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M J Welch

Publications and source records attributed to M J Welch.

At least 55 records · Page 3Linked to original sources
PubMed1999

Synthesis and biological evaluation of Tc-99m-cyclopentadienyltricarbonyltechnetium-labeled octreotide.

Octreotide was labeled at its N-terminus with Tc-99m-cyclopentadienyltricarbonyltechnetium, and the biodistribution of the labeled conjugate was studied in adult female Sprague-Dawley rats. The synthesis began with the preparation of Tc-99m-(methoxycarbonylcyclopentadienyl) tricarbonyltechnetium from Tc-99m-pertechnetate using a novel double ligand transfer reaction; it was completed in a total of five steps, with an 8% overall radiochemical yield (15% decay-corrected). The 99mTc-cyclopentadienyltricarbonyltechnetium-labeled octreotide conjugate (99mTc-CpTT-octreotide) showed receptor-mediated uptake in the pancreas and adrenals, which was blocked (80% and 93%, respectively) by excess unlabeled octreotide. These studies illustrate a new method for labeling a peptide with Tc-99m through an organometallic linkage that is stable, nonpolar, and low molecular weight; it complements labeling approaches that utilize inorganic metal complexes.

Adrenal Glands↗
PubMed1999

Comparative breast tumor imaging and comparative in vitro metabolism of 16alpha-[18F]fluoroestradiol-17beta and 16beta-[18F]fluoromoxestrol in isolated hepatocytes.

16beta-[18F]Fluoromoxestrol ([18]betaFMOX) is an analog of 16alpha-[18F]fluoroestradiol-17beta ([18F]FES), a radiopharmaceutical known to be an effective positron emission tomography (PET) imaging agent for estrogen receptor-positive (ER+) human breast tumors. Based on comparisons of target tissue uptake efficiency and selectivity in a rat model, [18F]betaFMOX was predicted to be as effective an imaging agent as [18F]FES. However, in a preliminary PET imaging study with [18F]FMOX of 12 patients, 3 of whom had ER+ breast cancer, no tumor localization of [18F]betaFMOX was observed. In search for an explanation for the unsuccessful [18F]betaFMOX clinical trial, we have examined the rate of metabolism of [18F]FMOX and [18F]FES in isolated rat, baboon, and human hepatocytes. We have also studied the effect of the serum protein sex hormone-binding globulin (SHBG), which binds [18F]FES better than [18F]betaFMOX, on these rates of metabolism. Immature rat hepatocytes were found to metabolize [18F]FES 31 times faster than [18F]betaFMOX, whereas mature rat cells metabolized [18F]FES only 3 times faster, and baboon and human hepatocytes only 2 times faster than [18F]betaFMOX. In the presence of SHBG, the metabolic consumption rate for [18F]FES in mature rat hepatocytes decreased by 26%. Thus, the very favorable target tissue uptake characteristics of [18F]betaFMOX determined in the rat probably result from its comparative resistance to metabolism (vis-a-vis [18F]FES) in this species, an advantage that is strongly reflected in comparative metabolism rates in rat hepatocytes. In the baboon and human, [18F]FES is extensively protein bound and protected from metabolism, an effect that may be reflected to a degree as a decrease in the rate of metabolism of this compound in baboon and human hepatocytes relative to [18F]betaFMOX. Thus in primates, SHBG may potentiate the ER-mediated uptake of [18F]FES in ER+ tumors by selectively protecting this ligand from metabolism and ensuring its delivery to receptor-containing cells. In addition to current screening methods for 18F-estrogens that involve evaluating in vivo ER-mediated uptake in the immature female rat, studies comparing the metabolism of the new receptor ligands in isolated hepatocytes, especially those from primates or humans, may assist in predicting the potential of these ligands for human PET imaging.

Adult↗
PubMed1999

Synthesis, biological evaluation, and baboon PET imaging of the potential adrenal imaging agent cholesteryl-p-[18F]fluorobenzoate.

Cholesteryl-p-[18F]fluorobenzoate ([18F]CFB) was investigated as a potential adrenal positron emission tomography (PET) imaging agent for the diagnostic imaging of adrenal disorders. We describe the synthesis, biodistribution, adrenal autoradiography, and baboon PET imaging of [18F]CFB. The synthesis of [18F]CFB was facilitated by the use of a specially designed microwave cavity that was instrumental in effecting 70-83% incorporation of fluorine-18 in 60 s via [18F]fluoro-for-nitro exchange. Tissue distribution studies in mature female Sprague-Dawley rats showed good accumulation of [18F]CFB in the steroid-secreting tissues, adrenals and ovaries, at 1 h postinjection. The effectiveness of [18F]CFB to accumulate in diseased adrenals was shown through biodistribution studies in hypolipidemic rats, which showed a greater than threefold increase in adrenal uptake at 1 h and increased adrenal/liver and adrenal/kidney ratios. Analysis of the metabolites at 1 h in the blood, adrenals, spleen, and ovaries of hypolipidemic and control rats showed the intact tracer representing greater than 86%, 93%, 92%, and 82% of the accumulated activity, respectively. [18F]CFB was confirmed to selectively accumulate in the adrenal cortex versus the adrenal medulla by autoradiography. Normal baboon PET imaging with [18F]CFB effectively showed adrenal localization as early as 15 min after injection of the tracer, with enhanced adrenal contrast seen at 60-70 min. These results suggest that [18F]CFB may be useful as an adrenal PET imaging agent for assessing adrenal disorders.

