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M R Kilbourn

Publications and source records attributed to M R Kilbourn.

At least 109 records · Page 6Linked to original sources
PubMed1988

NMDA receptor channels: labeling of MK-801 with iodine-125 and fluorine-18.

Methods for labeling the glutamate channel blocking agent MK-801 with iodine-125 (125I) and fluorine-18 (18F) are described. Radioiodine was incorporated in the 1- or 3-positions of the aromatic ring of (+/-)MK-801 by solid-state halogen exchange techniques. Attachment of the [18F]fluoromethyl group to the bridgehead methyl position was achieved by reaction of [18F]fluoride with the triflamide alcohol 8 or the novel cyclic sulfamate 9 recently reported by Merck chemists. Radiochemical yields of (+/-) 13-[18F]-fluoromethyl-MK-801 were greater than 72%, EOB; radiochemical purity greater than 99%. In competitive binding studies using rat brain homogenates, (+/-)3-bromo-MK-801 showed greater affinity than (+/-)MK-801 for the glutamate-linked channel. The experimental log P (2.1 +/- 0.1) of MK-801 is optimal for transit of the blood-brain barrier. These preliminary findings support further testing of 3-[123 I]iodo-MK-801 and (+/-)13-[18F]fluoromethyl-MK-801 as possible agents for in vivo mapping of the glutamate receptor complex.

Animals↗
PubMed1988

N-(3-[18F]fluoropropyl)-spiperone: the preferred 18F labeled spiperone analog for positron emission tomographic studies of the dopamine receptor.

The ligands currently used for PET studies of the dopamine receptor are fluorine-18-labeled spiperone (FSp) and carbon-11 or fluorine-18-labeled N-methyl-spiperone. All three of these ligands have drawbacks in either their chemical preparation or their biological behavior. We have previously prepared a series of N-fluoroalkyl-spiperone derivatives which are simple to prepare in high radiochemical yield. N-[18F]fluoropropyl-spiperone (3-F-Pr-Sp) and N-[18F]fluoroethyl-spiperone (2-F-Et-Sp) were the most promising ligands. In vitro competitive binding studies showed affinities for the dopamine receptor of 3-F-Pr-Sp greater than FSp greater than 2-F-Et-Sp. Brain extraction studies in a primate model showed that FSp, 2-F-Et-Sp, and 3-F-Pr-Sp were not completely extracted by the brain. High bone uptake and kidney clearance was observed with 3-F-Pr-Sp, while 2-F-Et-Sp cleared through the intestine in rats. This is in contrast to FSp where clearance is through the kidney. Studies to evaluate the extraction of metabolites in the brain were carried out by administering large doses (10 mCi) of FSp, 2-F-Et-Sp and 3-F-Pr-Sp to rats and reinjecting the metabolites in blood into other rats. These experiments showed that less than 0.02% of the metabolites from FSp and 3-F-Pr-Sp entered the brain, while 0.5% of the metabolites from 2-F-Et-Sp entered the brain. The majority of the activity present in the cerebellum after the administration of 2-F-Et-Sp is metabolites; therefore 2-F-Et-Sp is unsuitable for PET imaging studies. PET imaging studies in baboons and in one normal human volunteer with 3-F-Pr-Sp showed a high striatum-to-cerebellum ratio, showing that 3-F-Pr-Sp can replace ligands currently in use to study dopamine receptors.

Animals↗
PubMed1987

Radiolabeled hypoxic cell sensitizers: tracers for assessment of ischemia.

Hypoxic, non-functional, but viable, tissue may exist in heart and brain following an arterial occlusion. Identification of such tissue in vivo is crucial to the development of effective treatment strategies. It has been suggested that certain compounds capable of sensitizing hypoxic tumor cells to killing by x-rays (i.e., misonidazole) might serve as in vivo markers of hypoxic tissue in ischemic myocardium or brain if properly radiolabeled. To this end we have radiolabeled two fluorinated analogs of nitroimidazole based hypoxic cell sensitizers with the 110 minute half-lived positron-emitting fluorine-18. The ability of these tracers to quantitate the presence of hypoxic tissue has been studied in a gerbil stroke model. The in vivo uptake of one of these tracers [F-18]-fluoronormethyoxymisonidazole is dependent on the extent of tissue hypoxia, and thus, appears to have potential as a diagnostic indicator of non-functional but viable tissue when the tracer is used in conjunction with positron emission tomography.

Animals↗
PubMed1987

Characterization of the uptake of 16 alpha-([18F]fluoro)-17 beta-estradiol in DMBA-induced mammary tumors.

