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W C Eckelman

Publications and source records attributed to W C Eckelman.

At least 19 recordsLinked to original sources
PubMed1992

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.

Animals↗
PubMed1991

Positron-labeled angiotensin-converting enzyme (ACE) inhibitor: fluorine-18-fluorocaptopril. Probing the ACE activity in vivo by positron emission tomography.

To evaluate the feasibility of probing the distribution of angiotensin-converting enzyme (ACE) in vivo using positron emission tomography (PET), 4-cis-[18F]fluorocaptopril (18FCAP) was prepared by the reaction of the triflate 2 with K18F/Kryptofix 222 in MeCN followed by hydrolysis (2 N NaOH). The synthesis time was 1 hr with an average radiochemical yield (EOS) of 12% and a specific activity of greater than 300 Ci/mmol. In vivo biodistribution in rats at 30 min after administration showed high uptakes into organs known to have high ACE concentration (lung, kidney and aorta) and faster clearance of 18FCAP for lung and kidney, compared to the clearance from the aorta. When different amounts of unlabeled 4-cis-fluorocaptopril (SQ 25750) were coinjected in rats, a dose of greater than 5 micrograms/kg decreased the lung uptake by one-half while only 1 microgram/kg decreased the kidney uptake by one-half. In general, the binding in the four tissues studied was saturable with the expected capacity. 18FCAP was administered to a human and displaceable uptake observed in the lung and kidney. The results demonstrate the feasibility of probing ACE in vivo using PET.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1990

Development of radiochemically pure antibodies.

There are presently three approaches to radiolabeling antibodies: direct radiolabeling; radiolabeling of a chelating agent conjugated to an antibody; and radiolabeling of a chelating agent before conjugation to an antibody. Using either the direct radiolabeling or radiolabeling of a chelating agent conjugated to an antibody has not led to a radiochemically pure 99mTc-labeled protein. High radiochemical purity is obtained using a prelabeled ligand; therefore this method is preferred.

Antibodies↗
PubMed1990

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.

Animals↗
PubMed1990

A radioimmunoassay for SQ 27,519, the active phosphinic acid-carboxylic diacid of the prodrug fosinopril in human serum.

Fosinopril (SQ 28,555) is a member of a new chemical class of angiotensin converting enzyme inhibitors being developed by The Squibb Institute for Medical Research. During or following absorption, fosinopril, a prodrug, is hydrolyzed pharmacologically to the active diacid, SQ 27,519. A specific radioimmunoassay (RIA) for the measurement of SQ 27,519 in human serum has been developed. The assay utilizes a specific SQ 27,519 antibody, 125I-iodohistamine-SQ 27,519 radiolabel, and human serum standards. Satisfactory zero binding and assay sensitivity are achieved after a 2-h incubation at room temperature. Separation of the antibody-bound and free radiolabeled antigens is achieved by using polyethylene glycol-goat anti-rabbit gamma globulin separant. Recovery efficiencies ranged from 97.2 to 109.4%. The assay exhibited little or no cross-reactivity with captopril. Cross-reactivities for prodrug (SQ 28,555) and phenolic SQ 27,519 were 5 and 9%, respectively. Intra-assay variability (3.3-5.6%) and interassay variability (7.1-6.6%) were observed. Linear regression analysis indicates that RIA and [14C] thin-layer radiochromatography (TLRC) methods gave a highly significant correlation (RIA = 1.0 [14C]TLRC + 0.17, r = 0.991). Pharmacokinetic profiles of patient sera containing SQ 27,519 obtained by RIA and [14C]TLRC are identical. The RIA has been used routinely in support of the bioavailability and pharmacokinetic studies of fosinopril in humans.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1990

A neutral lipophilic technetium-99m complex for regional cerebral blood flow imaging.

Technetium-99m-DMG-2MP (Chloro[bis[2,3-butanedionedioxime(1-)-0][2,3- butanedionedioximato (2-)-N,N',N'',N''',N'''',N'''''] (2-methylpropyl borato (2-))technetium]), also known as SQ 32097 is a member of a family of neutral lipophilic compounds generally known as boronic acid adducts of technetium dioxime complexes (BATOs). After i.v. administration, the concentration of [99mTc]DMG-2MP in various regions of the brain appears to be proportional to blood flow. In rats, 1.1% ID was in the brain at 5 min postinjection when the blood contained less than 3% ID. Over 24 hr excretion was 59% in the feces and 23% in the urine. The activity in monkey brain at 5 min was 2.8% ID and it cleared with a t1/2 of 86 min. Autoradiographs of monkey brain sections showed excellent regional detail with a gray/white ratio of 3.6 at 10 min. The distribution of [99mTc]DMG-2MP in the monkey brain corresponds to the known cytoarchitectural pattern of cerebral glucose metabolism. The properties of [99mTc]DMG-2MP make it a potentially useful agent for cerebral perfusion imaging in man.

Animals↗
PubMed1989

In vitro and in vivo characteristics of [iodine-125] 3-(R)-quinuclidinyl (S)-4-iodobenzilate.

