Biomedical subjects

Judit Bartis

Publications and source records attributed to Judit Bartis.

6 recordsLinked to original sources

PubMed2004

Preparation and characterization of [99TcO] apcitide: a technetium labeled peptide.

[99mTcO] apcitide (99mTcO(P246)), the technetium complex of the 13 amino acid, apcitide, cyclo-(D-Tyr-Apc-Gly-Asp-Cys)-Gly-Gly-Cys(Acm)-Gly-Cys(Acm)-Gly-Gly-Cys-NH2, where Apc is L-[S-(3-aminopropyl)]cysteine (an arginine mimetic) and Acm is the acetamidomethyl protecting group, has high affinity and selectivity for the GPIIb/IIIa receptor that is expressed on the membrane surface of activated platelets and plays an integral role in platelet aggregation and thrombus formation. Bibapcitide, a 26 amino acid, bis-succinimidomethyl ether-linked dimer of the peptide apcitide has been formulated as a single-vial, lyophilized kit having the trade name AcuTect. When sterile, nonpyrogenic sodium pertechnetate (99mTcO4-) in 0.9% sodium chloride is added to the AcuTect radiopharmaceutical kit and the resulting kit is heated, [99mTcO] apcitide forms. This is the first radiopharmaceutical to target acute deep vein thrombosis (DVT) in the lower extremities. We report here the preparation, purification, and isolation of the 99Tc complex of apcitide and its characterization to determine the mode of binding of Tc to apcitide. [99TcO] apcitide was prepared, on the macroscopic level, by reaction of [99TcOCl4]- with apcitide, purified by preparative HPLC and isolated as a trifluoroacetate salt. [99TcO] apcitide can also be formed from the reaction of bibapcitide and 99TcO4- in the presence of Sn(II) and glucoheptonate at 80 degrees C, conditions that mimic the radiopharmaceutical kit preparation. FTIR data show a Tc=O stretch at 961.2 cm(-1), in the range observed for anionic [TcVO]3+ amide thiolate complexes. The mass spectral data is in agreement with the formula, [C51H73O20N17S5Tc]-, consistent with retention of Acm groups and the Tc binding in the Gly11-Gly12-Cys13 region of the peptide. Despite significant spectral overlap due to numerous similar amino acids, all protons of apcitide and [99TcO] apcitide were unambiguously assigned. The observation of two nonequivalent Acm groups and the observation of only 10 NH-CH cross-peaks in the TOCSY and COSY spectra of [99TcO] apcitide (NH-CH cross-peaks were absent for Gly11-Gly12-Cys13), compared to all 13 cross-peaks found in apcitide, provided compelling evidence to support the 99Tc binding to the terminal Gly11-Gly12-Cys13 region of apcitide.

Amino Acid Sequence↗

PubMed2003

Design, synthesis, and evaluation of radiolabeled integrin alpha v beta 3 receptor antagonists for tumor imaging and radiotherapy.

The goal of this research is the development of tumor imaging and radiotherapeutic agents based on targeting of the integrin alpha(v)beta(3) (vitronectin receptor). Macrocyclic chelator DOTA has been conjugated to peptidomimetic vitronectin receptor antagonist SH066 to give TA138. TA138 and (89)Y-TA138 retain antagonist properties and high affinity for integrin alpha(v)beta(3) (IC(50) = 12 and 18 nM, respectively), and good selectivity versus integrin alpha(IIb)beta(3) (IC(50) > 10,000 nM). TA138 forms stable complexes with (111)In and (90)Y in > 95% RCP. (111)In-TA138 demonstrates high tumor uptake in the c-neu Oncomouse (Charles River Laboratories [Charles River, Canada]) mammary adenocarcinoma model (9.39% ID/g at 2 hours PI) and low background activity. Blood clearance is rapid and excretion is renal. Tumors are visible as early as 0.5 hours PI. Radiotherapy studies in the c-neu Oncomouse model demonstrated a slowing of tumor growth at a dose of 15 mCi/m(2), and a regression of tumors at a dose of 90 mCi/m(2).

Adenocarcinoma↗

PubMed2002

Lanthanide complexes of [alpha-2-P2W17O61]10-: solid state and solution studies.

We have isolated the 1:1 Ln:[alpha-2-P2W17O61]10- complexes for a series of lanthanides. The single-crystal X-ray structure of the Eu3+ analogue reveals two identical [Eu(H2O)3(alpha-2-P2W17O61)]7- moieties connected through two Eu-O-W bonds, one from each polyoxometalate unit. An inversion center relates the two polyoxometalate units. The Eu(III) ion is substituted for a [WO]4+ unit in the "cap" region of the tungsten-oxygen framework of the parent Wells-Dawson ion. The point group of the dimeric molecule is Ci. The extended structure is composed of the [Eu(H2O)3(alpha-2-P2W17O61)]214- anions linked together by surface-bound potassium cations. The space group is P, a = 12.7214(5) A, b = 14.7402(7) A, c = 22.6724(9) A, alpha = 71.550(3), beta = 84.019(3)degrees, gamma = 74.383(3), V = 3883.2(3) A3, Z = 1. The solution studies, including 183W NMR spectroscopy and luminescence lifetime measurements, show that the molecules dissociate in solution to form monomeric [Ln(H2O)4(alpha-2-P2W17O61)]7- species.

Chemical Phenomena↗

PubMed1999

Lanthanide Complexes of the alpha-1 Isomer of the [P(2)W(17)O(61)](10-) Heteropolytungstate: Preparation, Stoichiometry, and Structural Characterization by (183)W and (31)P NMR Spectroscopy and Europium(III) Luminescence Spectroscopy.

