Skip to main content
SpringerLink
Log in

Whole Body PET Imaging with a Norepinephrine Transporter Probe 4-[18F]Fluorobenzylguanidine: Biodistribution and Radiation Dosimetry

  • Research Article
  • Published:
Molecular Imaging and Biology Aims and scope Submit manuscript

Abstract

Purpose

4-[18F]Fluorobenzylguanidine ([18F]PFBG) is a positron emission tomography (PET) probe for non-invasive targeting of the norepinephrine transporter. The aim of this study was to assess uptake and distribution characteristics of this PET probe.

Procedures

Three cynomolgus monkeys were injected with 269 ± 51 MBq (7.3 ± 1.4 mCi) of [18F]PFBG and 21 whole body PET scans were acquired over 165 min. s around organs to generate time-activity curves. The absorbed doses to individual organs and the effective dose to the whole body were estimated.

Results

Favorable distribution of [18F]PFBG was noted with a fast wash-in and wash-out of radioactivity from several tissues. [18F]PFBG rapidly distributed in the heart, liver, kidneys, and adrenal glands. The uptake presented as %ID in the brain, lung, and spleen was 1.06 ± 0.45, 6.28 ± 0.33, and 1.39 ± 0.35 at 1 min and decreased to 0.29 ± 0.02, 1.78 ± 0.31, and 0.66 ± 0.22 by 112 min. In general, a two- to fourfold reduction was noted from peak radioactivity levels. Rapid uptake and significant retention of radioactivity was noted in the heart and the septal wall was distinctly visible by 20 min. Fast wash-in and washout kinetics for [18F]PFBG resulted in shorter residence times. The residence time for the liver, lungs, kidneys, and spleen were 28.01 ± 7.73 min, 2.97 ± 0.56 min, 6.04 ± 3.41 min, and 1.09 ± 0.33 min, respectively. The mean effective dose for the 70-kg male was 0.04 ± 0.00 mSv/MBq. The organs receiving the highest radiation dose in the 70-kg male model were the testes (0.11 ± 0.02 mGy/MBq), adrenals (0.08 ± 0.01 mGy/MBq), and urinary bladder wall (0.08 ± 0.01 mGy/MBq).

Conclusions

[18F]PFBG shows a favorable biodistribution pattern. Rapid and persistent uptake was noted in innervated organs. Renal clearance was the major path for elimination of [18F]PFBG. The estimated radiation burden from [18F]PFBG was significantly lower than that from [124I]MIBG.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1.
Fig. 2.
Fig. 3.
Fig. 4.
Fig. 5.
Fig. 6.

Similar content being viewed by others

References

  1. Altmann A, Kissel M, Zitzmann S, Kübler W, Mahmut M, Peschke P, Haberkorn U (2003) Increased MIBG uptake after transfer of the human norepinephrine transporter gene in rat hepatoma. J Nucl Med 44:973–980

    CAS  PubMed  Google Scholar 

  2. Smets LA, Loesberg C, Janssen M, Metwally EA, Huiskamp R (1989) Active uptake and extravesicular storage of m-iodobenzylguanidine in human neuroblastoma SK-N-SH cells. Cancer Res 49:2941–2944

    CAS  PubMed  Google Scholar 

  3. Nakajo M, Shapiro B, Copp J, Kalff V, Gross MD, Sisson JC, Beierwaltes WH (1983) The normal and abnormal distribution of the adrenomedullary imaging agent m-[I-131]iodobenzylguanidine (I-131 MIBG) in man: evaluation by scintigraphy. J Nucl Med 24:672–682

    CAS  PubMed  Google Scholar 

  4. Wakasugi S, Wada A, Hasegawa Y, Nakano S, Shibata N (1992) Detection of abnormal cardiac adrenergic neuron activity in adriamycin-induced cardiomyopathy with iodine-125-metaiodobenzylguanidine. J Nucl Med 33:208–214

    CAS  PubMed  Google Scholar 

  5. Stanton MS, Tuli MM, Radtke NL, Heger JJ, Miles WM, Mock BH, Burt RW, Wellman HN, Zipes DP (1989) Regional sympathetic denervation after myocardial infarction in humans detected noninvasively using I-123-metaiodobenzylguanidine. J Am Coll Cardiol 14:1519–1526

    Article  CAS  PubMed  Google Scholar 

  6. Freitas JE (1995) Adrenal cortical and medullary imaging. Semin Nucl Med 25:235–230

    Article  CAS  PubMed  Google Scholar 

  7. Shulkin BL, Shapiro B, Francis IR et al (1986) Primary extra-adrenal pheochromocytoma: positive I-123 MIBG imaging with negative I-131 MIBG imaging. Clin Nucl Med 11:851–854

