title: Cardiac hypoxia imaging: second-generation analogues of 64Cu-ATSM.
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) ((64)Cu-ATSM) has promise, but its selectivity and sensitivity could be improved by structural modification. We have therefore evaluated a range of (64)Cu-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 (18)F-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 (64)Cu-ATSM provided significant gains in hypoxic-to-normoxic contrast (14:1 for (64)Cu-2,3-butanedione bis(thiosemicarbazone) (ATS), 17:1 for (64)Cu-2,3-pentanedione bis(thiosemicarbazone) (CTS), 8:1 for (64)Cu-ATSM, P < 0.05). Hypoxic first-pass uptake was 78.2% ± 7.2% for (64)Cu-ATS and 70.7% ± 14.5% for (64)Cu-CTS, compared with 63.9% ± 11.7% for (64)Cu-ATSM. Cardiac retention of (18)F-fluoromisonidazole increased from 0.44% ± 0.17% during normoxia to 2.24% ± 0.08% during hypoxia. In vivo, normoxic cardiac retention of (64)Cu-CTS was significantly lower than that of (64)Cu-ATSM and (64)Cu-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. (64)Cu-CTS also exhibited lower uptake in liver and lung.
  
  
  CONCLUSIONS
  (64)Cu-ATS and (64)Cu-CTS exhibit better cardiac hypoxia selectivity and imaging characteristics than the current lead hypoxia tracers, (64)Cu-ATSM and (18)F-fluoromisonidazole.
authors.affiliation: Division of Imaging Sciences and Biomedical Engineering, King's College London, London, United Kingdom.
authors.forename: Maxwell G
authors.initials: MG
authors.lastname: Handley
authors.forename: Rodolfo A
authors.initials: RA
authors.lastname: Medina
authors.forename: Erika
authors.initials: E
authors.lastname: Mariotti
authors.forename: Gavin D
authors.initials: GD
authors.lastname: Kenny
authors.forename: Karen P
authors.initials: KP
authors.lastname: Shaw
authors.forename: Ran
authors.initials: R
authors.lastname: Yan
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Eykyn
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Blower
authors.forename: Richard
authors.initials: R
authors.lastname: Southworth
mesh_terms: D000818:Animals; D015687:Cell Hypoxia; D056831:Coordination Complexes; D008297:Male; D009206:Myocardium / Q000166:cytology*; D009942:Organometallic Compounds / Q000737:chemistry* / Q000493:pharmacokinetics; D049268:Positron-Emission Tomography; D051381:Rats; D017208:Rats, Wistar; D013882:Thiosemicarbazones / Q000737:chemistry* / Q000493:pharmacokinetics
chemical_list: D056831:Coordination Complexes; D009942:Organometallic Compounds; D013882:Thiosemicarbazones; C089548:copper (II) diacetyl-di(N(4)-methylthiosemicarbazone)
keywords: 18FMISO; 64Cu-ATSM; PET; bis(thiosemicarbazones); cardiac ischemia; hypoxia