Adrenal Glands↗
PubMed1999

Evaluation of gallium-68 tris(2-mercaptobenzyl)amine: a complex with brain and myocardial uptake.

Previous research into development of a gallium-radiolabeled agent that crosses the blood-brain barrier has met with limited success. In this study, we focused our attention on a Ga(III) complex of a 4-coordinate amine trithiolate tripod ligand, tris(2-mercaptobenzyl) amine (S3N). The Ga(III) S3N complex is small, neutral, and lipophilic, meeting the requirements for a potential brain imaging agent. The Ga-68 complex was easily formed with a radiochemical purity of >95%. In vitro stability of the Ga-S3N complex, determined in rat serum incubated at 37 degrees C, was greater than 95% intact at 2 h by silica gel and reversed-phase radio-thin layer chromatography. Biodistribution studies conducted in female Sprague-Dawley rats showed the complex cleared rapidly from the blood with initial high liver uptake followed by rapid washout. Significant uptake was observed in the brain, with brain:blood ratios increasing from 0.11 at 2 min postinjection to 3.8 at 60 min postinjection. Uptake was also observed in the heart going from a heart:blood ratio of 2.3 at 2 min postinjection to 11 at 60 min postinjection. Molecular mechanics were used to determine the coordination number, and demonstrated that the Ga(III) complex prefers to be 4-coordinate. Imaging studies with 68Ga-S3N in a Nemestrina macaque showed significant brain uptake, similar to other lipophilic agents. The extraction of 68Ga-S3N into the brains of both rodents and primates, higher than any 68Ga agent reported in the literature, suggests that this compound may have potential as a brain imaging agent for positron emission tomography.

Animals↗
PubMed1999

High purity production and potential applications of copper-60 and copper-61.

Previously we described the high yield production of 64Cu using a target system designed specifically for low energy, biomedical cyclotrons. In this study, the use of this target system for the production of 60Cu and 61Cu is described and the utility of these isotopes in the labeling of biomolecules for tumor and hypoxia imaging is demonstrated. 60Cu and 61Cu were produced by the 60Ni(p,n)60Cu, 61Ni(p,n)61Cu, and 60Ni(d,n)61Cu nuclear reactions. The nickel target (>99% enriched or natural nickel) was plated onto a gold disk as described previously (54-225 microm thickness) and irradiated (14.7 MeV proton beam and 8.1 MeV deuteron beam). The copper isotopes were separated from the nickel via ion exchange chromatography and the radioisotopic purity was assessed by gamma spectroscopy. Yields of up to 865 mCi of 60Cu have been achieved using enriched 60Ni. 61Cu has been produced with a maximum yield of 144 mCi using enriched 61Ni and 72 mCi using enriched 60Ni. Specific activities (using enriched material) ranged from 80 to 300 mCi/microg Cu for 60Cu and from 20 to 81 mCi/microg Cu for 61Cu. Bombardments of natural Ni targets were performed using both protons and deuterons. Yields and radioisotopic impurities were determined and compared with that for enriched materials. 60Cu was used to radiolabel diacetyl-bis(N4-methylthiosemicarbazone), ATSM. 60Cu-ATSM was injected into rats that had an occluded left anterior descending coronary artery. Uptake of 60Cu-ATSM in the hypoxic region of the heart was visualized clearly using autoradiography. In addition, 60Cu-ATSM was injected into dogs and excellent images of the heart and heart walls were obtained using positron emission tomography (PET). 61Cu was labeled to 1,4,8,11-tetraazacyclotetradecane-N,N',N",N"'-tetraacetic acid-octreotide (TETA-octreotide) and the PET images of tumor-bearing rats were obtained up to 2 h postinjection. After decay of the 61Cu, the same rat was injected with 64Cu-TETA-octreotide and the images were compared. The tumor images obtained using 61Cu were found to be superior to those using 64Cu as predicted based on the larger abundance of positrons emitted by 61Cu vs. 64Cu.

Animals↗
PubMed1999

Evaluation of 64Cu-ATSM in vitro and in vivo in a hypoxic tumor model.