    Article  CAS  PubMed  Google Scholar 

  8. Shapiro B, Copp JE, Sisson JC, Eyre PL, Wallis J, Beierwaltes WH (1985) Iodine-131 metaiodobenzylguanidine for the locating of suspected pheochromocytoma: experience in 400 cases. J Nucl Med 26:576–585

    CAS  PubMed  Google Scholar 

  9. Sisson JC, Shulkin BL (1999) Nuclear medicine imaging of pheochromocytoma and neuroblastoma. Q J Nucl Med 43:217–223

    CAS  PubMed  Google Scholar 

  10. Hanson MW, Feldman JM, Blinder RA, Moore JO, Coleman RE (1989) Carcinoid tumors: iodine-131 MIBG scintigraphy. Radiology 172:699–703

    Article  CAS  PubMed  Google Scholar 

  11. Ansari AN, Siegel ME, DeQuattro V, Gazarian LH (1986) Imaging of medullary thyroid carcinoma and hyperfunctioning adrenal medulla using iodine-131 metaiodobenzylguanidine. J Nucl Med 27:1858–1860

    CAS  PubMed  Google Scholar 

  12. Feine U, Muller-Schauenburg W, Treuner J, Klingebiel T (1987) Metaiodobenzylguanidine (MIBG) labeled with 123I/131I in neuroblastoma diagnosis and follow-up treatment with a review of the diagnostic results of the International Workshop of Pediatric Oncology held in Rome, September 1986. Med Pediatr Oncol 15:181–187

    Article  CAS  PubMed  Google Scholar 

  13. Kuker R, Sztejnberg M, Gulec S (2017) I-124 imaging and dosimetry. Mol Imaging Radionucl Ther 26:66–73

    Article  PubMed  PubMed Central  Google Scholar 

  14. Lee CL, Wahnishe H, Sayre GA, Cho HM, Kim HJ, Hernandez-Pampaloni M, Hawkins RA, Dannoon SF, VanBrocklin HF, Itsara M, Weiss WA, Yang X, Haas-Kogan DA, Matthay KK, Seo Y (2010) Radiation dose estimation using preclinical imaging with 124I-metaiodobenzylguanidine (MIBG) PET. Med Phys 37:4861–4867

    Article  PubMed  PubMed Central  Google Scholar 

  15. Vaidyanathan G, Affleck DJ, Zalutsky MR (1994) (4-[18F]Fluoro-3-iodobenzyl)guanidine, a potential MIBG analogue for positron emission tomography. J Med Chem 37:3655–3662

    Article  CAS  PubMed  Google Scholar 

  16. Garg PK, Garg S, Zalutsky MR (1994) Synthesis and preliminary evaluation of para- and meta-[18F]fluorobenzylguanidine. Nuc Med Biol 21:97–103

    Article  CAS  Google Scholar 

  17. Zhang H, Huang R, Pillarsetty N, Thorek DLJ, Vaidyanathan G, Serganova I, Blasberg RG, Lewis JS (2014) Synthesis and evaluation of 18F-labeled benzylguanidine analogs for targeting the human norepinephrine transporter. Eur J Nucl Med Mol Imaging 41:322–332

    Article  CAS  PubMed  Google Scholar 

  18. Cavallo G, Metrangolo P, Milani R, Pilati T, Priimagi A, Resnati G, Terraneo G (2016) The halogen bond. Chem Rev 116:2478–2601

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Berry CR, Garg PK, DeGrado TR et al (1994) Para [F-18] fluorobenzylguanidine (PFBG) kinetics in a canine coronary artery occlusion model. J Nucl Med 35:157

    Google Scholar 

  20. Berry CR, DeGrado TR, Nutter F et al (2002) Imaging of pheochromocytoma in 2 dogs using p-[18F]fluorobenzylguanidine. Vet Radiol Ultrasound 43:183–186

    Article  PubMed  Google Scholar 

  21. Berry CR, Garg PK, Zalutsky MR, Coleman RE, DeGrado T (1996) Uptake and retention kinetics of para-fluorine-18-fluorobenzylguanidine in isolated rat heart. J Nucl Med 37:2011–2016

    CAS  PubMed  Google Scholar 

  22. Pandit-Taskar N, Zanzonico P, Staton KD, Carrasquillo JA, Reidy-Lagunes D, Lyashchenko S, Burnazi E, Zhang H, Lewis JS, Blasberg R, Larson SM, Weber WA, Modak S (2018) Biodistribution and dosimetry of 18F-Meta-Fluorobenzylguanidine: a first-in-human PET/CT imaging study of patients with neuroendocrine malignancies. J Nucl Med 59:147–153

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Berry CR, Garg PK, DeGrado TR et al (1996) Para-[18F]fluorobenzylguanidine kinetics in a canine coronary artery occlusion model. J Nucl Cardiol 3:119–129

