nach oben

European Journal of Nuclear Medicine and Molecular Imaging

Erschienen in:

02.12.2015 | Original Article

Preclinical and first clinical experience with the gastrin-releasing peptide receptor-antagonist [⁶⁸Ga]SB3 and PET/CT

verfasst von: Theodosia Maina, Hendrik Bergsma, Harshad R. Kulkarni, Dirk Mueller, David Charalambidis, Eric P. Krenning, Berthold A. Nock, Marion de Jong, Richard P. Baum

Erschienen in: European Journal of Nuclear Medicine and Molecular Imaging | Ausgabe 5/2016

Einloggen, um Zugang zu erhalten

Abstract

Purpose

Gastrin-releasing peptide receptors (GRPR) represent attractive targets for tumor diagnosis and therapy because of their overexpression in major human cancers. Internalizing GRPR agonists were initially proposed for prolonged lesion retention, but a shift of paradigm to GRPR antagonists has recently been made. Surprisingly, radioantagonists, such as [^99mTc]DB1 (^99mTc-N₄′-DPhe⁶,Leu-NHEt¹³]BBN(6–13)), displayed better pharmacokinetics than radioagonists, in addition to their higher inherent biosafety. We introduce here [⁶⁸Ga]SB3, a [^99mTc]DB1 mimic-carrying, instead of the ^99mTc-binding tetraamine, the chelator DOTA for labeling with the PET radiometal ⁶⁸Ga.

Methods

Competition binding assays of SB3 and [^natGa]SB3 were conducted against [¹²⁵I-Tyr⁴]BBN in PC-3 cell membranes. Blood samples collected 5 min postinjection (pi) of the [⁶⁷Ga]SB3 surrogate in mice were analyzed using high-performance liquid chromatography (HPLC) for degradation products. Likewise, biodistribution was performed after injection of [⁶⁷Ga]SB3 (37 kBq, 100 μL, 10 pmol peptide) in severe combined immunodeficiency (SCID) mice bearing PC-3 xenografts. Eventually, [⁶⁸Ga]SB3 (283 ± 91 MBq, 23 ± 7 nmol) was injected into 17 patients with breast (8) and prostate (9) cancer. All patients had disseminated disease and had received previous therapies. PET/CT fusion images were acquired 60–115 min pi.

Results

SB3 and [^natGa]SB3 bound to the human GRPR with high affinity (IC₅₀: 4.6 ± 0.5 nM and 1.5 ± 0.3 nM, respectively). [⁶⁷Ga]SB3 displayed good in vivo stability (>85 % intact at 5 min pi). [⁶⁷Ga]SB3 showed high, GRPR-specific and prolonged retention in PC-3 xenografts (33.1 ± 3.9%ID/g at 1 h pi – 27.0 ± 0.9%ID/g at 24 h pi), but much faster clearance from the GRPR-rich pancreas (≈160%ID/g at 1 h pi to <17%ID/g at 24 h pi) in mice. In patients, [⁶⁸Ga]SB3 elicited no adverse effects and clearly visualized cancer lesions. Thus, 4 out of 8 (50 %) breast cancer and 5 out of 9 (55 %) prostate cancer patients showed pathological uptake on PET/CT with [⁶⁸Ga]SB3.

Conclusion

[⁶⁷Ga]SB3 showed excellent pharmacokinetics in PC-3 tumor-bearing mice, while [⁶⁸Ga]SB3 PET/CT visualized lesions in about 50 % of patients with advanced and metastasized prostate and breast cancer. We expect imaging with [⁶⁸Ga]SB3 to be superior in patients with primary breast or prostate cancer.

Nur mit Berechtigung zugänglich

[99mTc]DB1

^99mTc-(N′₄)-DPhe-Gln-Trp-Ala-Val-Gly-His-Leu-NHEt)

[99mTc]DB4

^99mTc-N₄-Pro-Gln-Arg-Tyr-Gly-Asn-Gln-Trp-Ala-Val-Gly-His-Leu-Nle-NH₂

DOTA

1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid

Siegel R, Naishadham D, Jemal A. Cancer statistics, 2012. CA Cancer J Clin. 2012;62:10–29. doi:10.3322/caac.20138.CrossRefPubMed