In order to investigate possible correlations between the uptake of 16 alpha-([18F]fluoro)-17 beta-estradiol (18F-ES) by 7,12-dimethylbenz(a) anthracene (DMBA)-induced tumors in rats and the estrogen receptor (ER) content of these tumors, a comprehensive study was performed in which the tissue distribution of 18F-ES was measured in tumor-bearing rats, together with simultaneous measurements of blood volume (by technetium-labeled red blood cells) and blood flow (by iodoantipyrine infusion). In addition, the time course of 18F-ES metabolism and the tissue distribution of the metabolites was studied. Metabolism of 18F-ES is very rapid, and after 2 h, most of the activity in blood and nontarget tissues is due to metabolites; target tissue activity, however, is due mainly to unmetabolized compound. Most of the circulating activity, both 18F-ES and its metabolites, is strongly associated with macromolecules or cells, and while the metabolites are not taken up selectively by target tissues, they do enter nontarget tissues. Tumor blood volume and blood flow vary widely, but not in a way that appears related to tumor necrosis. The uptake of 18F-ES by the uterus and DMBA-induced mammary tumors of adult rats reaches maximum levels (ca 0.35 and 0.10% I.D./g X kg, respectively) at early times (0-1 h), and drops slowly thereafter. The uterus to nontarget or tumour to nontarget tissue ratios, however, start low and continue to increase, reaching maximum levels (ca 20 and 15, respectively) at 2-3 h. There does not, however, appear to be a simple relationship between tumor uptake (either as % I.D./g X kg or tumor to nontarget ratio) measured at a single 3 h time point and tumor ER content, even considering differences in tumor blood flow. This suggests that an estimation of tumor ER content will require the application of more complex pharmacodynamic models that involve the measurement of the complete profile of receptor lignad uptake, retention, and washout from target to nontarget areas. The application of such models will be assisted by the development of estrogen receptor binding ligands that are not converted to circulating metabolites.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1987

Positron emission tomographic measurement of cerebral blood flow and permeability-surface area product of water using [15O]water and [11C]butanol.

We have previously adapted Kety's tissue autoradiographic method for measuring regional CBF in laboratory animals to the measurement of CBF in humans with positron emission tomography (PET) and H2(15)O. Because this model assumes diffusion equilibrium between tissue and venous blood, the use of a diffusion-limited tracer, such as H2(15)O, may lead to an underestimation of CBF. We therefore validated the use of [11C]butanol as an alternative freely diffusible tracer for PET. We then used it in humans to determine the underestimation of CBF that occurs with H2(15)O, and thereby were able to calculate the extraction Ew and permeability-surface area product PSw of H2(15)O. Measurements of the permeability of rhesus monkey brain to [11C]butanol, obtained by means of an intracarotid injection, external detection technique, demonstrated that this tracer is freely diffusible up to a CBF of at least 170 ml/min-100 g. CBF measured in baboons with the PET autoradiographic method and [11C]butanol was then compared with CBF measured in the same animals with a standard residue detection method. An excellent correspondence was obtained between both of these measurements. Finally, paired PET measurements of CBF were made with both H2(15)O and [11C]butanol in 17 normal human subjects. Average global CBF was significantly greater when measured with [11C]butanol (53.1 ml/min-100 g) than with H2(15)O (44.4 ml/min-100 g). Average global Ew was 0.84 and global PSw was 104 ml/min-100 g. Regional measurements showed a linear relationship between local PSw and CBF, while Ew was relatively uniform throughout the brain. Simulations were used to determine the potential error associated with the use of an incorrect value for the brain-blood partition coefficient for [11C]butanol and to calculate the effect of tissue heterogeneity and errors in flow measurement on the calculation of PSw.

Adolescent↗
PubMed1987

MPTP-induced up-regulation of in vivo dopaminergic radioligand-receptor binding in humans.

We measured in vivo dopaminergic receptor binding using positron emission tomography and 18F-spiperone in an untreated symptomatic subject with MPTP-induced parkinsonism. Our technique determines four variables related to entry of 18F-spiperone into brain tissue and subsequent binding to receptors: (1) the combined forward-rate constant k1' (equal to the product of the maximum number of available specific binding sites, Bmax, times the association rate constant [ka] of 18F-spiperone and receptor); (2) the binding site dissociation rate constant k-1; (3) the free fraction of radioligand not specifically bound in brain tissue, f2; and (4) the regional permeability-surface-area product (PS) of the blood-brain barrier for spiperone. PS and f2 in the patient were not different from that of 10 normal volunteers, whereas the combined forward-rate constant (left caudate: k1' = 67.6 sec-1, normal = 0.140 +/- 0.056) and the dissociation rate constant (left caudate: k-1 = 0.116 sec-1, normal = 0.000339 +/- 0.000149) were evaluated. These findings provide potential new insights not only into the pathophysiology of this disease but into the clinical importance of dopamine receptor function as well.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1987

Fluorine-18 labeling of proteins.

