Isolation, characterization, and biological evaluation of syn and anti diastereomers of [(99m)Tc]technetium depreotide: a somatostatin receptor binding tumor imaging agent.
The early and later eluting [(99m)TcO]depreotide products on RP-HPLC were confirmed to be the anti and syn diastereomers, respectively, based on proton NMR and circular dichroism spectroscopy. NMR provided evidence of a folded, conformationally constrained structure for the syn diastereomer. The syn diastereomer is predominant (anti/syn approximately 10:90) in the [(99m)TcO]depreotide preparation and shows a slightly higher affinity (IC50 = 0.15 nM) for the somatostatin receptor than the anti diastereomer (IC50 = 0.89 nM). Both diastereomers showed higher binding affinities than the free peptide (IC(50) = 7.4 nM). Biodistribution studies in AR42J tumor xenograft nude mice also showed higher tumor uptake for syn [(99m)TcO]depreotide (6.58% ID/g) than for the anti [(99m)TcO]depreotide (3.38% ID/g). Despite the differences in biological efficacy, the favorable binding affinity, tumor uptake, and tumor-to-background ratio results for both diastereomeric species predict that both are effective for imaging somatostatin receptor-positive tumors in vivo.
Cyr
John E
JE
Diatide Research Laboratories, 9 Delta Drive, Londonderry, New Hampshire 03053, USA. john.cyr@bayer.com
Pearson
Daniel A
DA
Nelson
Carol A
CA
Lyons
Barbara A
BA
Zheng
Yongyong
Y
Bartis
Judit
J
He
Jiafang
J
Cantorias
Melchor V
MV
Howell
Robertha C
RC
Francesconi
Lynn C
LC
D000818:Animals; D045744:Cell Line, Tumor; D002942:Circular Dichroism; D005260:Female; D007553:Isotope Labeling; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000000981:diagnostic imaging* / Q000378:metabolism; D015609:Organotechnetium Compounds / Q000737:chemistry / Q000302:isolation & purification* / Q000493:pharmacokinetics; D010190:Pancreatic Neoplasms; D011869:Radioligand Assay; D011877:Radionuclide Imaging; D019275:Radiopharmaceuticals / Q000737:chemistry / Q000302:isolation & purification* / Q000493:pharmacokinetics; D051381:Rats; D017481:Receptors, Somatostatin / Q000378:metabolism*; D013004:Somatostatin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000302:isolation & purification / Q000493:pharmacokinetics; D013237:Stereoisomerism; D014018:Tissue Distribution
D015609:Organotechnetium Compounds; D019275:Radiopharmaceuticals; D017481:Receptors, Somatostatin; D013004:Somatostatin; C444119:technetium Tc 99m depreotide
Eur J Nucl Med. 1994 Apr;21(4):328-35
7911760
Inorg Chem. 2007 Sep 3;46(18):7326-40
17691766
Horm Metab Res Suppl. 1993;27:12-7
8392486
Eur J Nucl Med. 1993 Aug;20(8):716-31
8404961
Metabolism. 1990 Sep;39(9 Suppl 2):78-81
2169575
J Med Chem. 1996 Mar 29;39(7):1361-71
8691466
Bioconjug Chem. 2001 Jul-Aug;12(4):630-4
11459469
Inorg Chem. 2004 May 3;43(9):2867-75
15106974
Inorg Chem. 1997 Dec 3;36(25):5799-5808
11670202
Inorg Chem. 1998 Jul 13;37(14):3517-3520
11670436
J Med Chem. 2005 Mar 10;48(5):1506-14
15743193
Int J Rad Appl Instrum A. 1987;38(8):661-4
2822624
Trends Endocrinol Metab. 1997 Dec;8(10):398-405
18406829
Cancer Res. 1998 May 1;58(9):1850-9
9581824
Bioconjug Chem. 2002 Jul-Aug;13(4):721-8
12121126
Eur J Nucl Med. 1998 Mar;25(3):277-305
9580862
Peptides. 1994;15(7):1229-36
7854974
Chest. 1999 Jan;115(1):224-32
9925088
Eur J Clin Invest. 1997 Aug;27(8):645-7
9279526
Inorg Chem. 2001 Oct 22;40(22):5695-700
11599972
Life Sci. 1984 Apr 2;34(14):1371-8
6143233
J Inorg Biochem. 1997 Mar;65(4):277-9
9046108
Inorg Chem. 2001 Jul 2;40(14):3555-61
11421705
Endocrine. 2003 Apr;20(3):307-11
12721512
Proc Natl Acad Sci U S A. 1998 Oct 27;95(22):12814-8
9788997
J Nucl Med. 1998 Nov;39(11):1928-36
9829585
Eur J Nucl Med. 2000 Mar;27(3):273-82
10774879
Life Sci. 1991;49(22):1583-91
1658515
Curr Med Chem. 2000 Sep;7(9):971-94
10911025
J Nucl Med. 2006 Jul;47(7):1144-52
16818949
J Nucl Med. 1990 Sep;31(9):1501-9
1975618
Eur J Nucl Med. 1999 Jul;26(7):693-8
10398816