DeSantis C, Siegel R, Bandi P, Jemal A. Breast cancer statistics, 2011. CA Cancer J Clin. 2011;61:409–18. doi:10.3322/caac.20134.CrossRefPubMed

Roehl KA, Antenor JA, Catalona WJ. Serial biopsy results in prostate cancer screening study. J Urol. 2002;167:2435–9.CrossRefPubMed

Elter M, Schulz-Wendtland R, Wittenberg T. The prediction of breast cancer biopsy outcomes using two CAD approaches that both emphasize an intelligible decision process. Med Phys. 2007;34:4164–72.CrossRefPubMed

Hricak H, Choyke PL, Eberhardt SC, Leibel SA, Scardino PT. Imaging prostate cancer: a multidisciplinary perspective. Radiology. 2007;243:28–53. doi:10.1148/radiol.2431030580.CrossRefPubMed

Berg WA, Gutierrez L, NessAiver MS, Carter WB, Bhargavan M, Lewis RS, et al. Diagnostic accuracy of mammography, clinical examination, US, and MR imaging in preoperative assessment of breast cancer. Radiology. 2004;233:830–49. doi:10.1148/radiol.2333031484.CrossRefPubMed

Jadvar H. Imaging evaluation of prostate cancer with ¹⁸F-fluorodeoxyglucose PET/CT: utility and limitations. Eur J Nucl Med Mol Imaging. 2013;40 (Suppl 1):S5–10. doi:10.1007/s00259-013-2361-7.CrossRefPubMed

Escalona S, Blasco JA, Reza MM, Andradas E, Gomez N. A systematic review of FDG-PET in breast cancer. Med Oncol. 2010;27:114–29. doi:10.1007/s12032-009-9182-3.CrossRefPubMed

Markwalder R, Reubi JC. Gastrin-releasing peptide receptors in the human prostate: relation to neoplastic transformation. Cancer Res. 1999;59:1152–9.PubMed

10.

Körner M, Waser B, Rehmann R, Reubi JC. Early over-expression of GRP receptors in prostatic carcinogenesis. Prostate. 2014;74:217–24. doi:10.1002/pros.22743.CrossRefPubMed

11.

Beer M, Montani M, Gerhardt J, Wild PJ, Hany TF, Hermanns T, et al. Profiling gastrin-releasing peptide receptor in prostate tissues: clinical implications and molecular correlates. Prostate. 2012;72:318–25. doi:10.1002/pros.21434.CrossRefPubMed

12.

Schroeder RP, de Visser M, van Weerden WM, de Ridder CM, Reneman S, Melis M, et al. Androgen-regulated gastrin-releasing peptide receptor expression in androgen-dependent human prostate tumor xenografts. Int J Cancer. 2010;126:2826–34. doi:10.1002/ijc.25000.PubMed

13.

Mather SJ, Nock BA, Maina T, Gibson V, Ellison D, Murray I, et al. GRP receptor imaging of prostate cancer using [^99mTc]Demobesin 4: a first-in-man study. Mol Imaging Biol. 2014;16:888–95. doi:10.1007/s11307-014-0754-z.CrossRefPubMed

14.

Gugger M, Reubi JC. Gastrin-releasing peptide receptors in non-neoplastic and neoplastic human breast. Am J Pathol. 1999;155:2067–76. doi:10.1016/S0002-9440(10)65525-3.CrossRefPubMedPubMedCentral

15.

Reubi C, Gugger M, Waser B. Co-expressed peptide receptors in breast cancer as a molecular basis for in vivo multireceptor tumour targeting. Eur J Nucl Med Mol Imaging. 2002;29:855–62. doi:10.1007/s00259-002-0794-5.CrossRefPubMed

16.

Halmos G, Wittliff JL, Schally AV. Characterization of bombesin/gastrin-releasing peptide receptors in human breast cancer and their relationship to steroid receptor expression. Cancer Res. 1995;55:280–7.PubMed

17.

Maina T, Nock B, Mather S. Targeting prostate cancer with radiolabelled bombesins. Cancer Imaging. 2006;6:153–7. doi:10.1102/1470-7330.2006.0025.CrossRefPubMedPubMedCentral

18.

Yu Z, Ananias HJ, Carlucci G, Hoving HD, Helfrich W, Dierckx RA, et al. An update of radiolabeled bombesin analogs for gastrin-releasing peptide receptor targeting. Curr Pharm Des. 2013;19:3329–41.CrossRefPubMed

19.

