Top

European Journal of Nuclear Medicine and Molecular Imaging

Published in:

01-11-2016 | Original Article

Synthesis and preclinical evaluation of an Al¹⁸F radiofluorinated GLU-UREA-LYS(AHX)-HBED-CC PSMA ligand

Authors: Stefano Boschi, Jason T. Lee, Seval Beykan, Roger Slavik, Liu Wei, Claudio Spick, Uta Eberlein, Andreas K. Buck, Filippo Lodi, Gianfranco Cicoria, Johannes Czernin, Michael Lassmann, Stefano Fanti, Ken Herrmann

Published in: European Journal of Nuclear Medicine and Molecular Imaging | Issue 12/2016

Abstract

Purpose

The aim of this study was to synthesize and preclinically evaluate an ¹⁸F-PSMA positron emission tomography (PET) tracer. Prostate-specific membrane antigen (PSMA) specificity, biodistribution, and dosimetry in healthy and tumor-bearing mice were determined.

Methods

Several conditions for the labeling of ¹⁸F-PSMA-11 via ¹⁸F-AlF-complexation were screened to study the influence of reaction temperature, peptide amount, ethanol volume, and reaction time. After synthesis optimization, biodistribution and dosimetry studies were performed in C57BL6 mice. For proof of PSMA-specificity, mice were implanted with PSMA-negative (PC3) and PSMA-positive (LNCaP) tumors in contralateral flanks. Static and dynamic microPET/computed tomography (CT) imaging was performed.

Results

Quantitative labeling yields could be achieved with >97 % radiochemical purity. The ¹⁸F-PSMA-11 uptake was more than 24-fold higher in PSMA-high LNCaP than in PSMA-low PC3 tumors (18.4 ± 3.3 %ID/g and 0.795 ± 0.260 %ID/g, respectively; p < 4.2e-5). Results were confirmed by ex vivo gamma counter analysis of tissues after the last imaging time point. The highest absorbed dose was reported for the kidneys. The maximum effective dose for an administered activity of 200 MBq was 1.72 mSv.

Conclusion

¹⁸F-PSMA-11 using direct labeling of chelate-attached peptide with aluminum-fluoride detected PSMA-expressing tumors with high tumor-to-liver ratios. The kidneys were the dose-limiting organs. Even by applying the most stringent dosimetric calculations, injected activities of up to 0.56 GBq are feasible.

Available only for authorised users

Ghosh A, Heston WD. Tumor target prostate specific membrane antigen (PSMA) and its regulation in prostate cancer. J Cell Biochem. 2004;91:528–39. doi:10.1002/jcb.10661.CrossRefPubMed

Eder M, Schafer M, Bauder-Wust U, et al. 68Ga-complex lipophilicity and the targeting property of a urea-based PSMA inhibitor for PET imaging. Bioconjug Chem. 2012;23:688–97. doi:10.1021/bc200279b.CrossRefPubMed

Weineisen M, Schottelius M, Simecek J, et al. 68Ga- and 177Lu-labeled PSMA I&T: optimization of a PSMA targeted theranostic concept and first proof of concept human studies. J Nucl Med. 2015. doi:10.2967/jnumed.115.158550.PubMedCentral

Mease RC, Foss CA, Pomper MG. PET imaging in prostate cancer: focus on prostate-specific membrane antigen. Curr Top Med Chem. 2013;13:951–62.CrossRefPubMedPubMedCentral

Schiavina R, Ceci F, Romagnoli D, et al. Ga-PSMA-PET/CT-guided salvage retroperitoneal lymph node dissection for disease relapse after radical prostatectomy for prostate cancer. Clin Genitourin Cancer. 2015. doi:10.1016/j.clgc.2015.06.004.

Budaus L, Leyh-Bannurah SR, Salomon G, et al. Initial experience of Ga-PSMA PET/CT imaging in high-risk prostate cancer patients prior to radical prostatectomy. Eur Urol. 2015. doi:10.1016/j.eururo.2015.06.010.

