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Biomedical subjects

W C Eckelman

Publications and source records attributed to W C Eckelman.

At least 145 records · Page 8Linked to original sources
PubMed1980

In vivo receptor binding of iodinated beta-adrenoceptor blockers.

Six radiolabeled beta-adrenoceptor blocking agents with a range of affinity constants were evaluated as radioindicators for adrenoceptors in guinea-pig heart and lung. All concentrated in the heart and lung at levels in excess of 0.1% dose/g tissue. On the basis of displacement studies using propranolol, two of the six compounds showed beta-adrenoceptor binding in the lung, and one, H-3 carazolol, showed receptor binding in the heart. These results agree qualitatively with a bi-molecular reversible equilibrium model, and suggest that the beta-adrenoceptor blockers as a group will not be useful in vivo probes of receptor concentration in the heart because of the low affinity constants and high levels of nonreceptor binding associated with the present-day clinical beta blockers. Beta-adrenoceptor blocking agents with affinity constants in excess of 10(9) will be needed to give heart-to-blood ratios of 10.

Adrenergic beta-Antagonists↗
PubMed1980

Radioiodinated estrogen derivatives.

Monoiodohexestrol exhibits 10 to 15% specific binding to the 8S estrogen receptor while the remainder binds to nonreceptor 4S proteins. Reduction of nonreceptor binding with either thyroxine or 8-anilino-1-naphthalene sulfonic acid was not quantitative. Thus no accurate determination of the concentration of receptor sites in the radioreceptor assay was possible by graphical analysis. Two additional estrogens--17 alpha [125I]iodoethynylestradiol and 17 alpha-[125I]iodoethynyl-11 beta-methoxy estradiol--were synthesized at high specific activity. Although the iodoethynyl derivatives were stable under synthetic conditions, deiodination in the presence of proteins is too fast to allow either in vivo or in vitro use. To make these compounds clinically useful, therefore, chemical modification to reduce nonreceptor binding and the rate of dehalogenation must be undertaken.

Anilino Naphthalenesulfonates↗
PubMed1980

Radiolabeling of antibodies.

The radiolabeling of antibodies is considered in terms of the choice of radionuclide, the method of conjugation, and the effect of conjugation on plasma clearance. Iodination techniques are reviewed, but the major emphasis is placed on the methods of conjugating metallic radionuclides using bifunctional chelating agents. The technique of producing clinically useful radiolabeled antibodies by balancing altered substrate specificity caused by radiolabeling against accelerated plasma clearance is discussed.

Antibodies↗
PubMed1979

Cardioselectivity of beta-adrenoceptor blocking agents 1. 1-[(4-Hydroxyphenethyl)amino]-3-(aryloxy)propan-2-ols.

A series of 1-[(4-hydroxyphenethyl)amino]-3-(aryloxy)propan-2-ols was synthesized together with several 1-[(3,4-dimethoxyphenethyl)amino]-3-(aryloxy)propan-2-ols. Their affinity to beta 1- and beta-2-adrenoceptors was determined and compared with the affinity of known beta-blockers. We were able to confirm the substantial cardioselectivity of 1-(3,4-dimethoxyphenethyl)-3-[(4-substituted aryl)oxy]propan-2-ols when compared to those with a 1-(4-hydroxyphenethyl) group. An increase in the size of the 4 substitutent of the 3-(aryloxy) moiety to caproamido leads to a substantially higher affinity for the beta 1--adrenoceptor of rat ventricular muscle in the presence of the 3,4-dimethoxyphenethyl than in the presence of the 4-hydroxyphenethyl or isopropyl group; this combination also gave the highest cardioselectivity.

Adrenergic beta-Antagonists↗
PubMed1979

The distribution of the muscarinic acetylcholine receptor antagonists, quinuclidinyl benzilate and quinuclidinyl benzilate methiodide (both tritiated), in rat, guinea pig, and rabbit.