Two fluorine-18-labeled reagents, methyl 3-[18F]fluoro-5-nitrobenzimidate and 4-[18F]fluorophenacyl bromide, have been prepared for covalent attachment of fluorine-18 to proteins. Both reagents can be prepared in moderate yields (30-50%, EOB) in synthesis times of 50-70 min. Reaction of these reagents with proteins (human serum albumin, human fibrinogen, and human immunoglobulin A) is pH independent, protein concentration dependent, and takes 5-60 min at mild pH (8.0) and temperature (25-37 degrees C), in yields up to 95% (corrected). The 18F-labeled proteins are purified by size exclusion chromatography.

Fibrinogen↗
PubMed1986

Synthesis of no-carrier-added N-([18F]fluoroalkyl)spiperone derivatives.

3-N-([18F]fluoroalkyl)spiperone derivatives (2,3) can be prepared by N-alkylation of spiperone (1) with fluoroalkyl halides. The fluoroalkylating species 2-[18F]fluoroethyl bromide (7), 3-[18F]fluoropropyl bromide (8) and 4-[18F]fluorobutyl bromide (9) were prepared by [18F]fluoride ion displacement of the corresponding trifluoromethanesulfonates (triflates 4,5,6). By this method, the 2-[18F]fluoroethyl-, 3-[18F]fluoropropyl-, and 4-[18F]fluorobutyl spiperone derivatives (2a-c) can be prepared and purified rapidly and conveniently, within 40 min, in yields of 30-40% (end of synthesis, EOS). An alternative approach, suitable for the preparation of 2-[18F]fluoroalkyl (ethyl, propyl, butyl, pentyl and hexyl) spiperone derivatives (3a-d), involves iodo[18F]fluorination of terminal olefins, followed by N-alkylation of spiperone. This sequence is less convenient and proceeds in lower overall yields (less than 5%).

Chromatography, High Pressure Liquid↗
PubMed1986

Synthesis and biodistribution of 18F-labeled fluoronitroimidazoles: potential in vivo markers of hypoxic tissue.

Three 18F labeled fluoronitroimidazoles have been prepared as potential in vivo markers of hypoxic cells in tumors, and ischemic areas of the heart and brain. 1-(2-Nitroimidazolyl)-3-[18F]fluoro-2-hydroxypropanol (18F]fluoro-normethoxymisonidazole) 4, 1-(2-[18F]fluoroethyl)-2-nitroimidazole 7, and 1-(2-[18F]-fluoroethyl)-2-methyl-5-nitroimidazole ([18F]fluoro-norhydroxymetronidazole) 10 were prepared in average radiochemical yields of less than 1%, 23% and 15-43% (8% at the no carrier-added level) respectively at end-of-synthesis. The in vivo biodistribution in rats was determined for each of the 18F labeled fluoronitroimidazoles. At 1 and 3 h after administration, the tissue distribution of each of the 18F labeled nitroimidzaoles was quite uniform and consistent with that of nitroimidazoles previously studied. These results suggest the need for a suitable animal model to evaluate their potential as in vivo markers of hypoxic tissue in the brain.

Animals↗
PubMed1986

2-[18F]fluoroputrescine: preparation, biodistribution, and mechanism of defluorination.

A new radiolabeled analog of putrescine, 18F labeled 2-fluoroputrescine, has been prepared as a potential in vivo imaging agent for prostate and prostate derived tumors. The radiosynthesis yielded 1.5-4.5 mCi amounts of the 18F labeled putrescine analog (1-3% yields at end-of-synthesis), with specific activities ranging from 0.85-4.3 Ci/mmol, in a synthesis time of 2 h. The in vivo biodistribution in mature male rats showed considerable uptake by the bone, indicating defluorination of the compound. In animals pretreated with aminoguanidine, an inhibitor of diamine oxidase, the enzyme important in the metabolism of putrescine, defluorination was markedly reduced, but uptake by the prostate did not improve. These results suggest the need for development of a 18F labeled analog of putrescine which does not defluorinate in vivo, and which has biological properties similar to putrescine.

Animals↗
PubMed1986

NCA 16 alpha-[18F]fluoroestradiol-17 beta: the effect of reaction vessel on fluorine-18 resolubilization, product yield, and effective specific activity.

