title: Synthesis and evaluation of 4-[18F]fluoropropoxy-3-iodobenzylguanidine ([18F]FPOIBG): A novel 18F-labeled analogue of MIBG.
abstract: BACKGROUND
  Radioiodinated meta-iodobenzylguanidine (MIBG), a norepinephrine transporter (NET) substrate, has been extensively used as an imaging agent to study the pathophysiology of the heart and for the diagnosis and treatment of neuroendocrine tumors. The goal of this study was to develop an (18)F-labeled analogue of MIBG that like MIBG itself could be synthesized in a single radiochemical step. Towards this end, we designed 4-fluoropropoxy-3-iodobenzylguanidine (FPOIBG).
  
  
  METHODS
  Standards of FPOIBG and 4-fluoropropoxy-3-bromobenzylguanidine (FPOBBG) as well as their tosylate precursors for labeling with (18)F, and a tin precursor for the preparation of radioiodinated FPOIBG were synthesized. Radiolabeled derivatives were synthesized by nucleophilic substitution and electrophilic iododestannylation from the corresponding precursors. Labeled compounds were evaluated for NET transporter recognition in in vitro assays using three NET-expressing cell lines and in biodistribution experiments in normal mice, with all studies performed in a paired-label format. Competitive inhibition of [(125)I]MIBG uptake by unlabeled benzylguanidine compounds was performed in UVW-NAT cell line to determine IC50 values.
  
  
  RESULTS
  [(18)F]FPOIBG was synthesized from the corresponding tosylate precursor in 5.2 ± 0.5% (n = 6) overall radiochemical yields starting with aqueous fluoride in about 105 min. In a paired-label in vitro assay, the uptake of [(18)F]FPOIBG at 2h was 10.2 ± 1.5%, 39.6 ± 13.4%, and 13.3 ± 2.5%, in NET-expressing SK-N-SH, UVW-NAT, and SK-N-BE(2c) cells, respectively, while these values for [(125)I]MIBG were 57.3 ± 8.1%, 82.7 ± 8.9%, and 66.3 ± 3.6%. The specificity of uptake of both tracers was demonstrated by blocking with desipramine. The (125)I-labeled congener of FPOIBG gave similar results. On the other hand, [(18)F]FPOBBG, a compound recently reported in the literature, demonstrated much higher uptake, albeit less than that of co-incubated [(125)I]MIBG. IC50 values for FPOIBG were higher than those obtained for MIBG and FPOBBG. Unlike the case with [(18)F]FPOBBG, the heart uptake [(18)F]FPOIBG in normal mice was significantly lower than that of MIBG.
  
  
  CONCLUSIONS
  Although [(18)F]FPOIBG does not appear to warrant further consideration as an (18)F-labeled MIBG analogue, analogues wherein the iodine in it is replaced with a chlorine, fluorine or hydrogen might be worth pursuing.
  
  
  CONCLUSIONS
  An (18)F-labeled analogue of the well-known radiopharmaceutical MIBG could have significant impact, potentially improving imaging of NET related disease in cardiology and in the imaging of neuroendocrine tumors. Although (18)F-labeled analogues of MIBG have been reported including LMI1195, we undertook this work hypothesizing that based on its greater structural similarity to MIBG, FPOIBG might be a better analogue than LMI1195.
authors.affiliation: Department of Radiology, Duke University Medical Center, Durham, North Carolina 27710. Electronic address: ganesan.v@duke.edu.
authors.forename: Ganesan
authors.initials: G
authors.lastname: Vaidyanathan
authors.affiliation: Department of Radiology, Duke University Medical Center, Durham, North Carolina 27710.
authors.forename: Darryl
authors.initials: D
authors.lastname: McDougald
authors.affiliation: Department of Radiology, Duke University Medical Center, Durham, North Carolina 27710.
authors.forename: Eftychia
authors.initials: E
authors.lastname: Koumarianou
authors.affiliation: Department of Radiology, Duke University Medical Center, Durham, North Carolina 27710.
authors.forename: Jaeyeon
authors.initials: J
authors.lastname: Choi
authors.affiliation: Department of Radiology, Duke University Medical Center, Durham, North Carolina 27710.
authors.forename: Marc
authors.initials: M
authors.lastname: Hens
authors.affiliation: Department of Radiology, Duke University Medical Center, Durham, North Carolina 27710.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Zalutsky
mesh_terms: D019797:3-Iodobenzylguanidine / Q000737:chemistry*; D000818:Animals; D001345:Autoradiography; D005462:Fluorine Radioisotopes / Q000493:pharmacokinetics; D005910:Glioma / Q000000981:diagnostic imaging* / Q000378:metabolism; D006146:Guanidines / Q000138:chemical synthesis* / Q000493:pharmacokinetics*; D007462:Iodobenzenes / Q000138:chemical synthesis* / Q000493:pharmacokinetics*; D007553:Isotope Labeling; D008657:Metabolic Clearance Rate; D051379:Mice; D008807:Mice, Inbred BALB C; D009447:Neuroblastoma / Q000000981:diagnostic imaging* / Q000378:metabolism; D050484:Norepinephrine Plasma Membrane Transport Proteins / Q000378:metabolism; D049268:Positron-Emission Tomography / Q000379:methods*; D019275:Radiopharmaceuticals / Q000138:chemical synthesis* / Q000493:pharmacokinetics*; D014018:Tissue Distribution; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D005462:Fluorine Radioisotopes; D006146:Guanidines; D007462:Iodobenzenes; D050484:Norepinephrine Plasma Membrane Transport Proteins; D019275:Radiopharmaceuticals; C493227:SLC6A2 protein, human; D019797:3-Iodobenzylguanidine
keywords: Fluorine-18; MIBG; Neuroendocrine tumors; Norepinephrine transporter; PET imaging