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

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Abstract

Purpose

Both 131I- and 123I-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 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 hNET expression 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.

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Abbreviations

NET:

Norepinephrine transporter

hNET:

Human norepinephrine transporter

MIBG:

Meta-iodobenzylguanidine

[18F]MFBG:

Meta-[18F]fluorobenzylguanidine

[18F]PFBG:

Para-[18F]fluorobenzylguanidine

SPECT:

Single photon emission computed tomography

PET:

Positron emission tomography

[76Br]MBBG:

Meta-[76Br]bromobenzylguanidine

[18F]FIBG:

4-[18F]fluoro-3-iodobenzylguanidine

LMI1195:

N-[3-bromo-4-(3-(18)F-fluoro-propoxy)-benzyl]-guanidine

C6-WT:

C6 wild-type rat glioma cells

C6-hNET:

hNET gene stably transduced C6 cells

PIBG:

Para-iodobenzylguanidine

TBA[18F]F:

Tetrabutylammonium [18F]fluoride

MeCN:

acetonitrile

TFA:

Trifluoroacetic acid

PBS:

Phosphate-buffered saline

ROI:

Region of interest

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Acknowledgments

This work was supported by NIH grant P50 CA84638. We appreciate the assistance of staff from the MSKCC Small Animal Imaging Core Facility for the PET imaging and the MSKCC Radiochemistry & Molecular Imaging Probe Core for 18F production. These MSKCC Cores were supported by the NIH Center grant P30 CA08748. DLJT was supported by the R25T Molecular Imaging Fellowship: Molecular Imaging Training in Oncology (5R25CA096945-07; Principal investigator H. Hricak). We also thank Dr. Diane Abou for PET imaging assistance and valuable discussion. Dedicated to Prof. H. Maecke on the occasion of his 70th birthday.

Conflicts of interest

None.

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Authors and Affiliations

  1. Department of Radiology, Memorial Sloan-Kettering Cancer Center (MSKCC), New York, NY, 10065, USA

    Hanwen Zhang, Ruimin Huang, NagaVaraKishore Pillarsetty, Daniel L. J. Thorek, Ronald G. Blasberg & Jason S. Lewis

  2. Department of Neurology, Memorial Sloan-Kettering Cancer Center (MSKCC), New York, NY, 10065, USA

    Inna Serganova & Ronald G. Blasberg

  3. Molecular Pharmacology & Chemistry Program, Memorial Sloan-Kettering Cancer Center (MSKCC), New York, NY, 10065, USA

    Ronald G. Blasberg & Jason S. Lewis

  4. Department of Radiology, Duke University School of Medicine, Durham, NC, 27710, USA

    Ganesan Vaidyanathan

  5. Radiochemistry & Imaging Sciences Service, Department of Radiology, Molecular Pharmacology & Chemistry Program, SKI, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY, 10065, USA

    Jason S. Lewis

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  1. Hanwen Zhang
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Correspondence to Jason S. Lewis.

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Zhang, H., Huang, R., Pillarsetty, N. et al. Synthesis and evaluation of 18F-labeled benzylguanidine analogs for targeting the human norepinephrine transporter. Eur J Nucl Med Mol Imaging 41, 322–332 (2014). https://doi.org/10.1007/s00259-013-2558-9

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  • DOI: https://doi.org/10.1007/s00259-013-2558-9

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