Keywords: 111in, Cholecystokinin Receptors, Neuroendocrine Tumors, Peptides, Preclinical Studies, Cholecystokinin Octapeptide, Indium 111, Pentetate Indium In 111, Pentetic Acid, Cholecystokinin B Receptor, Diagnostic Agent, Drug Derivative, Indium Dtpa Glu G Cck8, Indium Dtpa-Glu-G-Cck8, Radiopharmaceutical Agent, Amino Terminal Sequence, Animal Experiment, Animal Model, Article, Controlled Study, Drug Clearance, Drug Distribution, Human, Human Cell, In Vitro Study, In Vivo Study, Incubation Time, Isotope Labeling, Ligand Binding, Mouse, Nonhuman, Priority Journal, Radioactivity, Tumor Xenograft, Cell Strain 3t3, Computer Assisted Emission Tomography, Evaluation, Metabolic Clearance Rate, Methodology, Nude Mouse, Scintiscanning, Squamous Cell Carcinoma, Tissue Distribution, Tumor Cell Line, 3t3 Cells, Sincalide, Emission-Computed,
Affiliations: *** IBB - CNR ***
Istituto di Biostrutture e Bioimmagini, Consiglio Nazionale Delle Ricerche, Naples, Italy
Dipartimento di Chimica Biologica, Centro Interuniversitario Per la Ricerca Sui Peptidi Bioattivi, Università Federico II, Naples, Italy
Istituto Nazionale Tumori, Fondazione G. Pascale, Naples, Italy
Dipartimento di Scienze Biomorfologiche e Funzionali, Universitá Federico II, Naples, Italy
References: Behr, T.M., Gotthardt, M., Barth, A., Behe, M., Imaging tumors with peptide-based radioligands (2001) Q J Nucl Med, 45, pp. 189-20
Kwekkeboom, D., Krenning, E.P., de Jong, M., Peptide receptor imaging and therapy (2000) J Nucl Med, 41, pp. 1704-1713
Virgolini, I., Raderer, M., Kurtaran, A., Vasoactive intestinal peptide-receptor imaging for the localization of intestinal adenocarcinomas and endocrine tumors (1994) N Engl J Med, 331, pp. 1116-1121
Reubi, J.C., Peptide receptors as molecular targets for cancer diagnosis and therapy (2003) Endocr Rev, 24, pp. 389-427
Wank, S.A., G protein-coupled receptors in gastrointestinal physiology. I. CCK receptors: An exemplary family (1998) Am J Physiol, 274, pp. G607-G613
Reubi, J.C., Schaer, J.C., Waser, B., Cholecystokinin(CCK)-A and CCK-B/gastrin receptors in human tumors (1997) Cancer Res, 57, pp. 1377-1386
Behr, T.M., Jenner, N., Radetzky, S., Targeting of cholecystokinin-B/ gastrin receptors in vivo: Preclinical and initial clinical evaluation of the diagnostic and therapeutic potential of radiolabelled gastrin (1998) Eur J Nucl Med, 25, pp. 424-430
Behr, T.M., Behe, M., Angerstein, C., Cholecystokinin-B/gastrin receptor binding peptides: Preclinical development and evaluation of their diagnostic and therapeutic potential (1999) Clin Cancer Res, 5 (SUPPL.), pp. 3124s-3138s
Behe, M., Becker, W., Gotthardt, M., Angerstein, C., Behr, T.M., Improved kinetic stability of DTPA-DGlu as compared with conventional monofunctional DTPA in chelating indium and yttrium: Preclinical and initial clinical evaluation of radiometal labelled minigastrin derivatives (2003) Eur J Nucl Med Mol Imaging, 30, pp. 1140-1146
Reubi, J.C., Waser, B., Schaer, J.C., Unsulfated DTPA- and DOTA-CCK analogs as specific high-affinity ligands for CCK-B receptor-expressing human and rat tissues in vitro and in vivo (1998) Eur J Nucl Med, 25, pp. 481-490
de Jong, M., Bakker, W.H., Bernard, B.F., Preclinical and initial clinical evaluation of 111In-labeled nonsulfated CCK8 analog: A peptide for CCK-B receptor-targeted scintigraphy and radionuclide therapy (1999) J Nucl Med, 40, pp. 2081-2087
