title: Synthesis and evaluation of 18F-labeled benzylguanidine analogs for targeting the human norepinephrine transporter.
abstract: OBJECTIVE
  Both (131)I- and (123)I-labeled meta-iodobenzylguanidine (MIBG) have been widely used in the clinic for targeted imaging of the norepinephrine transporter (NET). The human NET (hNET) gene has been imaged successfully with (124)I-MIBG positron emission tomography (PET) at time points of >24 h post-injection (p.i.). (18)F-labeled MIBG analogs may be ideal to image hNET expression at time points of <8 h p.i. We developed improved methods for the synthesis of known MIBG analogs, [(18)F]MFBG and [(18)F]PFBG and evaluated them in hNET reporter gene-transduced C6 rat glioma cells and xenografts.
  
  
  METHODS
  [(18)F]MFBG and [(18)F]PFBG were synthesized manually using a three-step synthetic scheme. Wild-type and hNET reporter gene-transduced C6 rat glioma cells and xenografts were used to comparatively evaluate the (18)F-labeled analogs with [(123)I]/[(124)I]MIBG.
  
  
  RESULTS
  The fluorination efficacy on benzonitrile was predominantly determined by the position of the trimethylammonium group. The para-isomer afforded higher yields (75 ± 7%) than meta-isomer (21 ± 5%). The reaction of [(18)F]fluorobenzylamine with 1H-pyrazole-1-carboximidamide was more efficient than with 2-methyl-2-thiopseudourea. The overall radiochemical yields (decay-corrected) were 11 ± 2% (n = 12) for [(18)F]MFBG and 41 ± 12% (n = 5) for [(18)F]PFBG, respectively. The specific uptakes of [(18)F]MFBG and [(18)F]PFBG were similar in C6-hNET cells, but 4-fold less than that of [(123)I]/[(124)I]MIBG. However, in vivo [(18)F]MFBG accumulation in C6-hNET tumors was 1.6-fold higher than that of [(18)F]PFBG at 1 h p.i., whereas their uptakes were similar at 4 h. Despite [(18)F]MFBG having a 2.8-fold lower affinity to hNET and approximately 4-fold lower cell uptake in vitro compared to [(123)I]/[(124)I]MIBG, PET imaging demonstrated that [(18)F]MFBG was able to visualize C6-hNET xenografts better than [(124)I]MIBG. Biodistribution studies showed [(18)F]MFBG and (123)I-MIBG had a similar tumor accumulation, which was lower than that of no-carrier-added [(124)I]MIBG, but [(18)F]MFBG showed a significantly more rapid body clearance and lower uptake in most non-targeting organs.
  
  
  CONCLUSIONS
  [(18)F]MFBG and [(18)F]PFBG were synthesized in reasonable radiochemical yields under milder conditions. [(18)F]MFBG is a better PET ligand to image hNET expression in vivo at 1-4 h p.i. than both [(18)F]PFBG and [(123)I]/[(124)I]MIBG.
authors.affiliation: Department of Radiology, Memorial Sloan-Kettering Cancer Center (MSKCC), New York, NY, 10065, USA.
authors.forename: Hanwen
authors.initials: H
authors.lastname: Zhang
authors.forename: Ruimin
authors.initials: R
authors.lastname: Huang
authors.forename: NagaVaraKishore
authors.initials: N
authors.lastname: Pillarsetty
authors.forename: Daniel L J
authors.initials: DL
authors.lastname: Thorek
authors.forename: Ganesan
authors.initials: G
authors.lastname: Vaidyanathan
authors.forename: Inna
authors.initials: I
authors.lastname: Serganova
authors.forename: Ronald G
authors.initials: RG
authors.lastname: Blasberg
authors.forename: Jason S
authors.initials: JS
authors.lastname: Lewis
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D005464:Fluorobenzenes / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D005910:Glioma / Q000000981:diagnostic imaging; D006146:Guanidines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D006801:Humans; D051379:Mice; D050484:Norepinephrine Plasma Membrane Transport Proteins / Q000378:metabolism*; D049268:Positron-Emission Tomography; D019275:Radiopharmaceuticals / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
chemical_list: C107924:3-fluorobenzylguanidine; C101472:4-fluorobenzylguanidine; D005464:Fluorobenzenes; D006146:Guanidines; D050484:Norepinephrine Plasma Membrane Transport Proteins; D019275:Radiopharmaceuticals