Cescato R, Maina T, Nock B, Nikolopoulou A, Charalambidis D, Piccand V, et al. Bombesin receptor antagonists may be preferable to agonists for tumor targeting. J Nucl Med. 2008;49:318–26. doi:10.2967/jnumed.107.045054.CrossRefPubMed

20.

Mansi R, Wang X, Forrer F, Kneifel S, Tamma ML, Waser B, et al. Evaluation of a 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid-conjugated bombesin-based radioantagonist for the labeling with single-photon emission computed tomography, positron emission tomography, and therapeutic radionuclides. Clin Cancer Res. 2009;15:5240–9. doi:10.1158/1078-0432.CCR-08-3145.CrossRefPubMed

21.

Bodei L, Ferrari M, Nunn A, Llull J, Cremonesi M, Martano L, et al. ¹⁷⁷Lu-AMBA bombesin analogue in hormone refractory prostate cancer patients: a phase I escalation study with single-cycle administrations. Eur J Nucl Med Mol Imaging. 2007;34:S221.

22.

Reile H, Armatis PE, Schally AV. Characterization of high-affinity receptors for bombesin/gastrin releasing peptide on the human prostate cancer cell lines PC-3 and DU-145: internalization of receptor bound ¹²⁵I-(Tyr⁴)bombesin by tumor cells. Prostate. 1994;25:29–38.CrossRefPubMed

23.

Nock BA, Nikolopoulou A, Galanis A, Cordopatis P, Waser B, Reubi JC, et al. Potent bombesin-like peptides for GRP-receptor targeting of tumors with ^99mTc: a preclinical study. J Med Chem. 2005;48:100–10. doi:10.1021/jm049437y.CrossRefPubMed

24.

Marsouvanidis PJ, Nock BA, Hajjaj B, Fehrentz JA, Brunel L, M'Kadmi C, et al. Gastrin releasing peptide receptor-directed radioligands based on a bombesin antagonist: synthesis, ¹¹¹In-labeling, and preclinical profile. J Med Chem. 2013;56:2374–84. doi:10.1021/jm301692p.CrossRefPubMed

25.

Marsouvanidis PJ, Maina T, Sallegger W, Krenning EP, de Jong M, Nock BA. Tumor diagnosis with new ¹¹¹In-radioligands based on truncated human gastrin releasing peptide sequences: synthesis and preclinical comparison. J Med Chem. 2013;56:8579–87. doi:10.1021/jm4010237.CrossRefPubMed

26.

Nock BA, Maina T, Krenning EP, de Jong M. “To serve and protect”: enzyme inhibitors as radiopeptide escorts promote tumor targeting. J Nucl Med. 2014;55:121–7. doi:10.2967/jnumed.113.129411.CrossRefPubMed

27.

Baum RP, Prasad V, Frischknecht M, Maecke H, Reubi J. Bombesin receptor imaging in various tumors: first results of Ga-68 AMBA PET/CT. Eur J Nucl Med Mol Imaging. 2007;34:S193-S.

28.

Linder KE, Metcalfe E, Arunachalam T, Chen J, Eaton SM, Feng W, et al. In vitro and in vivo metabolism of Lu-AMBA, a GRP-receptor binding compound, and the synthesis and characterization of its metabolites. Bioconjug Chem. 2009;20:1171–8. doi:10.1021/bc9000189.CrossRefPubMed

29.

Wieser G, Mansi R, Grosu AL, Schultze-Seemann W, Dumont-Walter RA, Meyer PT, et al. Positron emission tomography (PET) imaging of prostate cancer with a gastrin releasing peptide receptor antagonist—from mice to men. Theranostics. 2014;4:412–9. doi:10.7150/thno.7324.CrossRefPubMedPubMedCentral

30.

Kähkönen E, Jambor I, Kemppainen J, Lehtio K, Gronroos TJ, Kuisma A, et al. In vivo imaging of prostate cancer using [⁶⁸Ga]-labeled bombesin analog BAY86-7548. Clin Cancer Res. 2013;19:5434–43. doi:10.1158/1078-0432.CCR-12-3490.CrossRefPubMed

31.