    Article  CAS  PubMed  Google Scholar 

  24. Moroz MA, Serganova I, Zanzonico P, Ageyeva L, Beresten T, Dyomina E, Burnazi E, Finn RD, Doubrovin M, Blasberg RG (2007) Imaging hNET reporter gene expression with 124I-MIBG. J Nucl Med 48:827–836

    Article  CAS  PubMed  Google Scholar 

  25. DeGrado TR, Turkington TG, Williams JJ, Stearns CW, Hoffman JM, Coleman RE (1994) Performance characteristics of a whole-body PET scanner. J Nucl Med 35:1398–1406

    CAS  PubMed  Google Scholar 

  26. Lewellenm TK, Kohlmyer SG, Miyaoka RS et al (1996) Investigation of the performance of the General Electric ADVANCE positron emission tomograph in 3D mode. IEEE Trans Nucl Sc 43:2199–2206

    Article  Google Scholar 

  27. Lewellen TK, Kohlmyer SG, Miyaoka RS, Schubert S, Stearns CW (1995) Investigation of the count rate performance of general electric advance positron emission tomograph. IEEE Trans Nucl Sc 42:1051–1057

    Article  Google Scholar 

  28. Kinahan PE, Townsend DW, Beyer T, Sashin D (1998) Attenuation correction for a combined 3D PET/CT scanner. Med Phys 25:2046–2053

    Article  CAS  PubMed  Google Scholar 

  29. Kinahan PE, Rogers JG (1989) Analytical 3D image reconstruction using all detected events. IEEE Trans Nucl Sci 36:964–968

    Article  CAS  Google Scholar 

  30. Valentin J (2002) ICRP-89: basic anatomical and physiological data for use in radiological protection reference values. Ann ICRP 32

  31. Garg PK, Lokitz SJ, Nazih R, Garg S (2017) Biodistribution and radiation dosimetry of 11C-nicotine from whole-body PET imaging in humans. J Nucl Med 58:473–478

    Article  CAS  PubMed  Google Scholar 

  32. Makita T, Yamoto T, Ogawa K et al (1984) Body and organ weights of Macaca fuscata and Macaca cyclopis. Nihon Juigaku Zasshi 46:385–390

    Article  CAS  PubMed  Google Scholar 

  33. Mejia AA, Nakamura T, Masatoshi I, Hatazawa J, Masaki M, Watanuki S (1991) Estimation of absorbed doses in humans due to intravenous administration of fluorine-18-fluorodeoxyglucose in PET studies. J Nucl Med 32:699–706

    CAS  PubMed  Google Scholar 

  34. Stabin MG, Sparks RB, Crowe E (2005) OLINDA/EXM: the second-generation personal computer software for internal dose assessment in nuclear medicine. J Nucl Med 46:1023–1027

    PubMed  Google Scholar 

  35. ICRP-106 (2008) Radiation dose to patients from radiopharmaceuticals. Addendum 3 to ICRP publication 53. Ann ICRP 106(38):1–197

    Google Scholar 

  36. Stabin MG, Gelfand MJ (1998) Dosimetry of pediatric nuclear medicine procedures. Q J Nucl Med 42:93–112

    CAS  PubMed  Google Scholar 

  37. Brown AK, Fujita M, Fujimura Y, Liow JS, Stabin M, Ryu YH, Imaizumi M, Hong J, Pike VW, Innis RB (2007) Radiation dosimetry and biodistribution in monkey and man of 11C-PBR28: a PET radioligand to image inflammation. J Nucl Med 48:2072–2079

    Article  CAS  PubMed  Google Scholar 

  38. Doss M, Kolb HC, Zhang JJ, Belanger MJ, Stubbs JB, Stabin MG, Hostetler ED, Alpaugh RK, von Mehren M, Walsh JC, Haka M, Mocharla VP, Yu JQ (2012) Biodistribution and radiation dosimetry of the integrin marker 18F-RGD-K5 determined from whole-body PET/CT in monkeys and humans. J Nucl Med 53:787–795

    Article  PubMed  Google Scholar 

  39. Dence CS, Laforest R, Sun X, Sharp TL, Welch MJ, Mach RH (2010) Radiochemical synthesis, rodent biodistribution and tumor uptake, and dosimetry calculations of [11C] methylated LY2181308. Mol Imaging Biol 12:608–615

    Article  PubMed  Google Scholar 

  40. Bonasera TA, O'Neil JP, Xu M, Dobkin JA, Cutler PD, Lich LL, Choe YS, Katzenellenbogen JA, Welch MJ (1996) Preclinical evaluation of fluorine-18-labeled androgen receptor ligands in baboons. J Nucl Med 37:1009–1015