The distribution of [3H]quinuclidinyl benzilate and its methiodide salt was determined in rat, guinea pig, and rabbit. Accumulation in the myocardium of up to 2% of the injected dose per gram of tissue was obtained with both compounds, providing heart-to-blood ratios of approximately 30 and heart-to-lung ratios of approximately 4. The accumulation in the heart was blocked (89%) by preinjection of atropine. The distribution of tritium in rabbit heart corresponds to the muscarinic receptor densities determined in vitro. Calculation of the theoretical maximum for the bound-to-free ratio, based on in-vitro equilibrium binding isotherms, resulted in ratios in reasonable agreement with the experimental results. Because of the high accumulation in the heart with low serum concentration, we conclude that the methiodide salt of quinuclidinyl benzilate represents an ideal parent structure for the design of a receptor-binding gamma-emitting radiopharmaceutical for imaging of the myocardium.

Acetylcholine↗
PubMed1978

Radioiodinated derivatives of beta adrenoceptor blockers for myocardial imaging.

Four new beta-adrenoceptor blocking agents carrying tyramine as the amino moiety were synthesized and the distribution of their I-125-tagged derivatives evaluated in rats. This distribution was compared with the distribution of various agonists and antagonists labeled with H-3 and C-14, and with the in vitro binding affinity of the new derivatives. A radioiodinated derivative of a cardioselective blocker, alprenolol, showed poor blood clearance and no cardiac selectivity. A derivative of another cardioselective blocker, practolol, showed a promising heart-to-blood ratio (ca. 19) and cardioselectivity with a heart-to-lung ratio of ca. 2. Two additional practolol analogs showed no improvement over the practolol derivative; because of the increased lipophilicity of these derivatives, blood clearance and cardioselectivity were diminished. An inverse correlation is suggested between the dissociation constant for the beta adrenoceptor in the lung and the heart-to-blood and heart-to-lung values. We conclude that polarity plays an important role in the blood clearance and cardioselectivity of these beta-adrenoceptor derivatives.

Adrenergic beta-Antagonists↗
PubMed1977

Biological distribution of chemical analogs of fatty acids and long chain hydrocarbons containing a strong chelating agent.

The pharmaceutical preparation, chromatography, and biological distribution of a series of new chemical analogs of palmitic acid and diethylenetriaminepentaacetic acid, ethylenediaminetetraacetic acid, or diethylenetriamine are described. The biological distribution in rabbits 30 min after intravenous administration of these 99mTc-labeled and 57Co-labeled derivatives was compared to the biological distribution of the parent compound, 3H-palmitic acid. The average myocardial uptake for these compounds was 0.04%/g, compared to 0.15%/g for palmitic acid. The heart to blood ratio at 30 min reached a maximum of 3:1 for the best physiological analog of palmitic acid, compared to an average of 30:1 for palmitic acid. Although none of these analogs appears to be clinically useful, their production methods might be applicable to the synthesis of new compounds that might increase the specificity of radiopharmaceuticals.

Animals↗
PubMed1977

Estrogen derivatives for the external localization of estrogen-dependent malignancy.

Four radioiodinated estrogen derivatives were studied to determine their affinity for the estrogen-binding protein found in the cytosol of rabbit and rat uteri. In vitro determination of the binding properties by competitive-binding experiments and by sucrose-gradient centrifugation indicates that one of the derivatives, iodohexestrol, binds to the cytosol estrogen-binding protein. This in vitro behavior was related to in vivo distribution. Studies in immature female rats showed high uterine uptake of iodohexestrol at 2 hr (1.69% dose/gm). Iodohexestrol also has a high nonspecific binding in both the blood and the uterine cytosol. Thyroxine can diminish the nonspecific binding in vitro; in vivo the prior injection of thyroxine increased the 2-hr uterus-to-blood ratio from 1.9 to 10.4 The in vitro receptor-assay system was helpful in predicting in vivo distribution.

Animals↗
PubMed1976

Technetium-99m-pyridoxylideneglutamate, a new agent for gallbladder imaging: comparison with 131I-rose bengal.

Two agents used for hepatobiliary studies, 131I-rose bengal and 99mTc-pyridoxylideneglutamate, have been compared in rabbits. The 99mTc radiopharmaceutical is rapidly cleared from the blood by the liver and rapidly excreted through the common bile duct into the duodenum. Because of its rapid removal from the liver, visualization of the gallbladder and biliary passages was obtained within 15 min after injection in experimental animals.

Animals↗