The radioiodinated muscarinic acetylcholine receptor antagonist, [125I] 3-quinuclidinyl 4-iodobenzilate, has two high affinity diastereomeric forms, the (R,R) and (R,S)-isomers. The (R,S)-diastereomer is only threefold lower in affinity than the (R,R)-isomer, but the kinetic properties are considerably different--the dissociation rate constant is 13-fold faster for the (R,S)-isomer and the association rate constant is two to threefold faster. The calculated affinity is therefore only fourfold lower. In vivo, the clearance of (R,S)-4IQNB from receptor-rich tissue is also more rapid than that of the (R,R)-isomer, that is a reflection of the more rapid in vitro kinetic properties since the physicochemical properties and the metabolic clearance of the diastereomers is the same.

Animals↗
PubMed1989

A neutral technetium-99m complex for myocardial imaging.

Technetium-99m-CDO-MeB [Bis[1,2-cyclohexanedione-dioximato(1-)- O]-[1,2-cyclohexanedione dioximato(2-)-O]methyl-borato(2-)- N,N',N'',N''',N'''',N''''')-chlorotechnetium) belongs to a family of compounds generally known as boronic acid adducts of technetium dioxime complexes (BATOs). It has an intrinsic affinity for the myocardium, with negligible lung activity and rapid blood clearance. The uptake of 3.44% ID in rat heart at 1 min postinjection for [99mTc]CDO-MeB versus 3.03% for 201TI indicates high extraction of [99mTc]CDO-MeB by the myocardium. In dogs an ischemic defect is clearly seen in SPECT images obtained 10 min after injection of [99mTc]CDO-MeB. Tissue distribution data in rats show that [99mTc]CDO-MeB is excreted primarily in the feces and to a lesser extent in the urine. Approximately 80% of the activity is excreted within 24 hr after injection.

Animals↗
PubMed1988

Comparative chemical structure and pharmacokinetics of MRI contrast agents.

The blood clearance kinetics of five gadolinium complexes, Gd(L), were determined in rats and the results interpreted in terms of an open two-compartment pharmacokinetic model. The complexes were tested in vitro for stability in serum and in aqueous solutions of ions that they might encounter in vivo and that might be expected to react with the Gd(L) complexes to produce uncomplexed gadolinium. Reaction with serum was observed in two instances. Chemical structural differences among the chelating ligands appear to govern the overall reactivity of their Gd(L) complexes. It may be inferred from the results that a preferred structural feature of the ligand is the presence of a 12-membered 1,4,7,10-tetraaza macrocycle.

Animals↗
PubMed1987

[125I]17-alpha-iodovinyl 11-beta-methoxyestradiol interaction in vivo with estrogen receptors in hormone-independent MCF-7 human breast cancer transfected with the v-rasH oncogene.

[125I]17-alpha-Iodovinyl 11-beta-methoxyestradiol [( 125I]MIVE2) has been evaluated as a potential radiotracer for the diagnostic imaging of estrogen receptor (ER)-positive human breast cancer. In vivo distribution experiments with athymic ovariectomized nude mice bearing human breast tumors revealed an apparent correlation between uptake of 125I-labeled compound and estrogen receptor concentration in the tumors. At 4 h after i.v. injection of [125I]MIVE2, HS578T (ER negative), ZR75-B (intermediate ER), and MCF-7ras (high ER) tumors accumulated 0.320 +/- 0.186, 0.679 +/- 0.467, and 2.6163 +/- 1.0121% injected dose/g, respectively. With coinjection of unlabeled 17-beta-estradiol, levels of radioactivity in MCF-7ras tumors were decreased to 0.4859 +/- 0.1424% injected dose/g, indicating a receptor-mediated process. Peak activity of radioligand in MCF-7ras tumors and uteri was observed at 2 h and was retained for the 8-h time course. Blood and nontarget tissue, such as muscle, revealed a rapid clearance of 125I-labeled compound by 8 h. Eight hours after injection, uterus and tumor-to-blood ratios were calculated to be 225 and 21, respectively. Also, MCF-7ras tumors were shown to accumulate 6.5-fold more radioactivity than muscle. These data suggest that [125I]MIVE2 has the capability of interacting specifically and with high affinity with estrogen receptors in human breast tumors in nude mice and may possibly be used for imaging receptor-positive tumors in breast cancer patients with very low serum estrogen levels. Selective uptake of compound in MCF-7ras tumors emphasizes the usefulness of an estrogen receptor-positive tumor model which has a unique ability to grow in a host system without circulating estrogens.

Animals↗
PubMed1986

Syntheses and D2 receptor affinities of derivatives of spiperone containing aliphatic halogens.

The development of a high affinity dopamine receptor ligand labeled with the positron emitting radionuclide, 18F (t 1/2 = 110 min), is of considerable interest for imaging and quantification of dopamine receptors in vivo. Derivatives of spiperone, a dopamine antagonist, labeled with 18F have been prepared, but the syntheses either proceed with inefficient fluoride utilization or involve several synthetic steps subsequent to 18F incorporation. To date, only the short-lived radioisotope of carbon, 11C (t 1/2 = 20.4 min), has been efficiently incorporated in the final synthetic step of 3-N-[11C]methyl-spiperone. 3-N-Fluoroethyl, 3-N-chloroethyl, and 3-N-bromoethyl spiperone derivatives are prepared by alkylation of spiperone with the appropriate 2-tosyloxy ethyl halide. In addition, alpha-fluorospiperone, containing fluorine alpha to the butyrophenone carbonyl, has been prepared. The 3-N-haloethyl spiperones display high affinity for dopamine receptor in vitro. Incorporation of [18F]fluoride during the final synthetic step yields a high affinity, 18F-labeled dopamine receptor-binding ligand.

Animals↗