Morigi JJ, Stricker PD, van Leeuwen PJ, et al. Prospective comparison of 18F-fluoromethylcholine versus 68Ga-PSMA PET/CT in prostate cancer patients who have rising PSA after curative treatment and are being considered for targeted therapy. J Nucl Med. 2015;56:1185–90. doi:10.2967/jnumed.115.160382.CrossRefPubMed

Jadvar H. PSMA PET, in prostate cancer. J Nucl Med. 2015;56:1131–2. doi:10.2967/jnumed.115.157339.CrossRefPubMed

Ceci F, Uprimny C, Nilica B, et al. (68)Ga-PSMA PET/CT for restaging recurrent prostate cancer: which factors are associated with PET/CT detection rate? Eur J Nucl Med Mol Imaging. 2015;42:1284–94. doi:10.1007/s00259-015-3078-6.CrossRefPubMed

10.

Eiber M, Maurer T, Souvatzoglou M, et al. Evaluation of hybrid (6)(8)Ga-PSMA ligand PET/CT in 248 patients with biochemical recurrence after radical prostatectomy. J Nucl Med. 2015;56:668–74. doi:10.2967/jnumed.115.154153.CrossRefPubMed

11.

Kabasakal L, Demirci E, Ocak M, et al. Evaluation of PSMA PET/CT imaging using a 68Ga-HBED-CC ligand in patients with prostate cancer and the value of early pelvic imaging. Nucl Med Commun. 2015;36:582–7. doi:10.1097/MNM.0000000000000290.CrossRefPubMed

12.

Chakraborty PS, Kumar R, Tripathi M, Das CJ, Bal C. Detection of brain metastasis with 68Ga-labeled PSMA ligand PET/CT: a novel radiotracer for imaging of prostate carcinoma. Clin Nucl Med. 2015;40:328–9. doi:10.1097/RLU.0000000000000709.CrossRefPubMed

13.

Avanesov M, Karul M, Derlin T. (68)Ga-PSMA as a new tracer for evaluation of prostate cancer: comparison between PET-CT and PET-MRI in biochemical recurrence. Radiologe. 2015;55:89–91. doi:10.1007/s00117-014-2792-6.CrossRefPubMed

14.

Afshar-Oromieh A, Avtzi E, Giesel FL, et al. The diagnostic value of PET/CT imaging with the (68)Ga-labelled PSMA ligand HBED-CC in the diagnosis of recurrent prostate cancer. Eur J Nucl Med Mol Imaging. 2015;42:197–209. doi:10.1007/s00259-014-2949-6.CrossRefPubMed

15.

Uprimny C, Kroiss A, Nilica B, et al. (68)Ga-PSMA ligand PET versus (18)F-NaF PET: evaluation of response to (223)Ra therapy in a prostate cancer patient. Eur J Nucl Med Mol Imaging. 2015;42:362–3. doi:10.1007/s00259-014-2922-4.CrossRefPubMed

16.

Iwata R, Pascali C, Bogni A, Furumoto S, Terasaki K, Yanai K. [18F]fluoromethyl triflate, a novel and reactive [18F]fluoromethylating agent: preparation and application to the on-column preparation of [18F]fluorocholine. Appl Radiat Isot. 2002;57:347–52.CrossRefPubMed

17.

Evangelista L, Cervino AR, Guttilla A, Zattoni F, Cuccurullo V, Mansi L. (1)(8)F-fluoromethylcholine or (1)(8)F-fluoroethylcholine pet for prostate cancer imaging: which is better? a literature revision. Nucl Med Biol. 2015;42:340–8. doi:10.1016/j.nucmedbio.2014.12.019.CrossRefPubMed

18.

Chen Y, Pullambhatla M, Foss CA, et al. 2-(3-{1-Carboxy-5-[(6-[18F]fluoro-pyridine-3-carbonyl)-amino]-pentyl}-ureido)-pen tanedioic acid, [18F]DCFPyL, a PSMA-based PET imaging agent for prostate cancer. Clin Cancer Res. 2011;17:7645–53. doi:10.1158/1078-0432.CCR-11-1357.CrossRefPubMedPubMedCentral

19.

