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- Title
Synthesis and evaluation of F-labeled benzylguanidine analogs for targeting the human norepinephrine transporter.
- Authors
Zhang, Hanwen; Huang, Ruimin; Pillarsetty, NagaVaraKishore; Thorek, Daniel; Vaidyanathan, Ganesan; Serganova, Inna; Blasberg, Ronald; Lewis, Jason
- Abstract
Purpose: Both I- and 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 I-MIBG positron emission tomography (PET) at time points of >24 h post-injection (p.i.). 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, [F]MFBG and [F]PFBG and evaluated them in hNET reporter gene-transduced C6 rat glioma cells and xenografts. Methods: [F]MFBG and [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 F-labeled analogs with [I]/[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 [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 [F]MFBG and 41 ± 12 % ( n = 5) for [F]PFBG, respectively. The specific uptakes of [F]MFBG and [F]PFBG were similar in C6-hNET cells, but 4-fold less than that of [I]/[I]MIBG. However, in vivo [F]MFBG accumulation in C6-hNET tumors was 1.6-fold higher than that of [F]PFBG at 1 h p.i., whereas their uptakes were similar at 4 h. Despite [F]MFBG having a 2.8-fold lower affinity to hNET and approximately 4-fold lower cell uptake in vitro compared to [I]/[I]MIBG, PET imaging demonstrated that [F]MFBG was able to visualize C6-hNET xenografts better than [I]MIBG. Biodistribution studies showed [F]MFBG and I-MIBG had a similar tumor accumulation, which was lower than that of no-carrier-added [I]MIBG, but [F]MFBG showed a significantly more rapid body clearance and lower uptake in most non-targeting organs. Conclusion: [F]MFBG and [F]PFBG were synthesized in reasonable radiochemical yields under milder conditions. [F]MFBG is a better PET ligand to image hNET expression in vivo at 1-4 h p.i. than both [F]PFBG and [I]/[I]MIBG.
- Subjects
NORADRENALINE; GLIOMAS; XENOGRAFTS; ISOMERS; RADIOCHEMICAL analysis
- Publication
European Journal of Nuclear Medicine & Molecular Imaging, 2014, Vol 41, Issue 2, p322
- ISSN
1619-7070
- Publication type
Article
- DOI
10.1007/s00259-013-2558-9