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M R Kilbourn

Publications and source records attributed to M R Kilbourn.

124 records · Page 7Linked to original sources
PubMed1985

Research and clinical potential of receptor based radiopharmaceuticals.

Receptors are proteins that have specific binding affinity for substances that produce a physiological event in the body. Receptor-binding radiotracers are being used increasingly to study the function of receptors in health and disease. This review summarizes the proceedings of a symposium on research in the development of receptor-binding radiopharmaceuticals. The key phases in this research include: selection of the receptor system and ligand; synthesis of radiolabeled ligand; validation in animal models; and clinical application. Current research involves a variety of biological systems, such as butyrophenone neuroleptics for dopamine receptors and steroidal estrogens for the estrogen receptor. In the future, it is believed that receptor-binding radiopharmaceuticals will be useful, not only to validate receptor systems in vivo, but also to aid in the diagnosis and therapy of human diseases.

Animals↗
PubMed1984

A quantitative model for the in vivo assessment of drug binding sites with positron emission tomography.

We propose an in vivo method for use with positron emission tomography (PET) that results in a quantitative characterization of neuroleptic binding sites using radiolabeled spiperone. The data are analyzed using a mathematical model that describes transport, nonspecific binding, and specific binding in the brain. The model demonstrates that the receptor quantities Bmax (i.e., the number of binding sites) and KD-1 (i.e., the binding affinity) are not separably ascertainable with tracer methodology in human subjects. We have, therefore, introduced a new term, the binding potential, equivalent to the product BmaxKD-1, which reflects the capacity of a given tissue, or region of a tissue, for ligand-binding site interaction. The procedure for obtaining these measurements is illustrated with data from sequential PET scans of baboons after intravenous injection of carrier-added [18F]spiperone. From these data we estimate the brain tissue nonspecific binding of spiperone to be in the range of 94.2 to 95.3%, and the regional brain spiperone permeability (measured as the permeability-surface area product) to be in the range of 0.025 to 0.036 cm3/(s X ml). The binding potential of the striatum ranged from 17.4 to 21.6; these in vivo estimates compare favorably to in vitro values in the literature. To our knowledge this represents the first direct evidence that PET can be used to characterize quantitatively, locally and in vivo, drug binding sites in brain. The ability to make such measurements with PET should permit the detailed investigation of diseases thought to result from disorders of receptor function.

Animals↗
PubMed1984

Carrier-added and no-carrier-added syntheses of [18F]spiroperidol and [18F]haloperidol.

Syntheses of [18F]haloperidol and [18F]spiroperidol in both no-carrier-added and carrier-added forms have been accomplished. The no-carrier-added [18F]butyrophenone neuroleptics were prepared in low (less than 2%) yield by acid decomposition of aryl piperidine triazenes. Carrier-added 18F-neuroleptics were prepared in better (5-17%) yields by 18F-for-19F nucleophilic aromatic substitution. The preparation of all synthetic precursors, and procedures for radiolabeling are fully described.

Butyrophenones↗
PubMed1984

A simple 18O water target for 18F production.

A simple low-volume (3 mL) target has been constructed for the production of 18F via the proton irradiation of 18O enriched water. The target is constructed of copper with the water cavity electroplated with nickel. This target routinely produces more than a curie of 18F (as [18F]fluoride) suitable for radiopharmaceutical syntheses.

Fluorine↗
PubMed1984

Synthesis of DL-[3-11C]phenylalanine.

[3-11C]Phenylalanine has been prepared by a five-step synthesis beginning with 11CO2. [11C]Benzyl chloride was prepared by addition of 11CO2 to phenylmagnesium bromide, hydride reduction to [11C]benzyl alcohol, and chlorination (CCl4, tri-n-octylphosphine). The [11C]benzyl chloride was then used to alkylate the anion of N-diphenylmethylene)glycine ethyl ester using phase-transfer catalysis. The protecting groups were removed by acidic hydrolysis to yield DL-[3-11C]phenylalanine in 25-31% overall radiochemical yield (decay corrected) in a synthesis time of 60-70 min.

Carbon Radioisotopes↗
PubMed1984

Preparation of four fluorine- 18-labeled estrogens and their selective uptakes in target tissues of immature rats.

