Gastrin-releasing peptide receptor-based targeting using bombesin analogues is superior to metabolism-based targeting using choline for in vivo imaging of human prostate cancer xenografts
Prostate cancer (PC) is a major health problem. Overexpression of the gastrin-releasing peptide receptor (GRPR) in PC, but not in the hyperplastic prostate, provides a promising target for staging and monitoring of PC. Based on the assumption that cancer cells have increased metabolic activity, metabolism-based tracers are also being used for PC imaging. We compared GRPR-based targeting using the 68Ga-labelled bombesin analogue AMBA with metabolism-based targeting using 18F-methylcholine (18F-FCH) in nude mice bearing human prostate VCaP xenografts.
PET and biodistribution studies were performed with both 68Ga-AMBA and 18F-FCH in all VCaP tumour-bearing mice, with PC-3 tumour-bearing mice as reference. Scanning started immediately after injection. Dynamic PET scans were reconstructed and analysed quantitatively. Biodistribution of tracers and tissue uptake was expressed as percent of injected dose per gram tissue (%ID/g).
All tumours were clearly visualized using 68Ga-AMBA. 18F-FCH showed significantly less contrast due to poor tumour-to-background ratios. Quantitative PET analyses showed fast tumour uptake and high retention for both tracers. VCaP tumour uptake values determined from PET at steady-state were 6.7 ± 1.4%ID/g (20–30 min after injection, N = 8) for 68Ga-AMBA and 1.6 ± 0.5%ID/g (10–20 min after injection, N = 8) for 18F-FCH, which were significantly different (p <0.001). The results in PC-3 tumour-bearing mice were comparable. Biodistribution data were in accordance with the PET results showing VCaP tumour uptake values of 9.5 ± 4.8%ID/g (N = 8) for 68Ga-AMBA and 2.1 ± 0.4%ID/g (N = 8) for 18F-FCH. Apart from the GRPR-expressing organs, uptake in all organs was lower for 68Ga-AMBA than for 18F-FCH.
Tumour uptake of 68Ga-AMBA was higher while overall background activity was lower than observed for 18F-FCH in the same PC-bearing mice. These results suggest that peptide receptor-based targeting using the bombesin analogue AMBA is superior to metabolism-based targeting using choline for scintigraphy of PC.
- Jemal A, Siegel R, Ward E, Hao Y, Xu J, Thun MJ. Cancer statistics, 2009. CA Cancer J Clin. 2009;59(4):225–49. CrossRef
- Brawley OW. Prostate cancer screening; is this a teachable moment? J Natl Cancer Inst. 2009;101(19):1295–7. CrossRef
- Welch HG, Albertsen PC. Prostate cancer diagnosis and treatment after the introduction of prostate-specific antigen screening: 1986–2005. J Natl Cancer Inst. 2009;101(19):1325–9. CrossRef
- Castellucci P, Fuccio C, Nanni C, Santi I, Rizzello A, Lodi F, et al. Influence of trigger PSA and PSA kinetics on 11C-choline PET/CT detection rate in patients with biochemical relapse after radical prostatectomy. J Nucl Med. 2009;50(9):1394–400. CrossRef
- Jana S, Blaufox MD. Nuclear medicine studies of the prostate, testes, and bladder. Semin Nucl Med. 2006;36(1):51–72. CrossRef
- Yu KK, Hricak H. Imaging prostate cancer. Radiol Clin North Am. 2000;38(1):59–85. viii. CrossRef
- Markwalder R, Reubi JC. Gastrin-releasing peptide receptors in the human prostate: relation to neoplastic transformation. Cancer Res. 1999;59(5):1152–9.
- Schroeder RP, van Weerden WM, Bangma C, Krenning EP, de Jong M. Peptide receptor imaging of prostate cancer with radiolabelled bombesin analogues. Methods. 2009;48(2):200–4. CrossRef
- Lantry LE, Cappelletti E, Maddalena ME, Fox JS, Feng W, Chen J, et al. 177Lu-AMBA: synthesis and characterization of a selective 177Lu-labeled GRP-R agonist for systemic radiotherapy of prostate cancer. J Nucl Med. 2006;47(7):1144–52.