Kwekkeboom, D.J., Bakker, W.H., Kooij, P.P., Cholecystokinin receptor imaging using an octapeptide DTPA-CCK analogue in patients with medullary thyroid carcinoma (2000) Eur J Nucl Med, 27, pp. 1312-1317
Gigoux, V., Maigret, B., Escrieut, C., Arginine 197 of the cholecystokinin-A receptor binding site interacts with the sulfate of the peptide agonist cholecystokinin (1999) Protein Sci, 8, pp. 2347-2354
Pellegrini, M., Mierke, D.F., Molecular complex of cholecystokinin-8 and N-terminus of the cholecystokinin A receptor by NMR spectroscopy (1999) Biochemistry, 38, pp. 14775-14783
Giragossian, C., Mierke, D.F., Intermolecular interactions between cholecystokinin-8 and the third extracellular loop of the cholecystokinin-2 receptor (2002) Biochemistry, 41, pp. 4560-4566
Anelli PL, Fedeli F, Gazzotti O, Lattuada L, Lux G, Rebasti F. L-Glutamic acid and L-lysine as useful building blocks for the preparation of bifunctional DTPA-like ligands. Bioconjug Chem. 1999
10:137-140Ito, M., Iwata, N., Taniguchi, T., Murayama, T., Chihara, K., Matsui, T., Functional characterization of two cholecystokinin-B/gastrin receptor isoforms: A preferential splice donor site in the human receptor gene (1994) Cell Growth Differ, 5, pp. 1127-1135
Giard, D.J., Aaronson, S.A., Todaro, G.J., In vitro cultivation of human tumors: Establishment of cell lines derived from a series of solid tumors (1973) J Natl Cancer Inst, 51, pp. 1417-1423
Fichna, J., Janecka, A., Synthesis of target-specific radiolabeled peptides for diagnostic imaging (2003) Bioconjug Chem, 14, pp. 3-17
Eckelman, W.C., The application of receptor theory to receptor-binding and enzyme-binding oncologic radiopharmaceuticals (1994) Nucl Med Biol, 21, pp. 759-769
Behr, T. M., Gotthardt, M., Barth, A., Behe, M., Imaging tumors with peptide-based radioligands (2001) Q J Nucl Med, 45, pp. 189-20
Reubi, J. C., Peptide receptors as molecular targets for cancer diagnosis and therapy (2003) Endocr Rev, 24, pp. 389-427
Wank, S. A., G protein-coupled receptors in gastrointestinal physiology. I. CCK receptors: An exemplary family (1998) Am J Physiol, 274, pp. G607-G613
Reubi, J. C., Schaer, J. C., Waser, B., Cholecystokinin (CCK) -A and CCK-B/gastrin receptors in human tumors (1997) Cancer Res, 57, pp. 1377-1386
Behr, T. M., Jenner, N., Radetzky, S., Targeting of cholecystokinin-B/ gastrin receptors in vivo: Preclinical and initial clinical evaluation of the diagnostic and therapeutic potential of radiolabelled gastrin (1998) Eur J Nucl Med, 25, pp. 424-430
Behr, T. M., Behe, M., Angerstein, C., Cholecystokinin-B/gastrin receptor binding peptides: Preclinical development and evaluation of their diagnostic and therapeutic potential (1999) Clin Cancer Res, 5 (SUPPL.), pp. 3124s-3138s
Reubi, J. C., Waser, B., Schaer, J. C., Unsulfated DTPA- and DOTA-CCK analogs as specific high-affinity ligands for CCK-B receptor-expressing human and rat tissues in vitro and in vivo (1998) Eur J Nucl Med, 25, pp. 481-490
Kwekkeboom, D. J., Bakker, W. H., Kooij, P. P., Cholecystokinin receptor imaging using an octapeptide DTPA-CCK analogue in patients with medullary thyroid carcinoma (2000) Eur J Nucl Med, 27, pp. 1312-1317
10: 137-140Ito, M., Iwata, N., Taniguchi, T., Murayama, T., Chihara, K., Matsui, T., Functional characterization of two cholecystokinin-B/gastrin receptor isoforms: A preferential splice donor site in the human receptor gene (1994) Cell Growth Differ, 5, pp. 1127-1135
Giard, D. J., Aaronson, S. A., Todaro, G. J., In vitro cultivation of human tumors: Establishment of cell lines derived from a series of solid tumors (1973) J Natl Cancer Inst, 51, pp. 1417-1423