    CAS  PubMed  Google Scholar 

  41. Jahan M, Eriksson O, Johnstrom P et al (2011) Decreased defluorination using the novel beta-cell imaging agent [18F]FE-DTBZ-d4 in pigs examined by PET. EJNMMI Res 1:33

    Article  PubMed  PubMed Central  Google Scholar 

  42. Lash LH, Qian W, Putt DA, Jacobs K, Elfarra AA, Krause RJ, Parker JC (1998) Glutathione conjugation of trichloroethylene in rats and mice: sex-, species-, and tissue-dependent differences. Drug Metab Dispos 26:12–19

    CAS  PubMed  Google Scholar 

  43. Cannady EA, Chien C, Jones TM, Borel AG (2006) In vitro metabolism of the epoxide substructure of cryptophycins by cytosolic glutathione S-transferase: species differences and stereoselectivity. Xenobiotica 36:659–670

    Article  CAS  PubMed  Google Scholar 

  44. Shetty HU, Zoghbi SS, Simeon FG et al (2008) Radiodefluorination of 3-fluoro-5-(2-(2-[18F](fluoromethyl)-thiazol-4-yl)ethynyl)benzonitrile ([18F]SP203), a radioligand for imaging brain metabotropic glutamate subtype-5 receptors with positron emission tomography, occurs by glutathionylation in rat brain. J Pharmacol Exp Ther 327:727–735

    Article  CAS  PubMed  Google Scholar 

  45. Godin SJ, Crow JA, Scollon EJ, Hughes MF, DeVito MJ, Ross MK (2007) Identification of rat and human cytochrome p450 isoforms and a rat serum esterase that metabolize the pyrethroid insecticides deltamethrin and esfenvalerate. Drug Metab Dispos 35:1664–1671

    Article  CAS  PubMed  Google Scholar 

  46. Lee CM, Javitch JA, Snyder SH (1983) Recognition sites for norepinephrine uptake: regulation by neurotransmitter. Science 220:626–629

    Article  CAS  PubMed  Google Scholar 

  47. Jentzen W, Richter M, Poeppel TD, Schmitz J, Brandau W, Bockisch A, Binse I (2017) Discrepant salivary gland response after radioiodine and MIBG therapies. Q J Nucl Med Mol Imaging 61:331–339

    PubMed  Google Scholar 

  48. Nakajo M, Shapiro B, Sisson JC, Swanson DP, Beierwaltes WH (1984) Salivary gland accumulation of meta-[131I]iodobenzylguanidine. J Nucl Med 25:2–6

    CAS  PubMed  Google Scholar 

  49. Sisson JC, Wieland DM, Jaques S Jr et al (1987) Radiolabeled meta-iodobenzylguanidine and the adrenergic neurons of salivary glands. Am J Physiol Imaging 2:1–9

    CAS  PubMed  Google Scholar 

  50. Kim SK, Allen ED (1994) Structural and functional changes in salivary glands during aging. Microsc Res Tech 28:243–253

    Article  CAS  PubMed  Google Scholar 

  51. Huda W, Vance A (2007) Patient radiation doses from adult and pediatric CT. AJR Am J Roentgenol 188:540–546

    Article  PubMed  Google Scholar 

  52. Huda W, Scalzetti EM, Roskopf M (2000) Effective doses to patients undergoing thoracic computed tomography examinations. Med Phys 27:838–844

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

We would like to thank Kimberly Black, Leah Rutkowski, Andrew Lynch, and Holly Smith for their excellent technical help. Strong support from the Center for Biomolecular Imaging of Wake Forest University Health Sciences is greatly appreciated and acknowledged. All applicable institutional and/or national guidelines for the care and use of animals were followed.

Author information

Author notes

  1. Pradeep K. Garg

    Present address: Center for Molecular Imaging and Therapy, Biomedical Research Foundation, Shreveport, LA, 71103, USA

Authors and Affiliations

  1. Center for Molecular Imaging and Therapy, Biomedical Research Foundation, Shreveport, LA, 71103, USA

    Stephen J. Lokitz, Sudha Garg & Rachid Nazih

  2. Department of Radiology, Wake Forest University Health Science, Winston Salem, NC, USA

    Sudha Garg, Rachid Nazih & Pradeep K. Garg

Authors
  1. Stephen J. Lokitz
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sudha Garg
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Rachid Nazih
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Pradeep K. Garg
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Pradeep K. Garg.

Ethics declarations

Conflict of Interest

The authors declare that they have no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Lokitz, S.J., Garg, S., Nazih, R. et al. Whole Body PET Imaging with a Norepinephrine Transporter Probe 4-[18F]Fluorobenzylguanidine: Biodistribution and Radiation Dosimetry. Mol Imaging Biol 21, 686–695 (2019). https://doi.org/10.1007/s11307-018-1280-1

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11307-018-1280-1

Key words

Search

Navigation