Synthesis and evaluation of 18F-labeled benzylguanidine analogs for targeting the human norepinephrine transporter

Hanwen Zhang, Ruimin Huang, Naga Vara Kishore Pillarsetty, Daniel L.J. Thorek, Ganesan Vaidyanathan, Inna Serganova, Ronald G. Blasberg, Jason S. Lewis

Research output: Contribution to journalArticlepeer-review

35 Scopus citations


Purpose: Both 131I- and 123I-labeled meta-iodobenzyl-guanidine (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 124I-MIBG positron emission tomography (PET) at time points of >24 h post-injection (p.i.). 18F-labeled MIBG analogs may be ideal to image hNETexpression at time points of <8 h p.i. We developed improved methods for the synthesis of known MIBG analogs, [18F]MFBG and [18F]PFBG and evaluated them in hNET reporter gene-transduced C6 rat glioma cells and xenografts. Methods: [18F]MFBG and [18F]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 18F-labeled analogs with [123I]/[124I]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 [ 18F]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 [18F]MFBG and 41±12 % (n =5) for [18F]PFBG, respectively. The specific uptakes of [18F]MFBG and [18F]PFBG were similar in C6-hNET cells, but 4-fold less than that of [123I]/[124I]MIBG. However, in vivo [18F]MFBG accumulation in C6-hNET tumors was 1.6-fold higher than that of [18F]PFBG at 1 h p.i., whereas their uptakes were similar at 4 h. Despite [18F]MFBG having a 2.8-fold lower affinity to hNET and approximately 4-fold lower cell uptake in vitro compared to [123I]/[124I]MIBG, PET imaging demonstrated that [18F]MFBG was able to visualize C6-hNET xenografts better than [124I]MIBG. Biodistribution studies showed [18F]MFBG and 123I-MIBG had a similar tumor accumulation, which was lower than that of no-carrier-added [124I]MIBG, but [18F]MFBG showed a significantly more rapid body clearance and lower uptake in most non-targeting organs. Conclusion: [18F]MFBG and [18F]PFBG were synthesized in reasonable radiochemical yields under milder conditions. [ 18F]MFBG is a better PET ligand to image hNET expression in vivo at 1-4 h p.i. than both [18F]PFBG and [123I]/[ 124I]MIBG.

Original languageEnglish
Pages (from-to)322-332
Number of pages11
JournalEuropean Journal of Nuclear Medicine and Molecular Imaging
Issue number2
StatePublished - 2014


  • HNETreporter gene
  • PET imaging

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