UNLABELLED: We have evaluated Cu-diacetyl-bis(N4-methylthiosemicarbazone) (Cu-ATSM), an effective marker for the delineation of hypoxic but viable tissue, in vitro in the EMT6 carcinoma cell line under varying degrees of hypoxia and compared it with the flow tracer 64Cu-pyruvaldehyde-bis(N4-methylthiosemicarbazone) (Cu-PTSM) and the hypoxic tracer 18F-fluoromisonidazole (MISO). We have also compared the uptake of Cu-ATSM and Cu-PTSM in vivo and ex vivo in a murine animal model bearing the EMT6 tumor. METHODS: Uptake of 64Cu-ATSM, 64Cu-PTSM and 18F-MISO in vitro into EMT6 cells was investigated at the dissolved oxygen concentrations of 0, 1 x 10(3), 5 x 10(3), 5 x 10(4) and 2 x 10(5) ppm. Biodistribution performed at 1, 5, 10, 20 and 40 min compared 64Cu-ATSM with 64Cu-PTSM in BALB/c mice bearing EMT6 tumors. To determine long-term retention of 64Cu-ATSM, biodistribution was also performed at 1, 2 and 4 h. Ex vivo autoradiography of tumor slices after co-injection of 60Cu-PTSM (60Cu, T1/2 = 23.7 min) and 64Cu-ATSM (64Cu, t1/2 = 12.7 h) into the same animal was performed. RESULTS: After 1 h, 64Cu-ATSM was taken up by EMT6 cells: 90% at 0 ppm, 77% at 1 x 10(3) ppm, 38% at 5 x 10(3) ppm, 35% at 5 x 10(4) ppm and 31% at 2 x 10(5) ppm. 18F-MISO also showed oxygen concentration dependent uptake, but with lower percentages than 64Cu-ATSM. 64Cu-PTSM showed 83%-85% uptake into the cells after 1 h, independent of oxygen concentration. Biodistribution data of 64Cu-ATSM and 64Cu-PTSM showed optimal tumor uptake after 5 and 10 min, respectively (0.76% injected dose (ID)/organ for 64Cu-ATSM and 1.11%ID/organ for 64Cu-PTSM). Ex vivo imaging experiments showed 60Cu-PTSM uniform throughout the EMT6 tumor, but heterogeneous uptake of 64Cu-ATSM, indicative of selective trapping of 64Cu-ATSM into the hypoxic tumor cells. CONCLUSION: Cu-ATSM exhibits selectivity for hypoxic tumor tissue both in vivo and in vitro and may provide a successful diagnostic modality for the detection of tumor ischemia.

Animals↗
PubMed1998

The state of positron emitting radionuclide production in 1997.

Thirty years ago Michel M. Ter-Pogossian and Henry N. Wagner, Jr. wrote an article that was published in Nucleonics on the cyclotron production of isotopes for biomedical research. In this report we use the Nucleonics paper as the framework to relate their predictions to the current state of the art, we have broken this into four key areas; commercially available cyclotrons, costs of operating cyclotron facilities, the emergence of compact accelerators, and the cyclotron production of long-lived radionuclides for therapeutic applications. Companies producing cyclotrons commercially are; General Electric Medical Systems, CTI Cyclotron Systems, EBCO, IBA, NNK/Oxford Instruments, and Japan Steel Works. The majority of these machines are now negative ion systems, which allows the option of dual irradiation of two targets. All have a modular design, which allows the system to be customed to a particular facility's need. Cyclotron facility costs have increased dramatically since 1966. We have determined that the bulk of the increase lies in the costs to establish and staff the facility. Increased regulation by Federal and State organizations has severely impacted operational expenses. The growing demand for PET radiopharmaceuticals in the clinical arena has increased the staffing requirements of the facility. Surprisingly, the costs of cyclotrons have not increased (in terms of real dollars) especially when one considers the much greater sophistication in target design, automation, and computer control that has occurred during this time. Innovative approaches are being taken to develop low energy accelerators that are capable of producing PET isotopes. These are easier to operate and less expensive than commercially available cyclotrons. Although many of these systems have been developed, none have as yet gained commercial recognition. A number of groups have begun to address the production of longer lived isotopes on biomedical cyclotrons. Development of this technology may well help to further progress in targeted radiotherapy. We present an overview of potentially useful isotopes.

Costs and Cost Analysis↗
PubMed1998

Methyl hypofluorite in the synthesis of 16-methoxyestradiol stereoisomers.

