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Cardiac Hypoxia Imaging: Second Generation Analogues of 64Cu-ATSM

Research output: Contribution to journalArticle

Original languageEnglish
Pages (from-to)488-494
Number of pages7
JournalJournal of Nuclear Medicine
Volume55
Issue number3
DOIs
Publication statusPublished - 1 Mar 2014

Documents

  • Handley et al BTSC isolated heart JNM resubmission version 7-10-13

    Handley_et_al_BTSC_isolated_heart_JNM_resubmission_version_7_10_13.docx, 1.43 MB, application/vnd.openxmlformats-officedocument.wordprocessingml.document

    21/07/2015

    Accepted author manuscript

    This research was originally published in JNM. © by the Society of Nuclear Medicine and Molecular Imaging, Inc.

King's Authors

Abstract

Myocardial hypoxia is an attractive target for diagnostic and prognostic imaging, but current approaches are insufficiently sensitive for clinical use. The PET tracer copper(II)-diacetyl-bis(N4-methylthiosemicarbazone) (64Cu-ATSM) has promise, but its selectivity and sensitivity could be improved by structural modification. We have therefore evaluated a range of 64Cu-ATSM analogs for imaging hypoxic myocardium.

Methods: Isolated rat hearts (n = 5/group) were perfused with normoxic buffer for 30 min and then hypoxic buffer for 45 min within a custom-built triple-γ-detector system to quantify radiotracer infusion, hypoxia-dependent cardiac uptake, and washout. A 1-MBq bolus of each candidate tracer (and 18F-fluoromisonidazole for comparative purposes) was injected into the arterial line during normoxia, and during early and late hypoxia, and their hypoxia selectivity and pharmacokinetics were evaluated. The in vivo pharmacokinetics of promising candidates in healthy rats were then assessed by PET imaging and biodistribution.

Results: All tested analogs exhibited hypoxia sensitivity within 5 min. Complexes less lipophilic than 64Cu-ATSM provided significant gains in hypoxic-to-normoxic contrast (14:1 for 64Cu-2,3-butanedione bis(thiosemicarbazone) (ATS), 17:1 for 64Cu-2,3-pentanedione bis(thiosemicarbazone) (CTS), 8:1 for 64Cu-ATSM, P < 0.05). Hypoxic first-pass uptake was 78.2% ± 7.2% for 64Cu-ATS and 70.7% ± 14.5% for 64Cu-CTS, compared with 63.9% ± 11.7% for 64Cu-ATSM. Cardiac retention of 18F-fluoromisonidazole increased from 0.44% ± 0.17% during normoxia to 2.24% ± 0.08% during hypoxia. In vivo, normoxic cardiac retention of 64Cu-CTS was significantly lower than that of 64Cu-ATSM and 64Cu-ATS (0.13% ± 0.02% vs. 0.25% ± 0.04% and 0.24% ± 0.03% injected dose, P < 0.05), with retention of all 3 tracers falling to less than 0.7% injected dose within 6 min. 64Cu-CTS also exhibited lower uptake in liver and lung.

Conclusion: 64Cu-ATS and 64Cu-CTS exhibit better cardiac hypoxia selectivity and imaging characteristics than the current lead hypoxia tracers, 64Cu-ATSM and 18F-fluoromisonidazole.

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