期刊
JOURNAL OF NUCLEAR MEDICINE
卷 55, 期 3, 页码 488-494出版社
SOC NUCLEAR MEDICINE INC
DOI: 10.2967/jnumed.113.129015
关键词
hypoxia; PET; Cu-84-ATSM; bis(thiosemicarbazones); (FMISO)-F-18; cardiac ischemia
资金
- Engineering and Physical Sciences Research Council
- British Heart Foundation [PG/10/20/28211]
- National Institute for Health Research (NIHR) Biomedical Research Centre at Guy's and St. Thomas' NHS Foundation Trust
- National Institute for Health Research (NIHR) Biomedical Research Centre at King's College London
- Centre of Excellence in Medical Engineering
- Wellcome Trust
- EPSRC [WT088641/Z/09/Z]
- KCL
- UCL Comprehensive Cancer Imaging Centre
- CRUK
- MRC
- DoH
- British Heart Foundation [PG/10/20/28211] Funding Source: researchfish
- Cancer Research UK [16464] Funding Source: researchfish
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) (Cu-64-ATSM) has promise, but its selectivity and sensitivity could be improved by structural modification. We have therefore evaluated a range of Cu-64-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-gamma-detector system to quantify radiotracer infusion, hypoxia-dependent cardiac uptake, and washout. A 1-MBq bolus of each candidate tracer (and F-18-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 Cu-64-ATSM provided significant gains in hypoxic-to-normoxic contrast (14:1 for Cu-64-2,3-butanedione bis(thiosemicarbazone) (ATS), 17:1 for Cu-64-2,3-pentanedione bis(thiosemicarbazone) (CTS), 8:1 for Cu-64-ATSM, P < 0.05). Hypoxic first-pass uptake was 78.2% +/- 7.2% for Cu-64-ATS and 70.7% +/- 14.5% for Cu-64-CTS, compared with 63.9% +/- 11.7% for Cu-64-ATSM. Cardiac retention of F-18-fluoromisonidazole increased from 0.44% +/- 0.17% during normoxia to 2.24% +/- 0.08% during hypoxia. In vivo, normoxic cardiac retention of Cu-64-CTS was significantly lower than that of Cu-64-ATSM and Cu-64-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. Cu-64-CTS also exhibited lower uptake in liver and lung. Conclusion: Cu-64-ATS and Cu-64-CTS exhibit better cardiac hypoxia selectivity and imaging characteristics than the current lead hypoxia tracers, Cu-64-ATSM and F-18-fluoromisonidazole.
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