Malik N, Baur B, Winter G, Reske SN, Beer AJ, Solbach C. Radiofluorination of PSMA-HBED via AlF chelation and biological evaluations in vitro. Mol Imaging Biol. 2015. doi:10.1007/s11307-015-0844-6.PubMed

20.

Mease RC, Dusich CL, Foss CA, et al. N-[N-[(S)-1,3-Dicarboxypropyl]carbamoyl]-4-[18F]fluorobenzyl-L-cysteine, [18F]DCFBC: a new imaging probe for prostate cancer. Clin Cancer Res. 2008;14:3036–43. doi:10.1158/1078-0432.CCR-07-1517.CrossRefPubMedPubMedCentral

21.

McBride WJ, Sharkey RM, Goldenberg DM. Radiofluorination using aluminum-fluoride (Al18F). EJNMMI Res. 2013;3:36. doi:10.1186/2191-219X-3-36.CrossRefPubMedPubMedCentral

22.

McBride WJ, D’Souza CA, Karacay H, Sharkey RM, Goldenberg DM. New lyophilized kit for rapid radiofluorination of peptides. Bioconjug Chem. 2012;23:538–47. doi:10.1021/bc200608e.CrossRefPubMedPubMedCentral

23.

D’Souza CA, McBride WJ, Sharkey RM, Todaro LJ, Goldenberg DM. High-yielding aqueous 18F-labeling of peptides via Al18F chelation. Bioconjug Chem. 2011;22:1793–803. doi:10.1021/bc200175c.CrossRefPubMedPubMedCentral

24.

Loening AM, Gambhir SS. AMIDE: a free software tool for multimodality medical image analysis. Mol Imaging. 2003;2:131–7.CrossRefPubMed

25.

Repetto-Llamazares AH, Larsen RH, Mollatt C, Lassmann M, Dahle J. Biodistribution and dosimetry of (177)Lu-tetulomab, a new radioimmunoconjugate for treatment of non-Hodgkin lymphoma. Curr Radiopharm. 2013;6:20–7.CrossRefPubMedPubMedCentral

26.

Sparks RB, Aydogan B. Comparison of the effectiveness of some common animal data scaling techniques in estimating human radiation dose. . In: Stelson A, Stabin M, Sparks R, editors. Sixth International Radiopharmaceutical Dosimetry Symposium 1999. p. 705–16.

27.

International Commission on Radiological Protection (ICRP). Publication 89: basic anatomical and physiological data for use in radiological protection—reference values. Ann ICRP. 2002;32:1–278.

28.

Bitar A, Lisbona A, Thedrez P, et al. A voxel-based mouse for internal dose calculations using Monte Carlo simulations (MCNP). Phys Med Biol. 2007;52:1013–25. doi:10.1088/0031-9155/52/4/010.CrossRefPubMed

29.

Kletting P, Schimmel S, Kestler HA, et al. Molecular radiotherapy: the NUKFIT software for calculating the time-integrated activity coefficient. Med Phys. 2013;40:102504. doi:10.1118/1.4820367.CrossRefPubMed

30.

Stabin MG, Sparks RB, Crowe E. OLINDA/EXM: the second-generation personal computer software for internal dose assessment in nuclear medicine. J Nucl Med. 2005;46:1023–7.PubMed

31.

Dietlein M, Kobe C, Kuhnert G, et al. Comparison of [F]DCFPyL and [Ga]Ga-PSMA-HBED-CC for PSMA-PET imaging in patients with relapsed prostate cancer. Mol Imaging Biol. 2015. doi:10.1007/s11307-015-0866-0.PubMedPubMedCentral

32.

Szabo Z, Mena E, Rowe SP, et al. Initial evaluation of [F]DCFPyL for prostate-specific membrane antigen (PSMA)-targeted PET imaging of prostate cancer. Mol Imaging Biol. 2015. doi:10.1007/s11307-015-0850-8.PubMedPubMedCentral

33.