Although the reported synthesis of the title compound resulted in a high radiochemical yield (43% based on resolubilized 18F), the effective specific activity at EOS was low (166 Ci/mmol). Reduction in the amount of carrier fluoride in the target water improved the effective specific activity of the product, but with a concommitant decrease in the resolubilized yield of the fluoroestradiol (12.7%). A re-examination of the labeling parameters was performed to determine the conditions that would increase the yield of the fluoroestrogen and maintain a high effective activity for the product. Since the amount of resolubilized 18F in THF is important in obtaining high specific activity compounds in this type of synthesis, several types of vessels were investigated to determine their effect on the evaporation of the [18O]H2O target water and subsequent resolubilization of 18F into THF. Of the vessels (Pt crucible, borosilicate glass, siliconized borosilicate glass, Vacutainer), the Vacutainer afforded the highest resolubilization of 18F into THF (90%), resulting in an improved resolubilized yield for the fluoroestradiol (28%) and an increased effective specific activity at EOS for the product (1600-3939 Ci/mmol).

Estradiol↗
PubMed1986

Biodistribution of N-alkyl and N-fluoroalkyl derivatives of spiroperidol; radiopharmaceuticals for PET studies of dopamine receptors.

There is great interest in the application of positron labeled ligands to map the dopamine receptor in vivo. A series of fluorine-18-labeled N-alkyl and N-fluoroalkyl spiroperidol (SP) derivatives N-methyl[18F]SP; N-ethyl[18F]SP; N-(2-[18F]fluoroethyl)SP; N-propyl[18F]fluoropropyl) SP; N-(3-fluoropropyl) [18F]SP; N-(2-[18F]fluoropropyl)SP; N-(2-[18F]fluorobutyl)SP; N-(2-[18F]fluoropentyl)SP; and N-(2-[18F]fluorohexyl)SP were synthesized. The lipophilicity of these ligands (log octanol/water partition coefficient) varies from 2.67 to 5.56 and the initial brain uptake in rats, measured at 2 min, was greatest with the methyl, ethyl, propyl, fluoroethyl, and fluoropropyl derivatives. The highest striatum/cerebellum values 1 h after administration were obtained with the N-methyl, N-propyl, and N-3-fluoropropyl derivatives, while that of N-2-fluoroethyl showed the greatest uptake of total activity in the brain at this time. The uptake of all these ligands in the striatum could be blocked by cold SP showing the striatal uptake to be by the dopamine receptors.

Alkylation↗
PubMed1986

Strategies for in vivo measurement of receptor binding using positron emission tomography.

Dopaminergic ligands labeled with positron-emitting radionuclides have been synthesized for quantitative evaluation of dopaminergic binding in vivo. Two different methods, the explicit method and an operationally simplified ratio method, have been proposed for analysis of these positron emission tomographic (PET) data. The basis for both methods is the same three-compartment model. The two methods differ in the assumptions necessary for practical implementation. We have compared these two approaches using PET data obtained in our laboratory. Sequential scans and serial arterial blood samples from a baboon following intravenous injection of [18F]spiroperidol were collected. Application of the two methods to the same data yielded different values for corresponding parameters. Values calculated by the ratio method for the specific rate constant describing receptor binding varied depending upon the time after tracer injection, thus demonstrating an internal inconsistency in this approach. Tracer metabolism markedly affected the binding measurements calculated with either method and thus cannot be ignored. Our results indicate that the adoption of simplifying assumptions for operational convenience can lead to substantial errors and must be done with caution. Alternatively, we present simple new analytical solutions of the tracer conservation equations describing the complete, unsimplified three-compartment model that vastly reduce the computations necessary to implement the explicit method.

Animals↗
PubMed1986

Application of robotics to radiopharmaceutical preparation: controlled synthesis of fluorine-18 16 alpha-fluoroestradiol-17 beta.

A commercially available robot system, the Zymark Zymate Laboratory Automation System, has been utilized for the preparation of a positron-emitting radiopharmaceutical, 16 alpha-[18F] fluoroestradiol-17 beta. This radiopharmaceutical is prepared in a three-step synthesis (preparation of [18F]-tetrabutylammonium fluoride, SN2 displacement of a triflate, and ketone reduction) and is purified by high performance liquid chromatography (HPLC). All steps in the synthesis and HPLC purification are controlled by the robot system with no manual intervention. This represents a new approach to the complete automation of radiopharmaceutical production.

Automation↗
PubMed1985

Synthesis and uptake of no-carrier-added 1-[11C]putrescine into rat prostate.

No carrier-added 1-[11C]putrescine has been prepared using a simple two-step procedure. Radiochemical yields of 1-2% at end-of-synthesis were obtained in a synthesis time of 50-60 min. The in vivo uptake of no carrier-added 1-[11C]putrescine into rat prostate was determined and compared to the uptake of no carrier-added material containing varying amounts of non-radioactive putrescine. The in vivo results indicate that the mechanism of uptake into the prostate is saturable.

Animals↗