- Schroeder RP, Muller C, Reneman S, Melis ML, Breeman WA, de Blois E, et al. A standardised study to compare prostate cancer targeting efficacy of five radiolabelled bombesin analogues. Eur J Nucl Med Mol Imaging. 2010;37(7):1386–96. doi:10.1007/s00259-010-1388-2. CrossRef
- Jager PL, de Korte MA, Lub-de Hooge MN, van Waarde A, Koopmans KP, Perik PJ, et al. Molecular imaging: what can be used today. Cancer Imaging. 2005;5(Spec No A):S27–32. CrossRef
- Cook GJ. Oncological molecular imaging: nuclear medicine techniques. Br J Radiol. 2003;76(Spec No 2):S152–8. CrossRef
- Effert PJ, Bares R, Handt S, Wolff JM, Bull U, Jakse G. Metabolic imaging of untreated prostate cancer by positron emission tomography with 18fluorine-labeled deoxyglucose. J Urol. 1996;155(3):994–8. CrossRef
- Hofer C, Laubenbacher C, Block T, Breul J, Hartung R, Schwaiger M. Fluorine-18-fluorodeoxyglucose positron emission tomography is useless for the detection of local recurrence after radical prostatectomy. Eur Urol. 1999;36(1):31–5. CrossRef
- de Jong IJ, Pruim J, Elsinga PH, Vaalburg W, Mensink HJ. Preoperative staging of pelvic lymph nodes in prostate cancer by 11C-choline PET. J Nucl Med. 2003;44(3):331–5.
- Kotzerke J, Volkmer BG, Glatting G, van den Hoff J, Gschwend JE, Messer P, et al. Intraindividual comparison of [11C]acetate and [11C]choline PET for detection of metastases of prostate cancer. Nuklearmedizin. 2003;42(1):25–30.
- Kotzerke J, Volkmer BG, Neumaier B, Gschwend JE, Hautmann RE, Reske SN. Carbon-11 acetate positron emission tomography can detect local recurrence of prostate cancer. Eur J Nucl Med Mol Imaging. 2002;29(10):1380–4. CrossRef
- Nanni C, Castellucci P, Farsad M, Rubello D, Fanti S. 11C/18F-choline PET or 11C/18F-acetate PET in prostate cancer: may a choice be recommended? Eur J Nucl Med Mol Imaging. 2007;34(10):1704–5. CrossRef
- Price DT, Coleman RE, Liao RP, Robertson CN, Polascik TJ, DeGrado TR. Comparison of [18F]fluorocholine and [18F]fluorodeoxyglucose for positron emission tomography of androgen dependent and androgen independent prostate cancer. J Urol. 2002;168(1):273–80. CrossRef
- Shindou H, Hishikawa D, Harayama T, Yuki K, Shimizu T. Recent progress on acyl CoA: lysophospholipid acyltransferase research. J Lipid Res. 2009;50(Suppl):S46–51. CrossRef
- Warden CH, Friedkin M. Regulation of phosphatidylcholine biosynthesis by mitogenic growth factors. Biochim Biophys Acta. 1984;792(3):270–80.
- Warden CH, Friedkin M. Regulation of choline kinase activity and phosphatidylcholine biosynthesis by mitogenic growth factors in 3T3 fibroblasts. J Biol Chem. 1985;260(10):6006–11.
- Ackerstaff E, Pflug BR, Nelson JB, Bhujwalla ZM. Detection of increased choline compounds with proton nuclear magnetic resonance spectroscopy subsequent to malignant transformation of human prostatic epithelial cells. Cancer Res. 2001;61(9):3599–603.
- Kwee SA, DeGrado TR, Talbot JN, Gutman F, Coel MN. Cancer imaging with fluorine-18-labeled choline derivatives. Semin Nucl Med. 2007;37(6):420–8. CrossRef
- Belloli S, Jachetti E, Moresco RM, Picchio M, Lecchi M, Valtorta S, et al. Characterization of preclinical models of prostate cancer using PET-based molecular imaging. Eur J Nucl Med Mol Imaging. 2009;36(8):1245–55. doi:10.1007/s00259-009-1091-3. CrossRef
- Zheng QH, Gardner TA, Raikwar S, Kao C, Stone KL, Martinez TD, et al. [11C]Choline as a PET biomarker for assessment of prostate cancer tumour models. Bioorg Med Chem. 2004;12(11):2887–93. doi:10.1016/j.bmc.2004.03.051. CrossRef
- DeGrado TR, Baldwin SW, Wang S, Orr MD, Liao RP, Friedman HS, et al. Synthesis and evaluation of (18)F-labeled choline analogs as oncologic PET tracers. J Nucl Med. 2001;42(12):1805–14.