Eckelman, W. C., The application of receptor theory to receptor-binding and enzyme-binding oncologic radiopharmaceuticals (1994) Nucl Med Biol, 21, pp. 759-769
In vitro and in vivo evaluation of In-111-DTPAGlu-G-CCK8 for cholecystokinin-B receptor imaging
UNLABELLED: Regulatory peptides and their analogs are being extensively investigated as radiopharmaceuticals for cancer imaging and therapy. Receptors of the cholecystokinin family have been shown to be overexpressed in different types of neuroendocrine tumors. The purposes of this study were to evaluate the cholecystokinin octapeptide amide (CCK8) peptide tagged with a diethylenetriaminepentaacetic acid derivative (DTPAGlu) and to test whether a (111) In-labeled conjugate ((111) In-DTPAGlu-G-CCK8, a derivative containing the chelating agent DTPAGlu bound through a glycine linker at the N-terminal end of the bioactive peptide CCK8) is suitable for cholecystokinin-B receptor (CCKBR) imaging.; METHODS: CCK8 was synthesized by solid-phase techniques and covalently coupled to DTPAGlu through a glycine linker at its amino terminus. The compound was labeled with (111) In. The radiochemical purity and stability of the compound were assessed by chromatographic methods. NIH-3T3 and A431 cells overexpressing CCKBR were used to characterize the in vitro properties of the compound. Nude mice bearing control and CCKBR-overexpressing A431 xenografts were used as an in vivo model.; RESULTS: DTPAGlu-G-CCK8 showed rapid and efficient labeling with (111) In. The radiolabeled conjugate showed specific binding to both cell lines overexpressing CCKBR. Binding was saturable, with a dissociation constant of approximately 20 nmol/L in both cell systems. Both cell lines showed internalization of the ligand after interaction with the receptor. Biodistribution studies showed rapid localization of (111) In-DTPAGlu-G-CCK8 on CCKBR-overexpressing A431 xenografts that was severalfold higher than that on control tumors at all time points tested. Unbound activity showed rapid clearance of over 80% through the kidneys by 30 min after injection. The labeled peptide conjugate was very stable in serum but showed a rapid breakdown after injection. Incubation with kidney homogenates suggested that most breakdown occurred in the kidneys, favoring the clearance of unbound activity.; CONCLUSION: Our findings indicate that the in vitro and in vivo characteristics of (111) In-DTPAGlu-G-CCK8 are favorable for CCKBR imaging, as the peptide shows high-affinity binding to the receptor, is internalized in CCKBR-expressing cells, and shows avid uptake in CCKBR-overexpressing xenografts, with rapid clearance of unbound radioactivity through the kidneys. Furthermore, the ease of synthesis, high labeling efficiency, and chemical stability of DTPAGlu make this chelating moiety an ideal candidate for widespread use in peptide radiolabeling for nuclear medicine applications
In vitro and in vivo evaluation of In-111-DTPAGlu-G-CCK8 for cholecystokinin-B receptor imaging
Aloj L, Aurilio M, Rinaldi V, D'Ambrosio L, Tesauro D, Peitl PK, Maina T, Mansi R, Von Guggenberg E, Joosten L, Sosabowski JK, Breeman WA, De Blois E, Koelewijn S, Melis M, Waser B, Beetschen K, Reubi JC, De Jong M * The EEE project(449 views) Proc Int Cosm Ray Conf Icrc Universidad Nacional Autonoma De Mexico, 2007; 5(HEPART2): 977-980. Impact Factor:0 ViewExport to BibTeXExport to EndNote