Validation of (99m)Tc-labeled "4+1" fatty acids for myocardial metabolism and flow imaging: Part 1: myocardial extraction and biodistribution.
BACKGROUND
(13)C, (18)F and (123)I fatty acids (FA) are used for myocardial imaging. Recently, our group showed that [(99m)Tc]-labeled "4+1" FA are extracted into the rat and guinea pig myocardium. The present study evaluates determinants of myocardial uptake and whole body biodistribution of these FA derivatives.


METHODS
Studies were performed with isolated perfused hearts of Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHR) with a FAT/CD36 deficiency, as well as with heart type FA binding protein knockout mice (H-FABP)(-/-) and H-FABP(+/+). Eight 4+1-(99m)Tc-FA were applied for 3 min followed by 1-min washout. A mathematical model was used to analyze FA dynamics and binding to proteins. Whole-body distribution was studied in rats with and without Tween 80. In vitro fractionation studies with [(99m)Tc]-FA assessed red blood cell uptake as well as association with plasma lipoproteins very low-density lipoprotein (VLDL), low-density lipoprotein (LDL) and high-density lipoprotein (HDL).


RESULTS
Myocardial extraction was 19.0-33.0% of the infused dose in isolated WKY and 15.2-26.4% in SHR hearts. However, H-FABP(-/-) showed a marked reduction of tracer extraction [2.8+/-0.6%ID (percent injected dose) vs. 17+/-2%ID P<.001]. Uptake in red blood cells (<1.2%ID) and incorporation into lipoproteins were negligible. Incubation of (99m)Tc-FA with albumin reduced ventricular extraction (P<.001) into the range of established iodinated FA tracers. polyoxyethylene(20) sorbitan monooleate improved the heart-to-liver ratio in the biodistribution studies.


CONCLUSIONS
Myocardial uptake of [(99m)Tc]-FA 4+1 derivatives is dependent on H-FABP. These substances may therefore provide a new tool to specifically assess regional myocardial changes of H-FABP.
Mirtschink
Peter
P
Institute of Physiology, Technical University Dresden, 01307 Dresden, Germany. peter_mirtschink@web.de
Stehr
Sebastian N
SN
Walther
Martin
M
Pietzsch
Jens
J
Bergmann
Ralf
R
Pietzsch
Hans-Jürgen
HJ
Weichsel
Johannes
J
Pexa
Annette
A
Dieterich
Peter
P
Wunderlich
Gerd
G
Binas
Bert
B
Kropp
Joachim
J
Deussen
Andreas
A
D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D018955:CD36 Antigens / Q000378:metabolism; D002417:Cattle; D003600:Cytosol / Q000378:metabolism; D004912:Erythrocytes / Q000378:metabolism; D000074026:Fatty Acid Binding Protein 3; D050556:Fatty Acid-Binding Proteins / Q000378:metabolism; D005227:Fatty Acids / Q000737:chemistry / Q000378:metabolism* / Q000493:pharmacokinetics*; D005260:Female; D006321:Heart / Q000000981:diagnostic imaging / Q000187:drug effects / Q000502:physiology; D006352:Heart Ventricles / Q000378:metabolism; D006439:Hemodynamics; D006801:Humans; D066298:In Vitro Techniques; D042541:Intracellular Space / Q000378:metabolism; D007553:Isotope Labeling; D050356:Lipid Metabolism; D008297:Male; D051379:Mice; D008954:Models, Biological; D055414:Myocardial Perfusion Imaging; D009206:Myocardium / Q000166:cytology / Q000378:metabolism*; D015609:Organotechnetium Compounds / Q000737:chemistry*; D051381:Rats; D015203:Reproducibility of Results; D012710:Serum Albumin, Bovine / Q000494:pharmacology; D014018:Tissue Distribution
D018955:CD36 Antigens; C493409:Fabp3 protein, mouse; D000074026:Fatty Acid Binding Protein 3; D050556:Fatty Acid-Binding Proteins; D005227:Fatty Acids; D015609:Organotechnetium Compounds; D012710:Serum Albumin, Bovine