title: 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 antagonist with 99mTc.
abstract: A hydrazinonicotinamide-functionalized cyclic glycoprotein IIb/IIIa (GPIIb/IIIa) receptor antagonist [cyclo(D-Val-NMeArg-Gly-Asp-Mamb(5-(6-(6-hydrazinonicotin amido)hexanamide))) (HYNICtide)] was labeled with 99mTc using tricine and a water soluble phosphine [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 canine arteriovenous shunt (AV shunt) model and canine deep vein thrombosis imaging (DVT) model. All three agents were adequately incorporated into the arterial and venous portions of the growing thrombus (7.8-9.9 and 0.2-3.7% ID/g, respectively) in the canine AV shunt model. In the canine DVT model all three complexes had thrombus uptake that far exceeded the negative control, [99mTc]albumin. The findings indicate similar incorporation into a venous thrombus (% ID/g = 2.86 +/- 0.4, 3.4 +/- 0.9, and 3.38 +/- 1.1 for complexes 1, 2, and 3, respectively) and similar blood clearance with a t1/2 of approximately 90 min. Gamma camera scintigraphy allowed visualization of deep vein thrombosis in as little as 15 min with the thrombus/muscle ratios being 3.8 +/- 0.8, 2.8 +/- 0.4, and 3.0 +/- 0.8 for complexes 1, 2, and 3, respectively. The visualization of the thrombus improved over time, and the thrombus/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. The administration of complexes 1-3 did not alter platelet function, hemodynamics, or the coagulation cascade. Furthermore, complexes 1-3 did not significantly differ in their uptake into the growing thrombus, blood clearance, and target to background ratios. Therefore, all three complexes have the capability to detect rapidly growing venous and arterial thrombi.
authors.affiliation: DuPont Merck Pharmaceutical Company, Radiopharmaceuticals Division, North Billerica, Massachusetts 01862, USA.
authors.forename: J A
authors.initials: JA
authors.lastname: Barrett
authors.forename: A C
authors.initials: AC
authors.lastname: Crocker
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: J L
authors.initials: JL
authors.lastname: Lazewatsky
authors.forename: M
authors.initials: M
authors.lastname: Kagan
authors.forename: T J
authors.initials: TJ
authors.lastname: Mazaika
authors.forename: T R
authors.initials: TR
authors.lastname: Carroll
mesh_terms: D000818:Animals; D001792:Blood Platelets / Q000000981:diagnostic imaging / Q000378:metabolism; D004285:Dogs; D005260:Female; D005340:Fibrinogen / Q000378:metabolism; D005998:Glycine / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000737:chemistry; D006439:Hemodynamics; D006834:Hydrazines / Q000138:chemical synthesis / Q000737:chemistry; D066298:In Vitro Techniques; D008024:Ligands; D008297:Male; D015394:Molecular Structure; D009536:Niacinamide / Q000138:chemical synthesis / Q000737:chemistry; D015609:Organotechnetium Compounds / Q000138:chemical synthesis* / Q000737:chemistry; D010720:Phosphines / Q000138:chemical synthesis / Q000737:chemistry; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000037:antagonists & inhibitors*; D011877:Radionuclide Imaging; D012995:Solubility; D013927:Thrombosis / Q000097:blood / Q000000981:diagnostic imaging* / Q000503:physiopathology; D014867:Water
chemical_list: D006834:Hydrazines; D008024:Ligands; D015609:Organotechnetium Compounds; D010720:Phosphines; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D014867:Water; D009536:Niacinamide; D005340:Fibrinogen; D005998:Glycine; C100184:tricine