PubMed Health⌕ Search

Biomedical subjects

W C Eckelman

Publications and source records attributed to W C Eckelman.

At least 127 records · Page 7Linked to original sources
PubMed1984

Synthesis and evaluation of radioiodinated derivatives of 1-azabicyclo[2.2.2]oct-3-yl alpha-hydroxy-alpha-(4-iodophenyl)-alpha- phenylacetate as potential radiopharmaceuticals.

Two derivatives of (RS)-1-azabicyclo[2.2.2]oct-3-yl (RS)-alpha-hydroxy-alpha-(4-iodophenyl)-alpha-phenylacetate (1a) and three partially resolved (R)- or (S)-1-azabicyclo[2.2.2]oct-3-yl (RS)-alpha-hydroxy-alpha-(4-iodophenyl)-alpha-phenylacetates labeled with no carrier added iodine-125 (1b, 18, and 19) and iodine-123 (1c and 18a) were synthesized by the Wallach triazene approach. We have found that this approach is necessary to obtain no carrier added labeling and gives far better results than the direct electrophilic iodination. The obtained yields were 7 to 18% when using iodine-123 (yield dependent on the source of iodide) and up to 17% for iodine-123 (yield dependent on the source of iodide) and up to 17% for iodine-125 labeled compounds. Our preliminary distribution studies indicate that 1b localizes in the organs known to have a large concentration of muscarinic receptors and that this localization is due to binding to those receptors.

Animals↗
PubMed1984

Synthesis and evaluation of (17 alpha,20E)-21-[125I]iodo-19-norpregna-1,3,5(10),20-tetraene-3,17 -diol and (17 alpha,20E)-21-[125I]iodo-11 beta-methoxy-19-norpregna-1,3,5(10),20-tetraene-3,17-diol (17 alpha-(iodovinyl)estradiol derivatives) as high specific activity potential radiopharmaceuticals.

Two 17 alpha-[125I]iodovinyl estradiol derivatives 4b,d possessing high specific activity have been prepared and tested as potential radiopharmaceuticals. The use of the 3-acetyl derivatives 2c,e and the replacement of iodine monochloride with sodium iodide and Chloramine-T in THF/phosphate buffer (pH 7.0) permitted us to synthesize no-carrier-added (17 alpha,20E)-21-[125I]iodo-19-norpregna-1,3,5(10),20-tetraene-3,17-d iol (4b) and (17 alpha,20E)-21-[125I]iodo-11 beta-methoxy-19-norpregna-1,3,5(10),20-tetraene-3,17-diol (4d) with 50% radiochemical yield and high purity. Although the specific activity represents only half of the theoretical value in some cases, this modified approach is a substantial improvement over the previously published method. Our preliminary distribution studies indicate that although both 4b and 4d localize in the tissues known to have a large concentration of estrogen receptors, 4d accumulates in higher amounts in target tissues and provides a high target to nontarget ratio.

Animals↗
PubMed1984

Labeling monoclonal antibodies and F(ab')2 fragments with (111In) indium using cyclic DTPA anhydride and their in vivo behavior in mice bearing human tumor xenografts.

Monoclonal antibodies (MAb) and their F(ab')2 fragments to human colorectal carcinoma (CRC) and human melanoma-associated antigens were conjugated to diethylenetriaminepentaacetic acid (DTPA) via an acylation reaction using cyclic DTPA dianhydride. Relative immunoreactivity of the F(ab')2 fragments was as high as 70% when an average of only 0.7 DTPA molecules was conjugated per fragment, decreasing rapidly to less than 5% when 9.0 DTPA molecules were conjugated. The 111In-labeled whole MAb in mice bearing human tumor xenografts showed higher concentrations in tumor, liver, kidney, and spleen 7 days after injection of MAb when compared with the same MAb labeled with 131I. F(ab')2 labeled with 111In showed a marked persistence in the tumor-bearing mice with higher concentrations in all organs except blood, when compared with 131I-labeled F(ab')2. Radioactivity was particularly high in the kidneys. Although images of human tumor xenografts were easily visualized using 131I-labeled F(ab')2 3 days after injection, it was difficult to visualize tumor grafts with 111In-labeled F(ab')2 due to persistently high renal, liver, and background activity. Increased catabolism of the 131I-labeled MAb may be the cause of the difference; but antibodies with high immunological activity are a necessity for in vivo imaging studies before firm conclusions can be drawn.

Animals↗
PubMed1984

[I-125] 17 alpha-Iodovinyl 11 beta-methoxyestradiol: in vivo and in vitro properties of a high-affinity estrogen-receptor radiopharmaceutical.

