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J R Ballinger

Publications and source records attributed to J R Ballinger.

86 records · Page 5Linked to original sources
PubMed1989

Technetium-99m dithiocarbamates as potential brain agents: evaluation of aliphatic and amine-containing analogues.

Technetium-99m forms a lipophilic complex with diethyldithiocarbamate (DDC) but this complex is not retained in the brain as is thallium-201 DDC. We therefore prepared a series of aliphatic and amine-containing analogues of DDC and evaluated the properties of their 99mTc complexes in vitro and in vivo. The ethyl acetate/buffer partition coefficients of the amine-containing derivatives showed a response to pH. Four of the five complexes were less stable than DDC in vitro and showed greater retention in rabbit brain. These agents warrant further investigation for cerebral perfusion imaging with SPECT.

Animals↗
PubMed1989

Clinical use of technetium-99m HM-PAO for determination of brain death.

We report our clinical experience with the use of [99mTc]hexamethyl propyleneamine oxime (HM-PAO) in establishing a diagnosis of brain death in 11 patients following trauma to the head and four patients who suffered atraumatic injuries. In 9/15 studies there was no intracranial flow present and brain death was then confirmed by standard criteria. Of the remaining 6/15 studies which showed evidence of cerebral perfusion, 3/6 patients underwent a subsequent HM-PAO study which showed cessation of perfusion. One additional patient died of pneumonia and two patients survived. Thus, in all cases where there was no flow present the diagnosis of brain death was later confirmed whereas three patients clinically thought to be brain dead showed significant perfusion and survived the cerebral trauma. HM-PAO may be useful in determination of brain death because it provides unequivocal results, can be performed by planar imaging at the bedside, and does not require withdrawal of medical therapy, thus allowing a diagnosis to be established more rapidly.

Brain↗
PubMed1988

Stabilization of stannous pyrophosphate kits with gentisic acid.

We evaluated the ability of gentisic acid, an antioxidant, to stabilize stannous pyrophosphate (Sn:PPi) kits and extend the shelf-life of the kit after reconstitution. In vitro studies showed that gentisic acid (0.5 mg/mL) stabilized the stannous ion against oxidation by various levels of exogenous hydrogen peroxide. In patients who received stabilized Sn:PPi for in vivo red blood cell labelling, the left ventricle-to-background activity ratio was significantly higher than that in patients who received a standard formation of Sn:PPi. Gentisic acid is now used routinely in the Sn:PPi kit formulation in this institution.

Drug Stability↗
PubMed1988

Technetium-99m red blood cell labeling in patients treated with doxorubicin.

Radionuclide angiography is useful in monitoring cardiotoxicity of doxorubicin, but in vivo RBC labeling in these patients is believed to be poorer than that in general patients. The left ventricle-to-background activity ratio (R) was not significantly lower in patients treated with doxorubicin (3.24 +/- 1.15, N = 13) than in control patients (3.89 +/- 1.60, N = 14). With both modified in vivo and in vitro labeling, R was significantly improved in patients treated with doxorubicin (4.37 +/- 0.91, N = 8, and 4.37 +/- 1.22, N = 13, respectively). However, with the modified in vivo method, labeling efficiency remained a function of hematocrit, whereas the in vitro method removed this dependency. Both modified in vivo and in vitro labeling result in improved image quality over in vivo labeling in patients treated with doxorubicin, and the choice of method can be based on other factors.

Doxorubicin↗
PubMed1988

Technetium-99m HM-PAO stereoisomers: differences in interaction with glutathione.

[99mTc]HM-PAO exists as two stereoisomers, d,1 and meso, only one of which is retained in the brain. It has been suggested recently that the biodistribution of [99mTc]d,1-HM-PAO can be explained by its interaction with glutathione (GSH) in the tissues. We studied the interactions of the d,1 and meso isomers with GSH in vitro by measuring the partitioning of activity between ethyl acetate and aqueous GSH solutions at various concentrations. Partitioning of both isomers demonstrated a sigmoidal relationship with GSH concentration, but the d,1 isomer showed eightfold greater reactivity than the meso isomer. In a separate experiment, the d,1 isomer showed a sevenfold greater interaction rate with GSH than the meso isomer. These results suggest that the stereoisomers of [99mTC]HM-PAO show differences in their interaction rate with GSH which may explain their different retention in the brain.

Glutathione↗
PubMed1987

Technetium-99m diethyldithiocarbamate (DDC): comparison with thallium-201 DDC as an agent for brain imaging.

