title: Retention Kinetics of the 18F-Labeled Sympathetic Nerve PET Tracer LMI1195: Comparison with 11C-Hydroxyephedrine and 123I-MIBG.
abstract: (18)F-N-[3-bromo-4-(3-fluoro-propoxy)-benzyl]-guanidine ((18)F-LMI1195) is a new PET tracer designed for noninvasive assessment of sympathetic innervation of the heart. The (18)F label facilitates the imaging advantages of PET over SPECT technology while allowing centralized manufacturing. Highly specific neural uptake of (18)F-LMI1195 has previously been established, but the retention kinetics are not yet fully understood.
  
  
  METHODS
  Healthy New Zealand White rabbits were studied with (18)F-LMI1195 using a small-animal PET system. Dynamic 40-min chest scans were started just before intravenous bolus injection of (18)F-LMI1195. Imaging was performed under norepinephrine transport inhibition with desipramine pretreatment, a 1.5 mg/kg desipramine chase administered 10 min after tracer injection, and saline treatment of controls. As a reference, cardiac uptake of (11)C-hydroxyephedrine and (123)I-metaiodobenzylguanidine ((123)I-MIBG) was examined by PET and planar scintigraphy, respectively.
  
  
  RESULTS
  Cardiac uptake of all 3 tracers was inhibited by pretreatment with desipramine. Stable cardiac tracer retention was delineated by dynamic PET in control rabbits for (11)C-hydroxyephedrine (washout rate, 0.42% ± 0.57%/min) and (18)F-LMI1195 (washout rate, 0.058% ± 0.28%/min). A desipramine chase increased (11)C-hydroxyephedrine washout from the heart (2.43% ± 0.15%/min, P < 0.001), whereas (18)F-LMI1195 washout was not influenced (0.059% ± 0.11%/min, not statistically significant). Additionally, a desipramine chase did not change the cardiac (123)I-MIBG uptake (delayed heart-to-mediastinum ratio, 1.99 ± 0.12 (desipramine chase) vs. 2.05 ± 0.16 (controls), not statistically significant).
  
  
  CONCLUSIONS
  In vivo norepinephrine transporter (NET) blockade with desipramine confirmed specific neural uptake of (18)F-LMI1195, (11)C-hydroxyephedrine, and (123)I-MIBG in rabbit hearts. (11)C-hydroxyephedrine cardiac retention was sensitive to a NET inhibitor chase, indicating a cycle of continuous NET uptake and release at the nerve terminals. In contrast, (18)F-LMI1195 and (123)I-MIBG demonstrated stable storage at the nerve terminal with resistance to a NET inhibitor chase, mimicking physiologic norepinephrine turnover.
authors.affiliation: Department of Nuclear Medicine, University of Wuerzburg, Wuerzburg, Germany Comprehensive Heart Failure Center (CHFC), University of Wuerzburg, Wuerzburg, Germany.
authors.forename: Rudolf A
authors.initials: RA
authors.lastname: Werner
authors.affiliation: Department of Nuclear Medicine, Klinikum rechts der Isar, Technische Universitaet Muenchen, Munich, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Rischpler
authors.affiliation: Lantheus Medical Imaging, North Billerica, Massachusetts.
authors.forename: David
authors.initials: D
authors.lastname: Onthank
authors.affiliation: Department of Nuclear Medicine, University of Wuerzburg, Wuerzburg, Germany.
authors.forename: Constantin
authors.initials: C
authors.lastname: Lapa
authors.affiliation: Lantheus Medical Imaging, North Billerica, Massachusetts.
authors.forename: Simon
authors.initials: S
authors.lastname: Robinson
authors.affiliation: Department of Nuclear Medicine, University of Wuerzburg, Wuerzburg, Germany.
authors.forename: Samuel
authors.initials: S
authors.lastname: Samnick
authors.affiliation: Division of Nuclear Medicine, Russell H. Morgan Department of Radiology, Johns Hopkins University, Baltimore, Maryland; and.
authors.forename: Mehrbod
authors.initials: M
authors.lastname: Javadi
authors.affiliation: Department of Nuclear Medicine, Klinikum rechts der Isar, Technische Universitaet Muenchen, Munich, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Schwaiger
authors.affiliation: Department of Nuclear Medicine, Klinikum rechts der Isar, Technische Universitaet Muenchen, Munich, Germany German Centre for Cardiovascular Research (DZHK), Partner Site Munich Heart Alliance, Munich, Germany.
authors.forename: Stephan G
authors.initials: SG
authors.lastname: Nekolla
authors.affiliation: Department of Nuclear Medicine, University of Wuerzburg, Wuerzburg, Germany Comprehensive Heart Failure Center (CHFC), University of Wuerzburg, Wuerzburg, Germany thiguchi@me.com.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Higuchi
mesh_terms: D019797:3-Iodobenzylguanidine / Q000493:pharmacokinetics*; D000818:Animals; D001342:Autonomic Nervous System Diseases / Q000000981:diagnostic imaging / Q000378:metabolism*; D004809:Ephedrine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D005462:Fluorine Radioisotopes / Q000737:chemistry / Q000493:pharmacokinetics*; D005464:Fluorobenzenes / Q000493:pharmacokinetics*; D006146:Guanidines / Q000493:pharmacokinetics*; D007553:Isotope Labeling / Q000379:methods; D007700:Kinetics; D008657:Metabolic Clearance Rate; D009928:Organ Specificity; D049268:Positron-Emission Tomography / Q000379:methods*; D011817:Rabbits; D019275:Radiopharmaceuticals / Q000138:chemical synthesis / Q000493:pharmacokinetics; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D014018:Tissue Distribution
chemical_list: D005462:Fluorine Radioisotopes; D005464:Fluorobenzenes; D006146:Guanidines; D019275:Radiopharmaceuticals; C065363:3-hydroxyephedrine; D019797:3-Iodobenzylguanidine; D004809:Ephedrine; C561360:flubrobenguane
keywords: 11C-hydroxyephedrine; 123I-metaiodobenzylguanidine; 18F-LMI1195; positron emission tomography; sympathetic nerve