17 alpha-[125I[Iodovinyl 11 beta-methoxyestradiol ([I-125]MIVE2) has been prepared with high specific activity (1500-2000 Ci/mmol) and a high affinity for the estrogen receptor (KA = 6.8 x 10(9) M/Ml). In vivo distribution studies using immature rats result in high levels of activity in the uterus (20-30% dose/g) with uterus-to-plasma ratios on the order of 68 to 100. Peak activity in the uterus is obtained between 2 and 4 hr, and by 6 hr 50% of the activity has washed out. The [I-125]MIVE2 exhibits a slower rate of washout relative to the washout of H-3 estradiol. By in vivo competition studies with nonradioactive estradiol, we found that 95% of the [I-125]MIVE2 bound in the uterus is specifically bound to estrogen receptors. The radioactive labeling of MIVE2 is sufficiently rapid so that [I-123]MIVE2 has been synthesized and is currently in clinical trials. These results suggest that MIVE2 would be an excellent agent for the study of estrogen receptors in vivo and in vitro.

Animals↗
PubMed1984

The characteristics of I-125 4-IQNB and H-3 QNB in vivo and in vitro.

The accumulation of (R)-(H-3)-3-quinuclidinyl benzilate (H-3 QNB) and (R,S)-1-azabicyclo(2.2.2)oct-3-yl (R,S)-alpha-hydroxy-(4-[I-125]iodophenyl) benzeneacetate (I-125 4- IQNB ) in heart, caudate/putamen, and cerebellum of rats was determined at intervals from 15 min to 4 hr after injection. The behavior of the two radiotracers in the heart is consistent with in vitro results with respect to affinities and specificities. In the brain, however, the compounds differ in tissue selectivity. At high specific activity, neither compound provides localization that is consistent with the concentration of receptor in the tissues. The results of this study do not indicate quantification of receptor concentration by means of single external images.

Animals↗
PubMed1983

Differences in affinities of muscarinic acetylcholine receptor antagonists for brain and heart receptors.

The affinities of atropine, scopolamine, 3-quinuclidinyl benzilate and twelve analogues of 3-quinuclidinyl benzilate were determined for the muscarinic acetylcholine receptor (m-AChR) using membrane preparations from caudate/putamen. The affinity constants thus obtained were compared with affinities previously reported for the m-AChR obtained from ventricular muscle. The affinities differed significantly for six of the compounds, the largest difference being 16-fold. Neither solubilization nor variation of physiologically significant salts led to a significant change in the affinity of that compound. These results are interpreted as supporting the subclassification of the muscarinic acetylcholine receptor.

Animals↗
PubMed1983

Cardioselectivity of beta-adrenoceptor blocking agents. 2. Role of the amino group substituent.

A series of 1-(aralkylamino)-3-(aryloxy)propan-2-ols were synthesized, and their apparent dissociation constants (Kapp) were determined by using rat ventricular muscle (RVM) and rat lung membrane (RLM) preparations. Analysis of the binding studies suggests the existence of different modes of binding dependent on the presence or absence of the 4-substituent in the aryloxy ring and the nature of that ring. Without 4-substitution only one compound (4), bearing the 2-(2-methoxyphenoxy)ethyl substituent on the amino group, shows high cardioselectivity. Introduction of the 4-acylamido substituent into the phenoxy ring renders all compounds cardioselective. The cardioselective influence of 4-substitution is diminished or eliminated when the phenoxy ring is replaced by naphth-1-yloxy.

Adrenergic beta-Antagonists↗
PubMed1983

Optimization of the DTPA mixed-anhydride reaction with antibodies at low concentration.

Diethylenetriaminepentaacetic acid (DTPA) was conjugated with antibody to human serum albumin (Ab) at low concentration (300 micrograms/ml, 2.0 microM) via the DTPA carboxycarbonyl mixed-anhydride method. To study parameters determining the balance between the degree of conjugation and the antibody-binding activity of Ab, a known concentration of the anhydride prepared at isobutylchloroformate (IBC)-to-DTPA ratios of 1, 2.1, or 4.2 was reacted with Ab. The percentage yields of the anhydride were determined by spectrophotometric and gravimetric titration. By the former method the percentage yields, based on DTPA concentration, were 18, 24, and 220, respectively, when the IBC-to-DTPA ratios were 1, 2.1, and 4.2. The corresponding percentage yields were 17, 39, and 262 when determined by the latter method. When the anhydride was prepared at an IBC-to-DTPA ratio of 2.1, an optimum conjugation giving three indium atoms per Ab was obtained, with 64% retention of antibody-binding activity. For an IBC-to-DTPA ratio of 1, the antibody retained almost 100% binding activity but the number of indium atoms incorporated (0.2) was too small. For an IBC-to-DTPA ratio of 4.2, up to 22 indium atoms were incorporated but antibody-binding activity was completely destroyed.