Technetium-99m diethyldithiocarbamate (99mTc-DDC) was prepared by reduction of [99mTc]pertechnetate with formamidine sulfinic acid in the presence of DDC at alkaline pH, both from extemporaneous solutions and in a kit formulation. The properties of 99mTc-DDC were compared in vitro and in vivo with those of 201Tl-DDC, an agent used for cerebral perfusion imaging (CPI). 99mTc-DDC is a lipophilic complex but its oil/water partition coefficient is lower than that of 201Tl-DDC. 99mTc-DDC also shows greater binding to plasma proteins. Studies in rabbits show that 99mTc-DDC enters the brain but is not retained to the same extent as 201Tl-DDC. This lack of retention may be because 99mTc-DDC does not decompose rapidly in lipid media as 201Tl-DDC does. These results suggest that 99mTc-DDC in its present formulation is not suitable for CPI with SPECT.

Animals↗
PubMed1981

Decomposition of Tc-99m pyrophosphate by peroxides in pertechnetate used in preparation.

We describe an investigation of the stability of Tc-99m pyrophosphate (Tc-99m PPi). We hve shown that addition of exogenous hydrogen peroxide to Tc-99m PPi can initiate the oxidation of the complex, giving rise to 95% unbound pertechnetate. The presence of endogenous hydrogen peroxide in the sodium pertechnetate used in the preparation of Tc-99m PPi has been thought to influence its stability. We have prepared it using pertechnetate solutions of different specific activities. After preparation, an alumina column was used to detect free 99mTcO4-. The Tc-99m PPi and Na99mTcO4 solutions were then assayed by iodometric titration for hydrogen peroxide, which was detected in the pertechnetate solutions. The higher the specific activity of the solution used for the tracer preparation, the faster was the production of free pertechnetate.

Diphosphates↗
PubMedDate not supplied

Convenient preparation of no-carrier-added technetium-99m radiopharmaceuticals using solid-phase technology.

A solid-phase technetium chelation chemistry was developed as a means of preparing (99m)Tc radiopharmaceuticals at high effective specific activity (HSA). Three peptidic N(3)S (99m)Tc ligands [mercaptoacetyl-Gly-Gly-Gly (MAG3), picolinyl-Ser-Cys-Gly-Thr-Lys-Pro-Pro-Arg (RP063), and dimethyl-Gly-Ser-Cys-Gly-Thr-Lys-Pro-Pro-Arg (RP128)] were used. The free thiol of Cys in each was attached to a series of commercially available amine-functionalized supports in a two-step process. The amine groups on the solid supports were converted to maleimide groups followed by the attachment of the (99m)Tc chelators through a thiol ether linkage with Cys. The optimized loading of the supports ranged 6-122 micromol/g support as determined by amino acid analysis. Each of the peptide-loaded supports (50-100 mg) was placed in either glass syringe vessels or disposable chromatography columns. Labeling with [(99m)Tc]pertechnetate (200-800 MBq) in the presence of stannous gluconate was achieved at room temperature for 30-60 min or in a 100 degrees C water bath for 10 min. Up to 80% of the activity was eluted from the column with saline to give products with purity up to 99.8% as determined by HPLC. Amino acid analysis indicated as little as 100 pmol of peptide present in the (99m)Tc products, demonstrating that extremely high effective specific activity can be achieved without the need for purification.

Amino Acid Sequence↗
PubMedDate not supplied

Synthesis and evaluation of two technetium-99m-labeled peptidic 2-nitroimidazoles for imaging hypoxia.

The presence of hypoxic cells in solid tumors is a marker for therapy-resistant, aggressive disease. The noninvasive detection of hypoxic cells in tumors by radiolabeled 2-nitroimidazoles is a diagnostic technique under current evaluation. Two peptidic agents, dimethylglycyl-L-seryl-L-cysteinyl-lysyl{N(epsilon)-[1-(2-nitro-1H -im idazolyl)acetamido]}glycine (RP435) and dimethylglycyl-tert-butylglycyl-L-cysteinyl-glycine-[2-(2-ni tro-1H-im idazolyl)ethyl]amide (RP535) have been synthesized. Both agents contain an N(3)S class chelator for (99m)Tc and Re and a 2-nitroimidazole group which can be enzymatically reduced and selectively trapped in cells under hypoxic conditions. Two isomers of (99m)TcO-RP435, which are assumed to be syn and anti conformations, were observed on HPLC analysis. The interconversion of the two isomers in aqueous solution was investigated. In contrast, RP535 chelated (99m)Tc to form a single isomer and no conversion to its counterpart has been observed on HPLC analysis. The tert-butyl group on the chelator may inhibit the formation and interconversion of the syn and anti isomers of (99m)TcO-RP535. Both tracers showed a significant degree of hypoxia-specific accumulation in an in vitro assay, with (99m)TcO-RP535 showing higher selectivity for hypoxic cells than (99m)TcO-RP435. These results suggest that (99m)TcO-RP535 represents a lead compound worthy of further investigation as an agent for imaging hypoxia in tumors.