The alpha-1 and alpha-2 [P(2)W(17)O(61)](10)(-) isomers, derivatives of the Wells-Dawson molecule, [alpha-P(2)W(18)O(62)](6)(-), may be useful ligands for stabilizing high-valent metal ions and lanthanides and actinides. However, the potential utility of the [alpha1-P(2)W(17)O(61)](10)(-) ligand has not been realized. Specifically, for the lanthanides, the stoichiometry, structure, and purity of the lanthanide complexes of the [alpha1-P(2)W(17)O(61)](10)(-) isomer are ambiguous. We have prepared lanthanide (Ln) complexes of the [alpha1-P(2)W(17)O(61)](10)(-) isomer in >/=98% isomeric purity, according to (31)P NMR data. (183)W NMR data clearly showed, for the first time, that the C(1) symmetry of the [alpha1-P(2)W(17)O(61)](10)(-) lanthanide complexes was maintained in solution. We determined the stoichiometry of the lanthanide complexes of the [alpha1-P(2)W(17)O(61)](10)(-) isomer in solution by two different methods: a complexometric titration method and excited state lifetime measurements and luminescence titrations for the europium(III) analogue. All experiments show a 1:1 Ln:[alpha1-P(2)W(17)O(61)](10)(-) ratio. The (31)P NMR data showed that the lanthanides with smaller ionic radii (higher charge-size ratio) form stable complexes, even surviving crystallization from hot water. On the other hand, the lanthanum analogues were not stable in solutions of high lithium content. The tetrabutylammonium salt of the [Lu(alpha1-P(2)W(17)O(61))](7)(-) complex showed >/=98% isomeric purity and the C(1) symmetry required for a derivative of [alpha1-P(2)W(17)O(61)](10)(-). Also the tetrabutylammonium cation stabilized the [Lu(alpha1-P(2)W(17)O(61))](7)(-) complex; a mixed tetrabutylammonium, lithium salt was stable in water for weeks according to (31)P NMR spectroscopy.

Journal Article↗

PubMed1996

Preparation and Tungsten-183 NMR Characterization of [alpha-1-P(2)W(17)O(61)](10)(-), [alpha-1-Zn(H(2)O)P(2)W(17)O(61)](8)(-), and [alpha-2-Zn(H(2)O)P(2)W(17)O(61)](8)(-).

The preparation of the alpha-1 and alpha-2 isomers of the Wells-Dawson 17 tungsto derivatives by standard methods is accompanied by a significant proportion of the other isomer present as an impurity. In this study, the alpha-1 and alpha-2 isomers of [Zn(H(2)O)P(2)W(17)O(61)](8)(-) have been prepared in >98% purity by reacting isomerically pure K(9)Li[alpha-1-P(2)W(17)O(61)] and K(10)[alpha-2-P(2)W(17)O(61)], respectively, with ZnCl(2), while rigorously controlling the pH at 4.7. The molecules were isolated as potassium salts. For (183)W NMR and (31)P NMR characterization, both molecules were ion exchanged by cation-exchange chromatography, maintaining the pH at 4.7, to obtain the lithium salts. Removal of water and isolation of a solid sample of [alpha-1-Zn(H(2)O)P(2)W(17)O(61)](8)(-) was achieved by lyophilization at -40 degrees C. The chemical shift data from (31)P and (183)W NMR spectroscopy of the isolated [alpha-1-Zn(H(2)O)P(2)W(17)O(61)](8)(-) and [alpha-2-Zn(H(2)O)P(2)W(17)O(61)](8)(-) isomers are consistent with a mixture of the alpha-1 and alpha-2 isomers reported previously;(1) the molecules have the expected C(1) and C(s)() symmetry, respectively. The [alpha-1-Zn(H(2)O)P(2)W(17)O(61)](8)(-) isomer is stable in the pH range of 4.6-6 at temperatures <35 degrees C. Using the same ion exchange and lyophilization techniques, the lacunary [alpha-1-P(2)W(17)O(61)](10)(-) isomer was isolated as the lithium salt; characterization by (183)W NMR spectroscopy confirms the C(1) symmetry.

Journal Article↗

PubMedDate not supplied

Structure-activity relationships of 111In- and 99mTc-labeled quinolin-4-one peptidomimetics as ligands for the vitronectin receptor: potential tumor imaging agents.

The integrin receptor alpha(v)beta(3) is overexpressed on the endothelial cells of growing tumors and on some tumor cells themselves. Radiolabeled alpha(v)beta(3) antagonists have demonstrated potential application as tumor imaging agents and as radiotherapeutic agents. This report describes the total synthesis of eight new HYNIC and DOTA conjugates of receptor alpha(v)beta(3) antagonists belonging to the quinolin-4-one class of peptidomimetics, and their radiolabeling with (99m)Tc (for HYNIC) and (111)In (for DOTA). Tethering of the radionuclide-chelator complexes was achieved at two different sites on the quinolin-4-one molecule. All such derivatives maintained high affinity for receptor alpha(v)beta(3) and high selectivity versus receptors alpha(IIb)beta(3), alpha(v)beta(5), alpha(5)beta(1). Biodistribution of the radiolabeled compounds was evaluated in the c-neu Oncomouse mammary adenocarcinoma model. DOTA conjugate (111)In-TA138 presented the best biodistribution profile. Tumor uptake at 2 h postinjection was 9.39% of injected dose/g of tissue (%ID/g). Activity levels in selected organs was as follows: blood, 0.54% ID/g; liver, 1.94% ID/g; kidney, 2.33% ID/g; lung, 2.74% ID/g; bone, 1.56% ID/g. A complete biodistribution analysis of (111)In-TA138 and the other radiolabeled compounds of this study are presented and discussed. A scintigraphic imaging study with (111)In-TA138 showed a clear delineation of the tumors and rapid clearance of activity from nontarget tissues.

Adenocarcinoma↗