Anhydrides↗
PubMed1983

Factors influencing DTPA conjugation with antibodies by cyclic DTPA anhydride.

Diethylenetriaminepentaacetic acid (DTPA) was conjugated with a practical concentration (300 micrograms/ml) of antibody to human albumin (Ab) and 1083 17-1A monoclonal colorectal antibody (MAb-17-1A) via an acylation reaction using cyclic DTPA anhydride (cDTPAA). The conjugation reaction was favored as pH increased. Bicarbonate buffer at pH 8.2 was chosen for studies of the effect of the cDTPAA-to-antibody ratio on DTPA conjugation with antibody because of its good buffer capacity at that pH. The reaction of cDTPAA with Ab at molar ratios of 2000, 1000, 500, and 100 in the bicarbonate buffer gave rise to 11, 9, 8, and 2 indium atoms incorporated per Ab with 47%, 55%, 59%, and 77% retention of the binding activity. For the conjugation reaction of MAb-17-1A, 29, 28, 31, 11, 4, and 1 indium atoms were incorporated, with the retention of less than 5%, less than 5%, less than 5%, 12%, 60%, and 93% of binding activity when the molar ratio was 5000, 2000, 1000, 500, 100, and 50.

Animals↗
PubMed1982

In vivo chemistry of 99mTc-chelates.

The structure-activity relationships involved in the in vivo localization and clearance of 99mTc-chelates is reviewed. Most 99mTc-chelates used for renal studies are mixed function agents and their uptake in the kidney is affected by the presence or absence of stannous ions; only a relatively few chelates are almost exclusively cleared from the body by glomerular filtration or tubular excretion. The uptake of 99mTc-phosphates and -phosphonates in metabolically active and metabolically inactive bone and the plasma clearance rate of these complexes depend upon the structure of the complexing ligand. 99mTc-chelates considered optimal for hepatobiliary imaging have a high liver extraction efficiency, are rapidly transported through the liver and have a comparatively slow renal clearance rate. Even though the elucidation of the in vivo behavior of 99mTc-chelates continues, quantitating structure-activity relationships requires that the structure of the chelates be carefully characterized, both before and after injection.

Animals↗
PubMed1982

The use of tritium labeled compounds to develop gamma-emitting receptor-binding radiotracers.

In an effort to evaluate receptor binding drugs for their potential as gamma labeled radiopharmaceuticals suitable for clinical heart scanning, in vivo data were compared with the results obtained from a theoretical model. The distribution of selected tritium-labeled, receptor-binding radiotracers was studied in animals to determine if the heart to blood ratios agree with those obtained using a theoretical model of receptor binding. In general, the in vivo studies agree with the theoretical model when the concentration of the radiotracer in the heart is due to specific receptor binding. The use of the theoretical model for a first approximation followed by in vivo biodistribution studies is an efficient strategy to select those few from among the large number of receptor binding compounds that will ultimately yield an efficacious radiopharmaceutical to study receptor changes in the intact human heart.

Adrenergic alpha-Antagonists↗
PubMed1982

Analogues of 3-quinuclidinyl benzilate.

A number of analogues of 3-quinuclidinyl benzilate (QNB) have been synthesized and their affinities to muscarinic receptor from rat or dog ventricular muscle measured. We have determined that the muscarinic receptor can to a different degree accommodate either a halogen in the ortho, meta, or para position of one phenyl ring or the replacement of one phenyl ring with an alkyl group. Our in vitro competition studies show that the affinities lie within a 270-fold range, from the highest affinity compound, 3-quinuclidinyl alpha-hydroxy-alpha-cyclopentylphenylacetate (2), to the lowest affinity compound, 3-quinuclidinyl alpha-hydroxy-alpha-2-propargylphenylacetate (11).

Animals↗
PubMed1982

Three radioligands compared for determining cytoplasmic estrogen-receptor content of human breast carcinomas.

We compared three radioligands for use in a cytoplasmic estrogen-receptor assay, using pooled cytosol from human breast adenocarcinomas. The estrogen receptor content was determined in vitro by a dextran-coated charcoal method involving a 4-h incubation with and without diethylstilbestrol. Tritiated moxestrol failed to come to equilibrium in 4 h, thereby preventing the use of conventional one-component Scatchard analysis. The use of 125I-labeled estradiol resulted in a higher estimate of estrogen-receptor concentration than that obtained with use of tritiated estradiol. This overestimation was not corrected by Scatchard, double-reciprocal, or Woolf plots, or by two different methods of data analysis: least squared and "robust." An underestimation of the specific activity of iodoestradiol with respect to that of tritiated estradiol and an unrecognized second component of nonreceptor binding could explain this disparity.

Breast Neoplasms↗