title: Validation of 18F-fluoro-4-thia-palmitate as a PET probe for myocardial fatty acid oxidation: effects of hypoxia and composition of exogenous fatty acids.
abstract: Fatty acid oxidation (FAO) is the predominant energy-producing pathway in the healthy heart. Abnormalities in FAO are associated with many ischemic and nonischemic disease states. The aim of the present study was to further validate 16-[(18)F]-fluoro-4-thia-palmitate ((18)F-FTP) as a metabolically trapped FAO probe in the isolated perfused rat heart model by examining both the effects of hypoxia and the effects of changes in exogenous fatty acid availability.
  
  
  METHODS
  Hearts were excised from Sprague-Dawley rats and perfused in the Langendorff mode with Krebs-Henseleit solution under the following conditions: palmitate at 0.4 mmol/L with 95% oxygen, palmitate at 0.4 mmol/L with 35% oxygen, palmitate at 0.2 mmol/L plus oleate at 0.2 mmol/L with 95% oxygen, and palmitate at 0.2 mmol/L plus oleate at 0.2 mmol/L with 35% oxygen. Hearts were paced at 270 beats per minute, and the rate of left ventricular pressure change (LV dP/dt) was monitored. (18)F-FTP in the perfusion medium was administered for 20 min, and this step was followed by a 20-min washout period without tracer in the perfusion medium. (18)F kinetics in the whole heart were monitored externally, and the time-activity curves were analyzed to determine the fractional trapping rate for (18)F-FTP (FTR(FTP)). A "lumped constant" (LC) was defined as the ratio of FTR(FTP) to the fractional rate of oxidation of fatty acid in the perfusion medium.
  
  
  RESULTS
  The kinetic data for (18)F-FTP demonstrated metabolic trapping of (18)F radioactivity that was insensitive to changes in the mixture of fatty acids in the perfusion medium but that was sensitive to the inhibition of mitochondrial FAO by hypoxia. LV dP/dt was reduced 47%-67% in hypoxic hearts relative to hearts with normal oxygenation (controls). FAO rates for palmitate and oleate were similar in group 3 (palmitate alone) and group 4 (palmitate and oleate). FAO was decreased 70%-76% with hypoxia, whereas FTR(FTP) was reduced 86%-88%, demonstrating hypersensitivity of a change in (18)F-FTP retention to FAO inhibition by oxygen deprivation. The (18)F-FTP LC was approximately 2 in myocardium with normal oxygenation and fell to 1.0-1.2 in hypoxic myocardium.
  
  
  CONCLUSIONS
  The results confirm (18)F-FTP to be a metabolically trapped palmitate analog that is capable of indicating rates of myocardial oxidation of exogenous long-chain fatty acids. The heterogeneous nature of fatty acids in plasma does not alter the quantitative analysis of (18)F-FTP kinetics. However, the decreased LC value in hypoxic myocardium suggests the need to develop an understanding of the relationship of (18)F-FTP processing to natural fatty acids at key limiting transport and metabolism processes, analogous to previous studies examining the LC values for radiolabeled deoxyglucose tracers used to estimate the glucose metabolic rate.
authors.affiliation: Department of Radiology, School of Medicine, Indiana University, Indianapolis, 46077, USA. tdegrado@iupui.edu
authors.forename: Timothy R
authors.initials: TR
authors.lastname: DeGrado
authors.forename: Mehmet T
authors.initials: MT
authors.lastname: Kitapci
authors.forename: Shuyan
authors.initials: S
authors.lastname: Wang
authors.forename: Jun
authors.initials: J
authors.lastname: Ying
authors.forename: Gary D
authors.initials: GD
authors.lastname: Lopaschuk
mesh_terms: D000818:Animals; D005227:Fatty Acids / Q000008:administration & dosage / Q000378:metabolism*; D006321:Heart / Q000000981:diagnostic imaging* / Q000187:drug effects; D000860:Hypoxia / Q000000981:diagnostic imaging* / Q000378:metabolism*; D066298:In Vitro Techniques; D015336:Molecular Probe Techniques; D009206:Myocardium / Q000378:metabolism*; D010084:Oxidation-Reduction / Q000187:drug effects; D010168:Palmitates / Q000493:pharmacokinetics; D049268:Positron-Emission Tomography / Q000379:methods*; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D013871:Thiones / Q000493:pharmacokinetics
chemical_list: C515150:16-fluoro-4-thiapalmitic acid; D005227:Fatty Acids; D010168:Palmitates; D019275:Radiopharmaceuticals; D013871:Thiones