- Korenchuk S, Lehr JE, MClean L, Lee YG, Whitney S, Vessella R et al. VCaP, a cell-based model system of human prostate cancer. In Vivo. 2001;15(2):163–8.
- Kaighn ME, Narayan KS, Ohnuki Y, Lechner JF, Jones LW. Establishment and characterization of a human prostatic carcinoma cell line (PC-3). Invest Urol. 1979;17(1):16–23.
- Breeman WA, de Jong M, de Blois E, Bernard BF, Konijnenberg M, Krenning EP. Radiolabelling DOTA-peptides with 68Ga. Eur J Nucl Med Mol Imaging. 2005;32(4):478–85. CrossRef
- Decristoforo C, Knopp R, von Guggenberg E, Rupprich M, Dreger T, Hess A, et al. A fully automated synthesis for the preparation of 68Ga-labelled peptides. Nucl Med Commun. 2007;28(11):870–5. CrossRef
- 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(3):347–52. CrossRef
- Buck AK, Herrmann K, Shen C, Dechow T, Schwaiger M, Wester HJ. Molecular imaging of proliferation in vivo: positron emission tomography with [18F]fluorothymidine. Methods. 2009;48(2):205–15. CrossRef
- Jensen RT, Battey JF, Spindel ER, Benya RV. International Union of Pharmacology. LXVIII. Mammalian bombesin receptors: nomenclature, distribution, pharmacology, signaling, and functions in normal and disease states. Pharmacol Rev. 2008;60(1):1–42. CrossRef
- Cescato R, Maina T, Nock B, Nikolopoulou A, Charalambidis D, Piccand V, et al. Bombesin receptor antagonists may be preferable to agonists for tumour targeting. J Nucl Med. 2008;49(2):318–26. doi:10.2967/jnumed.107.045054. CrossRef
- Garrison JC, Rold TL, Sieckman GL, Naz F, Sublett SV, Figueroa SD, et al. Evaluation of the pharmacokinetic effects of various linking group using the 111In-DOTA-X-BBN(7-14)NH2 structural paradigm in a prostate cancer model. Bioconjug Chem. 2008;19(9):1803–12. CrossRef
- Ebenhan T, Honer M, Ametamey SM, Schubiger PA, Becquet M, Ferretti S, et al. Comparison of [18F]-tracers in various experimental tumour models by PET imaging and identification of an early response biomarker for the novel microtubule stabilizer patupilone. Mol Imaging Biol. 2009;11(5):308–21. CrossRef
- Greco C, Cascini GL, Tamburrini O. Is there a role for positron emission tomography imaging in the early evaluation of prostate cancer relapse? Prostate Cancer Prostatic Dis. 2008;11(2):121–8. CrossRef
- Buscombe JR, Bombardieri E. Imaging cancer using single photon techniques. Q J Nucl Med Mol Imaging. 2005;49(2):121–31.
- Gastrin-releasing peptide receptor-based targeting using bombesin analogues is superior to metabolism-based targeting using choline for in vivo imaging of human prostate cancer xenografts
- Open Access
- Available under Open Access This content is freely available online to anyone, anywhere at any time.
European Journal of Nuclear Medicine and Molecular Imaging
Volume 38, Issue 7 , pp 1257-1266
- Cover Date
- Print ISSN
- Online ISSN
- Additional Links
- Positron emission tomography
- Prostatic neoplasms
- Xenograft model
- Metabolism-based tracer
- Industry Sectors
- Author Affiliations
- 1. Department of Nuclear Medicine, Erasmus MC, Rotterdam, The Netherlands
- 2. Department of Urology, Erasmus MC, Dr. Molenwaterplein 40, 3015 GE, Rotterdam, The Netherlands