title: Discrepant uptake of the radiolabeled norepinephrine analogues hydroxyephedrine (HED) and metaiodobenzylguanidine (MIBG) in rat hearts.
abstract: OBJECTIVE
  (11)C-Hydroxyephedrine (HED) and radioiodinated metaiodobenzylguanidine ((123)I/(131)I-MIBG) are catecholamine analogue tracers for sympathetic nerve positron emission tomography/single photon emission computed tomography (PET/SPECT) imaging. In contrast to humans, rat hearts demonstrate high nonneural catecholamine uptake-2 in addition to neural uptake-1, the contributions of which to tracer accumulation are not fully elucidated.
  
  
  METHODS
  Wistar rats were studied using the following pretreatments: uptake-1 blockade with desipramine 2 mg/kg IV, both uptake-1 and -2 blockade with phenoxybenzamine 50 mg/kg IV, or control with saline IV. HED or (123)I-MIBG was injected 10 min after pretreatment, and rats were sacrificed 10 min later. Heart to blood tissue count ratio (H/B ratio) was obtained using a gamma counter. To determine regional tracer uptake, dual-tracer autoradiography was performed with HED and (131)I-MIBG in Wistar rats with chronic infarction by transient coronary occlusion and reperfusion and in healthy control rats. Local tracer distributions were analyzed, and the infarcted rats' local tracer distributions were compared with histology.
  
  
  RESULTS
  The H/B ratios in control hearts were 34.4 ± 1.7 and 25.5 ± 2.1 for HED and (123)I-MIBG, respectively. Desipramine led to a significant decrease in HED (3.2 ± 0.5, p < 0.0001), while there was no change in (123)I-MIBG (25.5 ± 6.4, p = n.s.). Phenoxybenzamine led to a significant decrease in both HED and (123)I-MIBG (3.5 ± 0.02, 4.3 ± 0.7, p < 0.0001). Only HED showed a subepicardium-subendocardium gradient in healthy control hearts which is consistent with physiological innervation, while (131)I-MIBG was evenly distributed throughout the myocardium. (131)I-MIBG uptake defect closely matched the scar area determined by histology [3.8 ± 2.3% ((131)I-MIBG defect) vs 4.0 ± 2.4% (scar)]. However, the scar area was clearly exceeded by the HED uptake defect (9.1 ± 2.2%, p < 0.001).
  
  
  CONCLUSIONS
  HED uptake showed high specificity to neural uptake-1 in rat hearts. On the other hand, (123)I/(131)I-MIBG demonstrated distinct characters of regional tracer distribution and uptake mechanism that are compatible with significant contribution of nonneural uptake-2.
authors.affiliation: Division of Nuclear Medicine, The Russell H. Morgan Department of Radiology, Johns Hopkins University, Baltimore, MD, USA. rischpler@gmail.com
authors.forename: Christoph
authors.initials: C
authors.lastname: Rischpler
authors.forename: Kenji
authors.initials: K
authors.lastname: Fukushima
authors.forename: Takuro
authors.initials: T
authors.lastname: Isoda
authors.forename: Mehrbod S
authors.initials: MS
authors.lastname: Javadi
authors.forename: Robert F
authors.initials: RF
authors.lastname: Dannals
authors.forename: Roselle
authors.initials: R
authors.lastname: Abraham
authors.forename: Richard
authors.initials: R
authors.lastname: Wahl
authors.forename: Frank M
authors.initials: FM
authors.lastname: Bengel
authors.forename: Takahiro
authors.initials: T
authors.lastname: Higuchi
mesh_terms: D019797:3-Iodobenzylguanidine / Q000031:analogs & derivatives* / Q000378:metabolism*; D000818:Animals; D001345:Autoradiography; D001692:Biological Transport; D054059:Coronary Occlusion / Q000378:metabolism; D004809:Ephedrine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism; D007553:Isotope Labeling; D008297:Male; D015425:Myocardial Reperfusion; D009206:Myocardium / Q000378:metabolism*; D009638:Norepinephrine / Q000031:analogs & derivatives*; D051381:Rats; D017208:Rats, Wistar
chemical_list: C065363:3-hydroxyephedrine; D019797:3-Iodobenzylguanidine; D004809:Ephedrine; D009638:Norepinephrine
references.citation: Clin Exp Pharmacol Physiol. 2006 Dec;33(12):1269-74
references.pmid: 17184514
references.citation: Nucl Med Biol. 2013 Apr;40(3):331-7
references.pmid: 23306137
references.citation: J Am Coll Cardiol. 2010 May 18;55(20):2212-21
references.pmid: 20188504
references.citation: J Nucl Med. 2008 Jul;49(7):1189-95
references.pmid: 18552143
references.citation: J Nucl Med. 2010 Dec;51(12):1956-61
references.pmid: 21078800
references.citation: J Nucl Med. 2004 Sep;45(9):1536-41
references.pmid: 15347721
references.citation: J Nucl Med. 2007 Feb;48(2):288-94
references.pmid: 17268027
references.citation: Am J Physiol. 1998 Mar;274(3):H801-9
references.pmid: 9530191
references.citation: J Nucl Med. 1993 Aug;34(8):1287-93
references.pmid: 8326386
references.citation: Br J Pharmacol. 1972 Dec;46(4):647-57
references.pmid: 4676273
references.citation: J Nucl Med. 1999 Jun;40(6):911-6
references.pmid: 10452305
references.citation: Eur J Nucl Med. 2001 Mar;28(3):373-6
references.pmid: 11315607
references.citation: Cardiovasc Res. 2008 May 1;78(2):395-403
references.pmid: 18256073
references.citation: Circ Cardiovasc Imaging. 2011 Jul;4(4):435-43
references.pmid: 21555377
references.citation: Eur J Pharmacol. 2000 Mar 17;391(3):263-7
references.pmid: 10729367
references.citation: Nat Methods. 2012 Jul;9(7):671-5
references.pmid: 22930834
references.citation: Br Med Bull. 1973 May;29(2):130-5
references.pmid: 4356549
references.citation: Heart. 1999 Mar;81(3):262-70
references.pmid: 10026349
references.citation: J Nucl Med. 1990 Aug;31(8):1328-34
references.pmid: 2384800
references.citation: J Nucl Med. 2009 Nov;50(11):1881-6
references.pmid: 19837770
references.citation: J Nucl Med. 1985 Aug;26(8):897-907
references.pmid: 3162008
references.citation: Nat Med. 2007 May;13(5):604-12
references.pmid: 17417650
references.citation: J Nucl Med. 2005 Jan;46(1):172-5
references.pmid: 15632049
references.citation: Am J Cardiol. 1997 Aug 1;80(3):273-7
references.pmid: 9264418
references.citation: Eur Heart J. 2008 May;29(9):1147-59
references.pmid: 18349024
references.citation: Heart. 2008 Jun;94(6):809-16
references.pmid: 18480360
references.citation: Circulation. 2000 Jun 6;101(22):2579-85
references.pmid: 10840008
references.citation: J Nucl Med. 1987 Oct;28(10):1620-4
references.pmid: 3655914
references.citation: Naunyn Schmiedebergs Arch Pharmacol. 2004 Jul;370(1):9-16
references.pmid: 15300361