Biological Evaluation of Thrombus Imaging Agents Utilizing Water Soluble Phosphines and Tricine as Coligands When Used To Label a Hydrazinonicotinamide-Modified Cyclic Glycoprotein IIb/IIIa Receptor A

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• 作者：John A. Barrett ; Andrew C. Crocker ; David J. Damphousse ; Stuart J. Heminway ; Shuang Liu ; D. Scott Edwards ; Joel L. Lazewatsky ; Mikhail Kagan ; Theresa J. Mazaika ; and Timothy R. Carroll
• 刊名：Bioconjugate Chemistry
• 出版年：1997
• 出版时间：March 1997
• 年：1997
• 卷：8
• 期：2
• 页码：155 - 160
• 全文大小：296K
• 年卷期：v.8,no.2(March 1997)
• ISSN：1520-4812

文摘

A hydrazinonicotinamide-functionalized cyclic glycoprotein IIb/IIIa(GPIIb/IIIa) receptor antagonist[cyclo(D-Val-NMeArg-Gly-Asp-Mamb(5-(6-(6-hydrazinonicotinamido)hexanamide)))(HYNICtide)] waslabeled with ^99mTc using tricine and a water solublephosphine [trisodium triphenylphosphine-3,3',3''-trisulfonate (TPPTS); disodium triphenylphosphine-3,3'-disulfonate(TPPDS); or sodium triphenylphosphine-3-monosulfonate (TPPMS)] as coligands. Three complexes,[^99mTc(HYNICtide)(L)(tricine)](1,L = TPPTS; 2, L = TPPDS;3, L = TPPMS), were evaluated in the caninearteriovenous shunt (AVshunt) model and canine deep vein thrombosis imaging (DVT) model.All three agents were adequatelyincorporated into the arterial and venous portions of the growingthrombus (7.8-9.9 and 0.2-3.7%ID/g, respectively) in the canine AV shunt model. In the canineDVT model all three complexes hadthrombus uptake that far exceeded the negative control,[^99mTc]albumin. The findings indicatesimilarincorporation into a venous thrombus (% ID/g = 2.86 ± 0.4, 3.4 ±0.9, and 3.38 ± 1.1 for complexes1, 2, and 3, respectively) and similarblood clearance with a t_1/2 of approximately90 min. Gammacamera scintigraphy allowed visualization of deep vein thrombosis in aslittle as 15 min with thethrombus/muscle ratios being 3.8 ± 0.8, 2.8 ± 0.4, and 3.0 ± 0.8for complexes 1, 2, and 3,respectively.The visualization of the thrombus improved over time, and thethrombus/muscle ratios were 9.7 ±1.9, 13.8 ± 3.6, and 9.4 ± 2 for complexes 1,2, and 3, respectively, at 120 min postinjection.Theadministration of complexes 1-3 did not alterplatelet function, hemodynamics, or the coagulationcascade. Furthermore, complexes 1-3 didnot significantly differ in their uptake into the growingthrombus, blood clearance, and target to background ratios.Therefore, all three complexes have thecapability to detect rapidly growing venous and arterialthrombi.