a novel (123)I-labeled rotenone derivative developed for SPECT MPI. The objective of this study was to assess the image quality of CMICE-013 and compare its uptake with tetrofosmin, sestamibi, and (201)Tl in vivo in a porcine model of stress-induced myocardial ischemia.METHODSMicrospheres were injected simultaneously with the radiotracer injections at rest and stress to measure blood flow. Mimicking a 1-d tetrofosmin protocol, stress imaging used 3 times as much activity and occurred 1 h after the rest injection. SPECT images were obtained at both rest and stress. After imaging, the heart was sectioned into 44-50 pieces. In each heart sample, the tracer uptake was measured in a γ counter. The images were aligned, and the decay-corrected ratio of the signals at rest and stress was used to separate the well-counter signal into rest and stress components. The uptake at rest and stress was compared with microsphere flow measurements.RESULTSThe CMICE-013 images showed good contrast between the heart and surrounding organs, with heart-to-liver and heart-to-lung uptake ratios similar to those of the standard tracers. Uptake of CMICE-013 was 1.5% of the injected dose at rest and increased more rapidly with increased blood flow than did the standard SPECT tracers. The percentage injected dose of CMICE-013 taken up by the heart was greater (P < 0.05) than (201)Tl, tetrofosmin, or sestamibi at flows greater than 1.5 mL/min/g.CONCLUSIONCMICE-013 is a promising new SPECT MPI agent.

2014-04-01·Bioorganic & Medicinal Chemistry3区 · 医学

Characterization of the four isomers of 123I-CMICE-013: A potential SPECT myocardial perfusion imaging agent

3区 · 医学

Article

作者: Lockwood, Julia ; Ruddy, Terrence D ; Bensimon, Corinne ; Gan, Wei ; Mullett, Wayne ; Yan, Xuxu ; Wei, Lihui ; Gottlieb, Bram ; Duan, Yin ; Wells, R Glenn ; Fernando, Pasan

Myocardial perfusion imaging (MPI) with single photon emission computed tomography (SPECT) is widely used in the assessment of coronary artery disease (CAD). We have developed (123)I-CMICE-013 based on rotenone, a mitochondrial complex I (MC-1) inhibitor, as a promising new MPI agent. Our synthesis results in a mixture of four species of (123)I-CMICE-013 A, B, C, D. In this study, we separated the four species and evaluated their biodistribution and imaging properties. The cold analogs (127)I-CMICE-013 A, B, C, D were isolated and characterized and their chemical structures proposed.METHODS(123)I-CMICE-013 was synthesized by radiolabeling rotenone with Na(123)I in trifluoroacetic acid (TFA) with iodogen as the oxidizing agent at 60°C for 45min, and the four species were separated by RP-HPLC. The cold analogs (127)I-CMICE-013 A, B, C and D were isolated with a similar procedure and characterized by NMR and mass spectrometry. Biodistribution and microSPECT imaging studies were carried out on normal rats.RESULTSWe propose the mechanism of the rotenone iodination and the structures of the four species. First, I(+) forms an intermediate three-membered ring with 6' and 7' carbons. Second, the lone electron pair of the water molecule attacks the 6' or 7'-carbon, following by the formation of 6'-OH, and 7'-I bonds as in major products C and D, or 6'-I and 7'-OH bonds as in minor products A and B. The weaker 6'-I bond in the intermediate prompts the nucleophilic attachment of water at the favorable 6'-carbon to generate C and D. MicroSPECT images of (123)I-CMICE-013 A, B, C, D in rats showed clear visualization of myocardium and little interference from lung and liver. The imaging time activity curves and biodistribution data showed complex profiles for the four isomers, which is not expected from the structure activity relationship theory.CONCLUSION(123/127)I-CMICE-013 A and B are constitutional isomers with C and D, while A and C are diastereomers of B and D, respectively. Overall, the biological characteristics of the four species are not correlated perfectly with their molecular structures.

2014-01-01·EJNMMI Research3区 · 医学

Biodistribution and radiodosimetry of a novel myocardial perfusion tracer 123I-CMICE-013 in healthy rats

3区 · 医学

ArticleOA

作者: Duan, Yin ; Soueidan, Karen ; Ruddy, Terrence D. ; Bensimon, Corinne ; Wells, R. Glenn ; Fernando, Pasan ; Hunter, Chad ; Lockwood, Julia ; Wei, Lihui

BACKGROUND123I-CMICE-013 is a novel radiotracer previously reported to have promising characteristics for single-photon emission computed tomography (SPECT) myocardial perfusion imaging. We evaluated the biokinetics and radiodosimetry of this rotenone-like 123I-labeled tracer in a microSPECT imaging-based study.METHODS37 to 111 MBq of 123I-CMICE-013 was synthesized and administered intravenously to 14 healthy rats. Images were acquired with a microSPECT/CT camera at various time intervals and reconstructed to allow activity quantification in the tissues of interest. Radiation dosage resulted from the injection of 123I-CMICE-013 was estimated base on the biodistribution data. Tissue uptake values from image analysis were verified by gamma-counting dissected organs ex vivo.RESULTSThe heart/stomach and heart/intestine uptake ratios peaked shortly after the injection of 123I-CMICE-013, meanwhile the heart/liver ratio reached 2 as early as at 23 min post-injection. Little activity was observed in the lung and overnight clearance was significant in most of the measured tissues. The radiation dosimetry analysis based on the time-activity curves provided an estimate of the effective human dose of 6.99E-03 mSv/MBq using ICRP 60 and 7.15E-03 mSv/MBq using ICRP 103, which is comparable to the popular myocardium perfusion imaging (MPI) agents such as 99mTc-tetrofosmin and 99mTc-sestamibi, as well as other 123I-based radiotracers.CONCLUSIONS123I-CMICE-013 demonstrated desirable characteristics in its biokinetic and radiodosimetric profiles, supporting its potential application as a novel myocardial perfusion imaging agent.

100 项与 123I-CMICE-013 相关的药物交易

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