Purpose Stability of radiolabeled cholecystokinin 2 (CCK2) receptor targeting peptides has been a major limitation in the use of such radiopharmaceuticals esp. for targeted radionuclide therapy applications, e.g. for treatment of medullary thyroid carcinoma (MTC). The purpose of this study was to compare the in vitro stability of a series of peptides binding to the CCK2 receptor [selected as part of the COST Action on Targeted Radionuclide Therapy (BM0607)] and to identify major cleavage sites. Methods Twelve different 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid (DOTA)-minigastrin/CCK conjugates were provided within an European COST Action (BM0607) by different labs. and radiolabeled with 177Lu. Their in vitro stabilities were tested in fresh human serum. Radiochem. yields (RCY) and intact radioligands for half-life calcns. were detd. by radio-HPLC. Matrix-assisted laser desorption/ionisation time-of-flight mass spectrometry (MALDI-TOF MS) anal. of metabolites was performed to identify cleavage products using conjugates labeled with excess stable natLu, incubated in serum at 37°C. Urine metabolite anal. after injection in normal mice was performed by radio-HPLC anal. Results Variable stability in human serum was found for the different peptides with calcd. half-lives between 4.5 ± 0.1 h and 198 ± 0.1 h (n = 2). In urine of normal mice only metabolised peptide fragments were detected even at short times after injection for all peptides. MALDI-TOF MS revealed a major cleavage site of all minigastrin derivs. between Asp and Phe-NH2 at the C-terminal end. Conclusion Development of CCK2 receptor ligands esp. for therapeutic purposes in patients with MTC or small cell lung cancer (SCLC) is still ongoing in different labs. This comparative study provided valuable insight into the importance of biol. stability esp. in the context of other results of this comparative trial within the COST Action BM0607.

Comparison of biological stability and metabolism of CCK2 receptor targeting peptides, a collaborative project under COST BM0607 / M., Ocak; A., Helbok; C., Rangger; Peitl, P. K.; B., Nock; Morelli, Giancarlo; A., Eek; Sosabowski, J. K.; Breeman, W. A. P.; Reubi, J. C.; C., Decristoforo. - In: EUROPEAN JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING. - ISSN 1619-7089. - 38:8(2011), pp. 1426-1435. [10.1007/s00259-011-1818-9]

Comparison of biological stability and metabolism of CCK2 receptor targeting peptides, a collaborative project under COST BM0607

MORELLI, GIANCARLO;
2011

Abstract

Purpose Stability of radiolabeled cholecystokinin 2 (CCK2) receptor targeting peptides has been a major limitation in the use of such radiopharmaceuticals esp. for targeted radionuclide therapy applications, e.g. for treatment of medullary thyroid carcinoma (MTC). The purpose of this study was to compare the in vitro stability of a series of peptides binding to the CCK2 receptor [selected as part of the COST Action on Targeted Radionuclide Therapy (BM0607)] and to identify major cleavage sites. Methods Twelve different 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid (DOTA)-minigastrin/CCK conjugates were provided within an European COST Action (BM0607) by different labs. and radiolabeled with 177Lu. Their in vitro stabilities were tested in fresh human serum. Radiochem. yields (RCY) and intact radioligands for half-life calcns. were detd. by radio-HPLC. Matrix-assisted laser desorption/ionisation time-of-flight mass spectrometry (MALDI-TOF MS) anal. of metabolites was performed to identify cleavage products using conjugates labeled with excess stable natLu, incubated in serum at 37°C. Urine metabolite anal. after injection in normal mice was performed by radio-HPLC anal. Results Variable stability in human serum was found for the different peptides with calcd. half-lives between 4.5 ± 0.1 h and 198 ± 0.1 h (n = 2). In urine of normal mice only metabolised peptide fragments were detected even at short times after injection for all peptides. MALDI-TOF MS revealed a major cleavage site of all minigastrin derivs. between Asp and Phe-NH2 at the C-terminal end. Conclusion Development of CCK2 receptor ligands esp. for therapeutic purposes in patients with MTC or small cell lung cancer (SCLC) is still ongoing in different labs. This comparative study provided valuable insight into the importance of biol. stability esp. in the context of other results of this comparative trial within the COST Action BM0607.
2011
Comparison of biological stability and metabolism of CCK2 receptor targeting peptides, a collaborative project under COST BM0607 / M., Ocak; A., Helbok; C., Rangger; Peitl, P. K.; B., Nock; Morelli, Giancarlo; A., Eek; Sosabowski, J. K.; Breeman, W. A. P.; Reubi, J. C.; C., Decristoforo. - In: EUROPEAN JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING. - ISSN 1619-7089. - 38:8(2011), pp. 1426-1435. [10.1007/s00259-011-1818-9]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11588/486566
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