title: Biological evaluation of 99mTc-labeled cyclic glycoprotein IIb/IIIa receptor antagonists in the canine arteriovenous shunt and deep vein thrombosis models: effects of chelators on biological properties of [99mTc]chelator-peptide conjugates.
abstract: A series of 99mTc-labeled cyclic glycoprotein IIb/IIIa receptor antagonists, [99mTcO(L1-III)]-, [99mTcO-(L6-III)]-, [99mTcO(L1-V)]-, and [99mTcO(L6-V)]-, were evaluated in a canine arteriovenous (AV) shunt model for their potential use as thrombus imaging agents. The thrombus formed consists of a platelet-rich head and a fibrin-rich tail. All four agents were incorporated into the growing thrombus under both arterial (platelet-rich) and venous (platelet-poor) conditions. The rank order for uptake was [99mTcO(L1-V)]- > [99mTcO(L6-V)]- > [99mTcO(L6-III)]- > [99mTcO(L1-III)]- (arterial range, 5.8-0.47% id/g; venous range, 0.58-0.04% id/g). The uptakes of both [99mTcO(L6-III)]- and [99mTcO-(L1-III)]- under both arterial and venous conditions were not significantly greater than that of [99mTc]-albumin and [125I]fibrinogen. In contrast, the uptakes of both [99mTcO(L1-V)]- and [99mTcO(L6-V)]- were significantly greater than those of [99mTc]albumin and [125I]fibrinogen and comparable to that of [111In]platelets under both arterial and venous conditions. All four [99mTc]chelator-peptide conjugates are cleared faster than the controls with the clearance of the conjugates of peptide III faster than that of the conjugates of peptide V. The differences in incorporation are attributable to the effect of both the cyclic peptide and the chelator. The conjugate [99mTcO(L1-V)]- was also studied using a canine DVT (deep vein thrombosis) model. [99mTcO(L1-V)]- was actively incorporated into the growing thrombus with images clearly detectable within 15 min postinjection. At 2 h postinjection, thrombus/blood and thrombus/muscle ratios [region of interest (ROI)/background] were approximately 7/1 and 10/1, respectively. This clearly demonstrated that the conjugate [99mTcO(L1-V)]- has the potential for rapid diagnosis of thrombolic events occurring under both arterial and venous conditions.
authors.affiliation: Radiopharmaceuticals Division, Dupont Merck Pharmaceutical Company, North Billerica, Massachusetts 01862, USA.
authors.forename: J A
authors.initials: JA
authors.lastname: Barrett
authors.forename: D J
authors.initials: DJ
authors.lastname: Damphousse
authors.forename: S J
authors.initials: SJ
authors.lastname: Heminway
authors.forename: S
authors.initials: S
authors.lastname: Liu
authors.forename: D S
authors.initials: DS
authors.lastname: Edwards
authors.forename: R J
authors.initials: RJ
authors.lastname: Looby
authors.forename: T R
authors.initials: TR
authors.lastname: Carroll
mesh_terms: D000818:Animals; D001166:Arteriovenous Shunt, Surgical; D001792:Blood Platelets / Q000378:metabolism; D002614:Chelating Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D004285:Dogs; D005260:Female; D005340:Fibrinogen / Q000378:metabolism; D007553:Isotope Labeling; D008297:Male; D015394:Molecular Structure; D010456:Peptides, Cyclic / Q000493:pharmacokinetics; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000037:antagonists & inhibitors*; D011877:Radionuclide Imaging; D012709:Serum Albumin / Q000378:metabolism; D013670:Sodium Pertechnetate Tc 99m / Q000493:pharmacokinetics; D013924:Thrombophlebitis / Q000000981:diagnostic imaging* / Q000378:metabolism; D013927:Thrombosis / Q000000981:diagnostic imaging* / Q000378:metabolism
chemical_list: D002614:Chelating Agents; D010456:Peptides, Cyclic; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D012709:Serum Albumin; C099250:cyclic (arginyl-glycyl-aspartyl-phenylalanyl-lysyl); D005340:Fibrinogen; D013670:Sodium Pertechnetate Tc 99m