Synthesis,plasma clearance,and in vitro stability of protein containing a conjugated indium-111 chelate

A new bifunctional chelating agent, N′-(p-diazoniumbenzyl)-N,N N″,N″-diethylenetri-aminetetraacetic acid (DTTA) was synthesized. The compound as coupled to methyl p-hydroxybenzimidate and the resulting azoimidate was attached to lysine residues of monomeric human serum albumin (HSA) via the amidination reaction. Blood clearnace of¹¹¹In-labelled DTTA conjugated to HSA (AAHSA) in rabbits was biphasic. The first phase has a clearance indistinguishable from that of¹²⁵I-labeled HSA. During the second phase, the¹¹¹In-labeled AAHSA was cleared more rapidly so that between 24 hours and 48 hours the percent of the injected dose of¹¹¹In-labeled AAHSA in the blood was significantly lower than that of¹²⁵I-labeled HSA. Highly conjugated¹¹¹In-labeled AAHSA (0.9 DTTA/HSA) showed accelerated clearance at 24 and 48 hours compared to lightly conjugated protein (<0.9 DTTA/HSA). As a result we postulate that the level of conjugation is the critical parameter controlling the blood clearance.     

Exchange labeling of proteins:99mTc labeled transferrin

^99mTc-labeled transferrin was prepared by reduction of^99mTcO ₄ ⁻ ; with stannous DTPA or stannous citrate followed by equilibration of the technetium chelate with human transferrin. The rate of transfer of^99mTc to transferrin in the presence of 0.015M citrate buffer was dependent on pH in the order pH 2.1> pH 7.2> pH 4.1> pH 5.9. The incorporation rate was inversely proportional to the concentration of DTPA and citrate buffer. The replacement of citrate buffer by acetate buffer or oxalate buffer reduced drastically the formation of^99mTc-labeled transferrin at pH 4.1. The formation of^99mTc-labeled transferrin prepared from the reduction of^99mTcO ₄ ⁻ with stannous citrate was faster than that from the reduction with stannous DTPA in the presence of 0.015M citrate buffer and pH 2.5. Equilibration of transferrin with^99mTc-labeled pyrophosphate did not produce^99mTc-labeled transferrin at pH 4.5. The ligand exchange labeling of^99mTc to transferrin in 0.015M citrate did not cause appreciable denaturation of the protein at all pH values. This method also enabled labeling of the protein in a low concentration (2.6·10⁻⁴ M) via tin reduction. Sequential external imaging of the^99mTc-labeled transferrin in Sprague-Dawley rats bearing Walker-256 carcinosarcoma showed optimal tumor localization occurred at 3 hr after injection. In spite of this,^99mTc-labeled transferrin does not appear to be a suitable imaging agent because of the low tumor to blood ratio of^99mTc (0.50±0.17) at 3 hr post injection. This is similar to that of^{6 7}Ga-citrate (0.43±0.15%).     

Direct analysis of whole blood by internal surface reversed-phase chromatography: an examination of the binding and metabolism of technetium dioxime complexes.

We have developed a method using internal surface reversed-phase (ISRP) packing for rapid on-line separation of small hydrophobic compounds from cellular whole blood components. This is achieved by the use of 75-microns ISRP chromatographic material packed into a small high-performance liquid chromatographic (HPLC) column, in conjunction with column switching. We have applied this analytical method to study the in vitro metabolism of 99mTc-BATO (boronic acid adducts of technetium dioxime) cerebral and myocardial perfusion tracers in whole blood. The results from the ISRP procedure were compared with a conventional centrifugation method of analysis. This novel HPLC methods provides a rapid, convenient and reliable method for the analysis of radioactive and non-radioactive lipophilic components in whole blood.     

Pharmacokinetic analysis of blood distribution of intravenously administered 153Gd-labeled Gd(DTPA)2- and 99mTc(DTPA) in rats

Rat plasma distribution data obtained following IV administration of 99mTc(DTPA) alone or after co-administration of 99mTc(DTPA) and 153Gd-labeled Gd(DTPA)2- at 0.001, 0.1, and 1.0 mmol Gd/kg were evaluated using compartmental modeling techniques. A three-compartment open model was found to fit the data significantly better (P less than 0.01) than a two- or four-compartment open model. This model incorporates and links the plasma and urine data and includes a delay to account for the transit time through the kidneys/ureters. The two nonplasma compartments of the model were assumed to be related to rapidly and slowly equilibrating tissues. Tc(DTPA) and Gd(DTPA)2- had nearly identical pharmacokinetic profiles in plasma and the rate constants were essentially the same. No significant dose dependent pharmacokinetic differences were found for the range of Gd(DTPA)2- doses tested. Simulations of the proposed three-compartment model were used to generate concentration-time curves for each of the three compartments.     

Size of the freeze-out source in high energy heavy ion collisions

Based on a hydro-inspired azimuthally symmetric emission function, we analyze the HBT radius Rs and the single-particle transverse momentum spectra in Au+Au collisions measured by the STAR Collaboration at SNN = 200 GeV. The results show that consistent assumptions about transverse density (and/or flow profile) in the calculation of the HBT radius Rs and single-particle spectral analyses play an important role for understanding the size of the freeze-out source.     

Periodic wavetrains for systems of coupled nonlinear Schrödinger equations

Exact, periodic wavetrains for systems of coupled nonlinear Schrödinger equations are obtained by the Hirota bilinear method and theta functions identities. Both the bright and dark soliton regimes are treated, and the solutions involve products of elliptic functions. The validity of these solutions is verified independently by a computer algebra software. The long wave limit is studied. Physical implications will be assessed.