Synthesis and evaluation of 18F-labeled benzylguanidine analogs for targeting the human norepinephrine transporter Journal Article
| Authors: | Zhang, H.; Huang, R.; Pillarsetty, N.; Thorek, D. L. J.; Vaidyanathan, G.; Serganova, I.; Blasberg, R. G.; Lewis, J. S. |
| Article Title: | Synthesis and evaluation of 18F-labeled benzylguanidine analogs for targeting the human norepinephrine transporter |
| Abstract: | 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. © Springer-Verlag Berlin Heidelberg 2013. |
| Keywords: | unclassified drug; nonhuman; comparative study; positron emission tomography; animal cell; culture medium; animal experiment; animal model; in vitro study; wild type; xenograft; glioma cell; rat; radioactivity; radiopharmaceutical agent; (3 iodobenzyl)guanidine i 123; (3 iodobenzyl)guanidine i 124; noradrenalin transporter; reporter gene; pet imaging; (3 iodobenzyl)guanidine i 131; lipophilicity; synthesis; radiochemistry; halogenation; competitive inhibition; fluorination; male; article; hnetreporter gene; (3 iodobenzyl)guanidine f 18; meta fluorobenzylguanidine f 18; para fluorobenzylguanidine f 18; plasma protein binding; ultra performance liquid chromatography |
| Journal Title: | European Journal of Nuclear Medicine and Molecular Imaging |
| Volume: | 41 |
| Issue: | 2 |
| ISSN: | 1619-7070 |
| Publisher: | Springer |
| Date Published: | 2014-02-01 |
| Start Page: | 322 |
| End Page: | 332 |
| Language: | English |
| DOI: | 10.1007/s00259-013-2558-9 |
| PROVIDER: | scopus |
| PMCID: | PMC3947152 |
| PUBMED: | 24173571 |
| DOI/URL: | |
| Notes: | Export Date: 1 May 2014 -- CODEN: EJNMA -- Source: Scopus |
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