title: In vitro and in vivo structure-property relationship of (68)Ga-labeled Schiff base derivatives for functional myocardial pet imaging.
abstract: OBJECTIVE
  SPECT (e.g., with (99m)Tc-sestamibi) is routinely used for imaging myocardial damage, even though PET could offer a higher spatial resolution. Using the generator-gained isotope (68)Ga would allow a rapid supply of the tracer in the diagnostic unit. For this reason, the aim of the study was to develop (68)Ga-labeled PET tracers based on different Schiff base amines and to evaluate the cardiomyocyte uptake in vitro as well as the biodistribution of the tracers in vivo.
  
  
  METHODS
  Fifteen different Schiff bases (basing on 3 different backbones) were synthesized and labeled with (68)Ga. Lipophilicity varied between 0.87 ± 0.24 and 2.72 ± 0.14 (logD value). All tracers were positively charged and stable in plasma and apo-transferrin solution. In vitro uptake into cardiomyocytes was assessed in HL-1 cells in the absence and presence of the ionophor valinomycin. In vivo accumulation in the heart and in various organs was assessed by small animal PET imaging as well as by ex vivo biodistribution. The results were compared with (99m)Tc-sestamibi and (18)F-flurpiridaz.
  
  
  RESULTS
  All cationic Schiff bases were taken up into cardiomyocytes but the amount varied by a factor of 10. When destroying the membrane potential, the cellular uptake was markedly reduced in most of the tracers, indicating the applicability of these tracers for identifying ischemic myocardium. PET imaging revealed that the in vivo myocardial uptake reached a constant value approximately 10 min after injection but the intracardial amount of the tracer varied profoundly (SUV 0.46 to 3.35). The most suitable tracers showed a myocardial uptake which was comparable to that of (99m)Tc-sestamibi.
  
  
  CONCLUSIONS
  (68)Ga-based Schiff bases appear suitable for myocardial PET images with uptake comparable to (99m)Tc-sestamibi but offering higher spatial resolution. By systematical variation of the backbone and the side chains, tracers with optimal properties can be identified for further clinical evaluation.
authors.affiliation: Institute of Physiology, Martin-Luther-University Halle, Halle, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Thews
authors.forename: Melanie
authors.initials: M
authors.lastname: Zimny
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Eppard
authors.forename: Markus
authors.initials: M
authors.lastname: Piel
authors.forename: Nicole
authors.initials: N
authors.lastname: Bausbacher
authors.forename: Verena
authors.initials: V
authors.lastname: Nagel
authors.forename: Frank
authors.initials: F
authors.lastname: Rösch
mesh_terms: D000818:Animals; D057791:Cardiac Imaging Techniques / Q000379:methods*; D002460:Cell Line; D003287:Contrast Media / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics; D005260:Female; D005710:Gallium Radioisotopes / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics; D057927:Hydrophobic and Hydrophilic Interactions; D008297:Male; D051379:Mice; D009206:Myocardium / Q000166:cytology / Q000378:metabolism; D049268:Positron-Emission Tomography / Q000379:methods*; D011849:Radioactive Tracers; D051381:Rats; D017207:Rats, Sprague-Dawley; D012545:Schiff Bases / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics; D013329:Structure-Activity Relationship; D014018:Tissue Distribution
chemical_list: D003287:Contrast Media; D005710:Gallium Radioisotopes; D011849:Radioactive Tracers; D012545:Schiff Bases