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64CuCTS: a promising radiopharmaceutical for the identification of low grade cardiac hypoxia by PET

Research output: Contribution to journalArticle

Original languageEnglish
Article number56
Pages (from-to)921
Number of pages5
JournalJournal of Nuclear Medicine
Volume56
Issue number6
Early online date16 Apr 2015
DOIs
Publication statusPublished - Jun 2015

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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.

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