Projects per year
Abstract
The subtle hypoxia underlying chronic cardiovascular disease is an attractive target for PET imaging, but the lead hypoxia imaging agents 64CuATSM and 18FMISO are trapped only at extreme levels of hypoxia and hence are insufficiently sensitive for this purpose. We have therefore sought an analog of 64CuATSM better suited to identify compromised but salvageable myocardium, validated using parallel biomarkers of cardiac energetics comparable to those observed in chronic cardiac ischemic syndromes.Methods: Rat hearts were perfused with aerobic buffer for 20 min, followed by a range of hypoxic buffers (using a computer-controlled gas mixer) for 45 min. Contractility was monitored by intraventricular balloon, energetics by 31P NMR spectroscopy, lactate and creatine kinase release spectrophotometrically, and HIF1 by Western blotting. Results: We identify a key hypoxia threshold at a 30% buffer O2 saturation which induces a stable and potentially survivable functional and energetic compromise: LV developed pressure was depressed by 20%, and cardiac phosphocreatine was depleted by 65.5 ± 14% (p<0.05 vs control), but ATP levels were maintained. Lactate release was elevated (0.21 ± 0.067 versus 0.056 ± 0.01 mmol/L/min, p<0.05), but not maximal (0.46 ± 0.117 mmol/L/min), indicating residual oxidative metabolic capacity. HIF1 was elevated, but not maximal. At this key threshold, 64CuCTS selectively deposited significantly more 64Cu than any other tracer we examined (61.8 ± 9.6% injected dose versus 29.4 ± 9.5% for 64CuATSM p<0.05). Conclusion: The hypoxic threshold which induced survivable metabolic and functional compromise was 30% O2. At this threshold, only 64CuCTS delivered a hypoxic:normoxic contrast of 3:1, and it therefore warrants in vivo evaluation for imaging chronic cardiac ischemic syndromes.
| Original language | English |
|---|---|
| Article number | 56 |
| Pages (from-to) | 921--926 |
| Number of pages | 5 |
| Journal | Journal of Nuclear Medicine |
| Volume | 56 |
| Issue number | 6 |
| Early online date | 16 Apr 2015 |
| DOIs | |
| Publication status | Published - Jun 2015 |
Access to Document
- Cu-CTS: A Promising Radiopharmaceutical_MEDINA_Epub16Apr2015_GREEN AAM
This research was originally published in JNM. © by the Society of Nuclear Medicine and Molecular Imaging, Inc.
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Dive into the research topics of '64CuCTS: a promising radiopharmaceutical for the identification of low grade cardiac hypoxia by PET'. Together they form a unique fingerprint.Projects
- 2 Finished
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PET imaging of cardiac hypoxia and ischaemia with radiocopper complexes
Southworth, R. (Primary Investigator), Blower, P. (Co-Investigator), Marsden, P. (Co-Investigator) & Nagel, E. (Co-Investigator)
1/04/2010 → 10/10/2013
Project: Research
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BHF Centre of Research Excellence
Avkiran, M. (Primary Investigator), Blower, P. (Primary Investigator), Botnar, R. (Primary Investigator), Chowienczyk, P. (Primary Investigator), Eaton, P. (Primary Investigator), Ehler, E. (Primary Investigator), Garcia-Manyes, S. (Primary Investigator), Gautel, M. (Primary Investigator), Geissmann, F. (Primary Investigator), Hussain, M. (Primary Investigator), Irving, M. (Primary Investigator), Kalra, L. (Primary Investigator), Marber, M. (Primary Investigator), Mayr, M. (Primary Investigator), Nagel, E. (Primary Investigator), Otsu, K. (Primary Investigator), Razavi, R. (Primary Investigator), Ridley, A. (Primary Investigator), Shah, A. (Primary Investigator), Shanahan, C. (Primary Investigator), Smith, N. (Primary Investigator), Xu, Q. (Primary Investigator), Alastruey, J. (Co-Investigator), Ameer-Beg, S. (Co-Investigator), Bishop, M. (Co-Investigator), Brain, S. (Co-Investigator), Burgoyne, J. (Co-Investigator), Conte, M. (Co-Investigator), Dhanjal, T. (Co-Investigator), Eminaga, S. (Co-Investigator), Eykyn, T. (Co-Investigator), Gee, T. (Co-Investigator), Heintzmann, R. (Co-Investigator), Hughes, S. (Co-Investigator), Iskratsch, T. (Co-Investigator), Ivetic, A. (Co-Investigator), Jones, G. E. (Co-Investigator), Kentish, J. (Co-Investigator), Lamata de la Orden, P. (Co-Investigator), Lombardi, G. (Co-Investigator), Mullen, G. (Co-Investigator), Okonko, D. (Co-Investigator), Parsons, M. (Co-Investigator), Pfuhl, M. (Co-Investigator), Phinikaridou, A. (Co-Investigator), Rodaway, A. (Co-Investigator), Shattock, M. (Co-Investigator), Sinkus, R. (Co-Investigator), Springett, R. (Co-Investigator), Steiner, R. (Co-Investigator), Stroud, M. (Co-Investigator), Sun, Y.-B. (Co-Investigator), Wardle, F. (Co-Investigator), Warren, D. (Co-Investigator), Webb, A. (Co-Investigator), Zampetaki, A. (Co-Investigator), Zeng, L. (Co-Investigator) & academic, A. (Co-Investigator)
1/01/2008 → 31/03/2019
Project: Research
Activities
- 1 Invited talk
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From perfusion bench to preclinical scanner bedside: adventures in radiotracer development
Southworth, R. (Speaker)
14 Nov 2018Activity: Talk or presentation › Invited talk