Four fluorine- 18-labeled estrogens--16 alpha-[18F]fluoro-estradiol-17 beta (1), 16 beta-[18F]fluoro-estradiol-17 beta (2), (2R, 3S)-1-[18F]fluoro-2,3-bis(4-hydroxyphenyl)-pentane (1-[18F]fluoropentestrol) (3), and (3R, 4S)-1-[18F]fluoro-3,4-bis(4-hydroxyphenyl)hexane (1-[18F]fluorohexestrol) (4)--have been prepared by simple displacement reactions utilizing reactive trifluoromethane sulfonate (triflate) precursors and F-18 fluoride ion. All four fluoroestrogens have high affinity for the estrogen receptor. In immature female rats, they are taken up by target tissues, such as the uterus, with very high selectivity: uterus-to-blood ratios at 1 hr are: Compound 1, 39; Compound 2, 12; Compound 3, 13; and Compound 4, 19. Average uterus-to-blood ratios exceed 80 for Compound 1 at 2 hr. That the uptake process involves an estrogen-specific binder of limited capacity is demonstrated by the suppressive effect of coadministered unlabeled estradiol on target tissue uptake.

Animals↗
PubMed1983

(2R*, 3S*)-1-[18F]fluoro-2,3-bis(4-hydroxyphenyl)pentane [( 18F]fluoronor-hexestrol), a positron-emitting estrogen that shows highly-selective, receptor-mediated uptake by target tissues in vivo.

The positron-emitting, non-steroidal estrogen (2R*, 3S*)-1-[18F]fluoro-2,3-bis(4-hydroxyphenyl)pentane [( 18F]-fluoronor-hexestrol), has been prepared by fluoride ion displacement on a labile trifluoromethanesulfonate (triflate) derivative of a suitably protected precursor, followed by removal of the aryl triflate groups with lithium aluminum hydride and purification by HPLC. In immature female rats, this compound is taken up selectively by the uterus and is retained for prolonged periods, due to its binding to the estrogen receptor. This compound and related 18F-labeled estrogens thus appear to be promising agents for imaging estrogen receptor-positive breast tumors in humans.

Animals↗
PubMed1983

Comparison in animal models of 18F-spiroperidol and 18F-haloperidol: potential agents for imaging the dopamine receptor.

Fluorine-18-labeled haloperidol and spiroperidol have been prepared by an exchange reaction using the corresponding non-labeled compound or the nitro analog. Studies in rats have shown that the distribution of labeled spiroperidol has a high striatum to cerebellum ratio which is not observed with haloperidol. A ratio of 10.66 +/- 1.6 is obtained two hours after administration of the 18F-spiroperidol. When 18F-spiroperidol was administered to a baboon and tomographic images obtained, the dopamine receptor rich areas were clearly visualized two hours after administration.

Animals↗
PubMed1983

Relationship between lipophilicity and brain extraction of C-11-labeled radiopharmaceuticals.

The brain extraction of fifteen C-11-labeled compounds during a single capillary transit was studied in adult baboons by external detection of these tracers after injection into the internal carotid artery. The log Poct (partition coefficient for octanol/water) values of these compounds range from --0.7 to greater than 4.0. A parabolic relationship was found between the log Poct value of the C-11-labeled compounds and the fraction of the radiopharmaceutical entering the brain. Compounds with log Poct values between 0.9 and 2.5 were found to pass freely across the blood-brain barrier at a cerebral blood flow of 100 ml X min-1 X hg-1. An apparently decreased extraction of very lipophilic compounds was shown to be related to binding of the tracer to blood components and macromolecules (red blood cells, albumin, etc.). These data suggest that a radiopharmaceutical designed to measure blood flow should have a log Poct value of between 0.9 and 2.5.

Alcohols↗
PubMed1981

Topography of rhodopsin in retinal rod outer segment disk membranes. Photochemical labeling with 1-azidopyrene.

1-Azido[3H]pyrene ([3H]AP) has been synthesized with high specific radioactivity (3 Ci/mmol) and used to photochemically label retinal rod outer segment disk membranes. The reagent reacts with rhodopsin and a Mr approximately 240000 protein as well as with membrane lipids. When [3H]AP-rhodopsin is digested with thermolysin in the disk membrane, both membrane-bound fragments of rhodopsin, F1 and F2, are found to contain [3H]AP. Reaction of the reagent appears to be restricted to the lipophilic surface of rhodopsin inasmuch as the presence of the nitrene scavenger glutathione in the aqueous medium does not significantly reduce 3H incorporation into rhodopsin. Labeled F1 and F2 were prepared, their cyanogen bromide peptides partially separated, and specific radioactivities determined. A factor of 4.4-fold in specific radioactivities of peptide pools was found, which suggests that some specificity has been shown in the reaction of [3H]AP toward different surfaces of rhodopsin.

Animals↗