Van de Wiele C, Phonteyne P, Pauwels P, Goethals I, Van den Broecke R, Cocquyt V, et al. Gastrin-releasing peptide receptor imaging in human breast carcinoma versus immunohistochemistry. J Nucl Med. 2008;49:260–4. doi:10.2967/jnumed.107.047167.CrossRefPubMed

32.

Shariati F, Aryana K, Fattahi A, Forghani MN, Azarian A, Zakavi SR, et al. Diagnostic value of ^99mTc-bombesin scintigraphy for differentiation of malignant from benign breast lesions. Nucl Med Commun. 2014;35:620–5. doi:10.1097/MNM.0000000000000112.CrossRefPubMed

33.

Scopinaro F, Di Santo GP, Tofani A, Massari R, Trotta C, Ragone M, et al. Fast cancer uptake of ^99mTc-labelled bombesin (^99mTc BN1). In Vivo. 2005;19:1071–6.PubMed

34.

Dalm SU, Martens JW, Sieuwerts AM, van Deurzen CH, Koelewijn SJ, de Blois E, et al. In-vitro and in-vivo application of radiolabeled gastrin releasing peptide receptor ligands in breast cancer. J Nucl Med. 2015;56:752–7. doi:10.2967/jnumed.114.153023.CrossRefPubMed

35.

Prignon A, Nataf V, Provost C, Cagnolini A, Montravers F, Gruaz-Guyon A, et al. ⁶⁸Ga-AMBA and ¹⁸F-FDG for preclinical PET imaging of breast cancer: effect of tamoxifen treatment on tracer uptake by tumor. Nucl Med Biol. 2015;42:92–8. doi:10.1016/j.nucmedbio.2014.10.003.CrossRefPubMed

36.

Beheshti M, Imamovic L, Broinger G, Vali R, Waldenberger P, Stoiber F, et al. ¹⁸F choline PET/CT in the preoperative staging of prostate cancer in patients with intermediate or high risk of extracapsular disease: a prospective study of 130 patients. Radiology. 2010;254:925–33. doi:10.1148/radiol.09090413.CrossRefPubMed

37.

Kitajima K, Murphy RC, Nathan MA. Choline PET/CT for imaging prostate cancer: an update. Ann Nucl Med. 2013;27:581–91. doi:10.1007/s12149-013-0731-7.CrossRefPubMed

38.

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

39.

Wright Jr GL, Grob BM, Haley C, Grossman K, Newhall K, Petrylak D, et al. Upregulation of prostate-specific membrane antigen after androgen-deprivation therapy. Urology. 1996;48:326–34.CrossRefPubMed

40.

Ristau BT, O'Keefe DS, Bacich DJ. The prostate-specific membrane antigen: lessons and current clinical implications from 20 years of research. Urol Oncol. 2014;32:272–9. doi:10.1016/j.urolonc.2013.09.003.CrossRefPubMedPubMedCentral

Titel: Preclinical and first clinical experience with the gastrin-releasing peptide receptor-antagonist [68Ga]SB3 and PET/CT
verfasst von: Theodosia Maina
Hendrik Bergsma
Harshad R. Kulkarni
Dirk Mueller
David Charalambidis
Eric P. Krenning
Berthold A. Nock
Marion de Jong
Richard P. Baum
Publikationsdatum: 02.12.2015
Verlag: Springer Berlin Heidelberg
Erschienen in: European Journal of Nuclear Medicine and Molecular Imaging / Ausgabe 5/2016
Print ISSN: 1619-7070
Elektronische ISSN: 1619-7089
DOI: https://doi.org/10.1007/s00259-015-3232-1

Springer Medizin

Abstract

Purpose

Methods

Results

Conclusion

Bitte loggen Sie sich ein, um Zugang zu diesem Inhalt zu erhalten

Weitere Artikel der Ausgabe 5/2016

Impact of consensus contours from multiple PET segmentation methods on the accuracy of functional volume delineation

Cancer theranostics with 64Cu/177Lu-loaded liposomes

In vivo biokinetic and metabolic characterization of the 68Ga-labelled α5β1-selective peptidomimetic FR366

Commentary on: “Occupational radiation exposure of medical staff performing 90Y-loaded microsphere radioembolization”

Diagnostic value of combining 11C-choline and 18F-FDG PET/CT in hepatocellular carcinoma

In vivo evaluation of PEGylated 64Cu-liposomes with theranostic and radiotherapeutic potential using micro PET/CT