title: Targeting of endothelin receptors in the healthy and infarcted rat heart using the PET tracer 18F-FBzBMS.
abstract: The endothelin subtype-A receptor (ET-A) is a promising therapeutic target in cardiovascular disease. We sought to determine the feasibility of an (18)F-labeled ligand, (18)F-(N-[[29-[[(4,5-dimethyl-3-isoxazolyl)amino]sulfonyl]-4-(2-oxazolyl)[1,19-biphenyl]-2-yl]methyl]-N,4-fluorobenzamide) ((18)F-FBzBMS), for imaging ET-A in the healthy and injured rat heart.
  
  
  METHODS
  Male Wistar rats were used for all experiments. The specificity of cardiac (18)F-FBzBMS uptake was determined in healthy animals (n = 23) using pretreatment with various blocking agents and doses. Myocardial infarction (MI) was induced by permanent left coronary ligation in 32 animals. Autoradiography was conducted to determine regional FBzBMS distribution relative to tissue perfusion at various times after MI. Histology and immunohistochemistry were performed for validation. The feasibility of in vivo detection of the tracer signal was tested using dedicated small-animal PET (n = 6).
  
  
  RESULTS
  At autoradiography, intravenous pretreatment with the selective ET-A blocker BMS-207940 reduced myocardial FBzBMS uptake by 93% ± 0.7%. Oral pretreatment with the clinical blocker bosentan resulted in a dose-dependent partial blockade (5 mg/kg, 48% ± 6%; 50 mg/kg, 61% ± 7%; and 100 mg/kg, 88% ± 0.7%). After MI, FBzBMS uptake was preserved in the infarct region from day 1 to month 6, whereas the perfusion tracer (201)Tl showed a persistent defect (MI-to-remote ratios: (201)Tl, 0.23 ± 0.28, 0.39 ± 0.07, 0.31 ± 0.07, 0.24 ± 0.12, 0.29 ± 0.10, and 0.23 ± 0.09; and FBzBMS, 0.94 ± 0.28, 0.92 ± 0.20, 0.88 ± 0.13, 0.82 ± 0.12, 0.80 ± 0.11, and 0.84 ± 0.08 at day 1, day 3, week 1, month 1, month 2, and month 6, respectively) (P < 0.01 vs. (201)Tl). Ex vivo analysis confirmed ET-A expression in the infarct area, where the signal was partially colocalized with CD31 expression on endothelial cells. In vivo small-animal PET successfully confirmed specific uptake and blockade of FBzBMS in healthy myocardium.
  
  
  CONCLUSIONS
  Cardiac uptake of the PET tracer (18)F-FBzBMS is specific for ET-A expression in rats, shows infarct-related alterations, and can be imaged noninvasively. Further efforts to establish myocardial ET-A imaging methodology are warranted, with the perspective of determining role, efficacy, and benefit of ET-A targeted drug treatment in cardiovascular disease.
authors: Division of Nuclear Medicine, Russell H. Morgan Department of Radiology, Johns Hopkins University, Baltimore, Maryland, USA.
authors: Takahiro
authors: T
authors: Higuchi
authors: Christoph
authors: C
authors: Rischpler
authors: Kenji
authors: K
authors: Fukushima
authors: Takuro
authors: T
authors: Isoda
authors: Jinsong
authors: J
authors: Xia
authors: Mehrbod S
authors: MS
authors: Javadi
authors: Zsolt
authors: Z
authors: Szabo
authors: Robert F
authors: RF
authors: Dannals
authors: William B
authors: WB
authors: Mathews
authors: Frank M
authors: FM
authors: Bengel
mesh_terms: D000818:Animals; D001549:Benzamides; D000077300:Bosentan; D004305:Dose-Response Relationship, Drug; D005462:Fluorine Radioisotopes; D006321:Heart / Q000000981:diagnostic imaging* / Q000502:physiology*; D008297:Male; D009203:Myocardial Infarction / Q000000981:diagnostic imaging* / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism; D009683:Nuclear Medicine / Q000379:methods; D010477:Perfusion; D049268:Positron-Emission Tomography / Q000379:methods*; D051381:Rats; D017208:Rats, Wistar; D017466:Receptors, Endothelin / Q000378:metabolism*; D013449:Sulfonamides / Q000494:pharmacology; D013794:Thallium Radioisotopes / Q000494:pharmacology; D013997:Time Factors
chemical_list: D001549:Benzamides; D005462:Fluorine Radioisotopes; C579336:N-((2'-(((4,5-dimethyl-3-isoxazolyl)amino)sulfonyl)-4-(2-oxazolyl)(1,1'-biphenyl)-2-yl)methyl)-N,4-fluorobenzamide; D017466:Receptors, Endothelin; D013449:Sulfonamides; D013794:Thallium Radioisotopes; D000077300:Bosentan