Synthesis and technetium-99m labeling of cyclic GP IIb/IIIa receptor antagonists conjugated to 4,5-bis(mercaptoacetamido)-pentanoic acid (mapt)

Bioorganic and Medicinal Chemistry Letters

Volumn 6, Issue 15, 1996, Pages 1737-1740

  Rajopadhye, Milind ^a   Edwards, D Scott ^a   Bourque, Jeffrey P ^a   Carroll, Timothy R ^a  

^a DUPONT COMPANY   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

4,5 BIS(MERCAPTOACETAMIDO)VALERIC ACID; CYCLOPEPTIDE; FIBRINOGEN RECEPTOR ANTAGONIST; TECHNETIUM 99M; UNCLASSIFIED DRUG; VALERIC ACID DERIVATIVE;

ARTICLE; CHELATION; DRUG SYNTHESIS; HIGH PERFORMANCE LIQUID CHROMATOGRAPHY; ISOTOPE LABELING; REACTION ANALYSIS; THROMBOSIS;

EID: 0030572483     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/0960-894X(96)00264-8     Document Type: Article

References (18)

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3. (c) Knight, L. K. J. Nuc. Med. 1993, 34, 554.
4. 2. Ojima, I.; Chakravarty, S.; Dong, Q. Bioorg. Med. Chem. 1995, 3, 337.
5. 3. Harris, T. D.; Barrett, J. A.; Bourque, J. P.; Carroll, T. R.; Damphousse, P. R.; Edwards, D. S.; Glowacka, D.; Liu, S.; Looby, R. J.; Poirier, M. J.; Rajopadhye, M.; Yu, K. J. Nucl. Med. 1994, 35, 245P.
6. 4. (a) Jackson, S.; DeGrado, W.; Dwivedi, A.; Parthasarathy, A.; Higley, A.; Krywko, J.; Rockwell, A.; Markwalder, J.; Wells, G.; Wexler, R.; Mousa, S.; Harlow, R. J. Am. Chem. Soc. 1994, 116, 3220.
7. (b) Wityak, J.; Fevig, J. M.; Jackson, S. A.; Johnson, A. L.; Mousa, S. M.; Parthasarathy, A.; Wells, G. J.; DeGrado, W. F.; Wexler, R. R. Bioorg. Med. Chem. Letters, 1995, 5, 2097.
8. 5. Barrett, J. A.; Damphousse, D. J.; Heminway, S. J.; Liu, S.; Edwards, D. S.; Looby, R. J.; Carroll, T. R. Bioconj. Chem. 1996, 7, 203. Compound 1 was actively incorporated into a growing thrombus (canine thrombus model) with images (gamma scintigraphy) clearly detectable. Thrombus/blood and thrombus/ muscle ratios at 2 h were approximately 7:1 and 10:1, respectively.
9. 6. Liu, S.; Edwards, D. S.; Looby, R. J.; Poirier, M. J.; Rajopadhye, M.; Bourque, J. P.; Carroll, T. R. Bioconj. Chem. 1996, 7, 196.
10. 7. (a) Fritzberg, A. R.; Abrams, P. G.; Beaumier, P. L.; Kasina, S.; Morgan, A. C.; Rao, T. N.; Reno, J. M.; Sanderson, J. A.; Srinivasan, A.; Wilbur, D. S. Proc. Natl. Acad. Sci. U.S.A. 1988, 85, 4025.
11. (b) Kasina, S.; Rao, T. N.; Srinivasan, A.; Sanderson, J. A.; Fitzner, J. N.; Reno, J. M.; Beaumier, P. L.; Fritzberg, A. R. J. Nucl. Med. 1991, 32, 1445.
12. (c) Rao, T. N.; Adhikesavalu, D.; Camerman, A.; Fritzberg, A. R. J. Am. Chem. Soc. 1990, 112, 5798.
13. 18 column (4.6 mm x 25 cm) at a flow rate of 1.0 mL/min.; a gradient mobile phase from 98% A (0.1% TFA in water) to 100% B (0.1% TFA in 90% acetonitrile, HPLC grade) at 45 min was used. UV detection was set at 220 nm.
14. 9. The authors wish to thank Danuta Glowacka and Thomas Harris for providing peptides (described in ref 3) 4 and 5, and Steven Johnson for peptide 2.
15. - in saline was obtained from a DuPont Merck Technelite® generator (eluate age < 2 h, prior elution < 24 h). A Glucoscan® kit contains 200 mg sodium glucoheptonate and 60 μg stannous chloride. Deionized water was obtained from a Millipore Milli-Q Water Purification System and was of > 18 MΩ quality.
16. 11. (a) Together with radio-HPLC, simultaneous detection by UV was also performed. The differences in the retention times, using the method described above, of the Tc-99m labeled mapt-peptide complexes and the unlabeled peptides (with or without mapt) is adequate for a facile separation. For example, in the indirect labeling method the mapt-peptide conjugates eluted about 2 min after the Tc-99m labeled mapt-peptide complexes (1 and 9). In the preformed chelate experiment described here, the unlabeled peptides (2 and 4) eluted 5-7 min prior to the Tc-99m mapt-peptide complexes.
17. (b) As discussed in ref 6 the diastereomers of the Tc-99m mapt-peptide complexes, arising from the use of racemic mapt and formation of a stereocenter at Tc(O), were not resolved under the HPLC conditions utilized. In all cases the diastereomeric mixture was evaluated in the canine thrombus model (described in ref 5).
18. (c) It should be noted that differences in the retention times of the mapt-peptide conjugates and the Tc-99m mapt-peptide complexes (and diastereomers) will vary depending on the peptide used.