Animals↗
PubMedDate not supplied

Targeting hypoxia in tumors using 2-nitroimidazoles with peptidic chelators for technetium-99m: effect of lipophilicity.

Tumor hypoxia is an important prognostic factor for response to therapy. Radiolabeled 2-nitroimidazoles have been used for imaging hypoxia, and the octanol/water partition coefficient (P) of these compounds appears to play a crucial role in their suitability for imaging. A series of 11 2-nitroimidazoles coupled to peptidic chelators for (99m)Tc with divergent P was developed and evaluated in an in vitro system. Two classes of N(3)S chelators were used: dialkyl-Gly-Ser-Cys-linker-2-nitroimidazole (Class I) and dialkyl-Gly-Lys(2-nitroimidazole)-Cys (Class II). The chelators were prepared by automated solid-phase peptide synthesis. Xanthine oxidase was able to reduce the 2-nitroimidiazole moiety on the ligands, but the rate of reduction varied 5-fold among the different chelators. The chelators were labeled by transchelation from [(99m)Tc]gluconate at temperatures between 22 and 100 degrees C. The reaction mixtures were analyzed by HPLC and their P values determined. The accumulation of each complex in suspension cultures of Chinese hamster ovary cells incubated under aerobic or extremely hypoxic conditions was determined. Radiochemical yields ranged from 5 to 80% for the 11 compounds. HPLC showed that some of the compounds formed two complexes with (99m)Tc, possibly syn and anti conformations with respect to the Tc=O bond. In general, the Class I chelators labeled more readily than the class II chelators. The P values of the (99m)Tc complexes varied from 0.0002 to 5 and were generally in accordance with predictions based on structure. There were also differences in P as a function of pH; the free acids had a lower P at pH 7.4 than at pH 2.0 due to ionization, whereas the amides did not show this effect. Accumulation levels in aerobic cells were related to P but varied over a narrow range. Four of the 11 compounds showed selective accumulation in hypoxic cells. The peptidic class of 2-nitroimidazoles, with flexible design and convenient solid-phase synthesis, deserves further study as agents for imaging hypoxia in tumors.

Animals↗
PubMedDate not supplied

A novel amine-dioxime chelator for technetium-99m: synthesis and evaluation of 2-nitroimidazole-containing analogues as markers for hypoxic cells.

A novel amine-dioxime chelator for (99m)Tc has been developed. It offers the advantages of ease of synthesis and flexibility in alteration of lipophilicity. Labeling by stannous reduction of pertechnetate takes place rapidly and efficiently at room temperature and is stable for 24 h. The (99m)Tc:ligand ratio is believed to be 1:2. Seven different alkyl moieties were used to achieve a range of lipophilicities. Three series of compounds were prepared: 2-nitroimidazoles as potential hypoxia-targeting agents, 4-nitroimidazoles as a less easily reduced isomer, and untargeted anilines. In an in vitro model of cellular hypoxia, the 2-nitroimidazole compounds all showed selective accumulation whereas 4-nitroimidazoles showed variable selectivity and aniline showed no selectivity. These experiments demonstrate the potential utility of the 2-nitroimidazole derivatives of the amine-dioxime class of chelator as hypoxia-targeting agents.

Animals↗
PubMedDate not supplied

Sestamibi accumulation in human nasopharyngeal carcinoma cell lines in vitro.

Sestamibi imaging is used to assess the staging of nasopharyngeal carcinoma (NPC), and to monitor response to therapy. Sestamibi was added to single-cell suspensions of the NPC cell lines CNE-1 and CNE-2Z, and aliquots were removed over 60 min and centrifuged to determine cell-associated radioactivity. Sestamibi accumulation reached similar plateau values in both cell lines within 30 min of addition. Saturating concentrations of P-glycoprotein (Pgp) modulators increased accumulation by 1.4-1.7 fold over controls. Hyperpolarization of the mitochondrial membrane with nigericin increased accumulation by 2.6-3.4 fold. In contrast, depolarization of the plasma membrane with isotonic high potassium buffer reduced accumulation to 70-75% of control values, and additional depolarization of the mitochondrial membrane with valinomycin further reduced accumulation to 21-29% of control levels. These results indicate that both cell lines contain a modest level of Pgp activity and that both are capable of further polarization of the mitochondria. This suggests that mitochondrial hyperpolarization is not the complete explanation for high accumulation of sestamibi in NPC.

ATP Binding Cassette Transporter, Subfamily B, Mem↗