Silver DA, Pellicer I, Fair WR, Heston WD, Cordon-Cardo C. Prostate-specific membrane antigen expression in normal and malignant human tissues. Clin Cancer Res. 1997;3:81–5.PubMed

34.

Fuchs AV, Tse BW, Pearce AK, et al. Evaluation of polymeric nanomedicines targeted to PSMA: effect of ligand on targeting efficiency. Biomacromolecules. 2015;16:3235–47. doi:10.1021/acs.biomac.5b00913.CrossRefPubMed

35.

Kochuparambil ST, Al-Husein B, Goc A, Soliman S, Somanath PR. Anticancer efficacy of simvastatin on prostate cancer cells and tumor xenografts is associated with inhibition of Akt and reduced prostate-specific antigen expression. J Pharmacol Exp Ther. 2011;336:496–505. doi:10.1124/jpet.110.174870.CrossRefPubMed

36.

Horoszewicz JS, Leong SS, Kawinski E, et al. LNCaP model of human prostatic carcinoma. Cancer Res. 1983;43:1809–18.PubMed

37.

Afshar-Oromieh A, Hetzheim H, Kratochwil C, et al. The novel theranostic PSMA-ligand PSMA-617 in the diagnosis of prostate cancer by PET/CT: biodistribution in humans, radiation dosimetry and first evaluation of tumor lesions. J Nucl Med. 2015. doi:10.2967/jnumed.115.161299.

38.

Afshar-Oromieh A, Zechmann CM, Malcher A, et al. Comparison of PET imaging with a (68)Ga-labelled PSMA ligand and (18)F-choline-based PET/CT for the diagnosis of recurrent prostate cancer. Eur J Nucl Med Mol Imaging. 2014;41:11–20. doi:10.1007/s00259-013-2525-5.CrossRefPubMed

39.

Lavergne V, Ghannoum M, Christie M, et al. Risk factors and consequences of hyperaluminemia in a peritoneal dialysis cohort. Perit Dial Int. 2012;32:645–51. doi:10.3747/pdi.2011.00203.CrossRefPubMedPubMedCentral

Title: Synthesis and preclinical evaluation of an Al18F radiofluorinated GLU-UREA-LYS(AHX)-HBED-CC PSMA ligand
Authors: Stefano Boschi
Jason T. Lee
Seval Beykan
Roger Slavik
Liu Wei
Claudio Spick
Uta Eberlein
Andreas K. Buck
Filippo Lodi
Gianfranco Cicoria
Johannes Czernin
Michael Lassmann
Stefano Fanti
Ken Herrmann
Publication date: 01-11-2016
Publisher: Springer Berlin Heidelberg
Published in: European Journal of Nuclear Medicine and Molecular Imaging / Issue 12/2016
Print ISSN: 1619-7070
Electronic ISSN: 1619-7089
DOI: https://doi.org/10.1007/s00259-016-3437-y

At a glance: The STEP trials

Springer Medicine

Synthesis and preclinical evaluation of an Al¹⁸F radiofluorinated GLU-UREA-LYS(AHX)-HBED-CC PSMA ligand

Abstract

Purpose

Methods

Results

Conclusion

At a glance: The STEP trials

Springer Medicine

Abstract

Purpose

Methods

Results

Conclusion

Please log in to get access to this content

Other articles of this Issue 12/2016

TLG-S criteria are superior to both EORTC and PERCIST for predicting outcomes in patients with metastatic lung adenocarcinoma treated with erlotinib

ImmunoPET for assessing the differential uptake of a CD146-specific monoclonal antibody in lung cancer

ImmunoPET to help stratify patients for targeted therapies and to improve drug development

99mTc-DPD-scintigraphy with intense uptake in fat tissue caused by AL-amyloidosis

Comparison of bone scintigraphy and 68Ga-PSMA PET for skeletal staging in prostate cancer

Comments on Van den Wyngaert et al., The EANM practice guidelines for bone scintigraphy