The usual chemistry of methyl hypofluorite provides a previously unexplored route for functionalizing the 16-position of estradiol. Three isomers of 16-methoxyestradiol were prepared via two synthetic routes, each using methyl hypofluorite. The estrogen receptor binding affinity of these compounds was determined to evaluate their potential as positron emission tomographic (PET) imaging agents targeting estrogen receptor-positive breast cancer. Radiolabeled methyl hypofluorite ([11C]CH3OF) would allow the rapid preparation of novel carbon-11 PET imaging agents. The 17-trimethylsilyl enol ethers of 3-benzyloxy and 3-trifloxyestrone were prepared as substrates to react with methyl hypofluorite. Conditions for the reaction of methyl hypofluorite with simple substrates were optimized to provide reasonable reaction yields with the steroidal substrates. Following introduction of the methoxy substituent at the 16-position, reduction and deprotection conditions were manipulated to yield the various methoxyestradiol isomers. Two-dimensional NMR techniques (HMQC and HMQC-TOCSY) were instrumental in the characterization of the methoxyestradiol isomers. NOESY experiments confirmed the stereochemistry of the 16- and 17-positions. 16 alpha-Methoxyestradiol-17 beta and 16 beta-methoxyestradiol-17 beta each with the preferred beta orientation for the 17-alcohol, were determined to have relative binding affinities of 1.5% and 2.3%, respectively. The stereoisomer with the unfavored alpha orientation at the 17-position, 16 alpha-methoxyestradiol-17 alpha, exhibited only a 0.5% relative binding affinity for the estrogen receptor. The biological evaluation of these compounds was not pursued further because of their low binding affinities.

Esters↗
PubMed1998

Cellular distribution of 111In-LDTPA galactose BSA in normal and asialoglycoprotein receptor-deficient mouse liver.

111In-LDTPA galactose BSA (bovine serum albumin) was used to evaluate the asialoglycoprotein receptor (ASGPR) system in both normal and ASGPR-deficient mice. The radiolabeled glycoprotein had complete liver uptake in both normal and ASGPR-deficient mice. Metabolism and hepatic cell-type distribution studies were performed. The normal mouse excreted greater than 60% of the hepatic activity, while the ASGPR-deficient mouse excreted less than 40% of the hepatic activity. 111In-LDTPA galactose BSA was metabolized to 111In-LDTPA-L-lysine in both mouse types. Normal mice showed 70% of the radioactivity in the hepatocyte, whereas the homozygous ASGPR-deficient mouse had equal activity in the hepatocyte and the hepatic endothelial cell.

Animals↗
PubMed1998

The in vivo behavior of copper-64-labeled azamacrocyclic complexes.

The use of copper radioisotopes in imaging and therapy applications has created a greater need for bifunctional chelates (BFCs) for complexing copper radioisotopes to biomolecules. It has been demonstrated that the charge and lipophilicity of the Cu-BFC complex has a significant effect on the in vivo behavior of the radiolabeled Cu-BFC-biomolecule conjugate. To evaluate the effects of charge, stability, and macrocyclic backbone size on the biological behavior of 64Cu complexes, a series of macrocyclic 64Cu complexes have been prepared, and the biodistributions of these agents were evaluated in normal Sprague-Dawley rats. Two macrocyclic backbones, dodecane and tetradecane, were evaluated; cyclen, DOTA, and DO2A were dodecane backbone derivatives, and cyclam, TETA, and et-cyclam were tetradecane backbone derivatives. The biodistributions of the 64Cu-labeled complexes correlated with differences in the size of the macrocycle backbone and the formal charge of the complex. All compounds showed uptake and clearance through the liver and kidneys; however, the positively charged 64Cu complexes showed significantly higher uptake in both of these organs than did the negatively charged or neutral complexes. 64Cu-TETA, a negatively charged complex with the tetradecane backbone, had the most efficient clearance by 24 hours' postinjection. These data suggest that negatively charged complexes may have more favorable clearance properties when used as BFCs.

Animals↗
PubMed1998

Positron emission tomography measurements of pulmonary vascular permeability with Ga-68 transferrin or C-11 methylalbumin.

OBJECTIVE: To compare estimates of pulmonary endothelial barrier integrity obtained using two different tracer proteins. DESIGN: Measure the pulmonary transcapillary escape rate with gallium (Ga)-68 labeled transferrin (PTCER(tf)) and positron emission tomography (PET) imaging and compare the results to similar measurements obtained with C-11 labeled methylalbumin (PTCER(alb)). SETTING: Laboratory investigation. SUBJECTS: Mongrel dogs. INTERVENTIONS: No intervention in one group of dogs (n = 3); oleic-acid induced lung injury in another set (n = 4). MEASUREMENTS AND MAIN RESULTS: Although PTCER(tf) was consistently higher than PTCER(alb) (mean difference: 50 x 10(-4)/min), the overall correlation between the two methods, after normalizing for differences in regression slope and intercept among the individual dogs, was excellent (r2 = .67). CONCLUSION: The data support the continued use of PET and Ga-68 transferrin as an appropriate means of evaluating and quantifying lung injury.

Albumins↗
PubMed1998

PET imaging of breast cancer with fluorine-18 radiolabeled estrogens and progestins.

Through the use of fluorine-18 radiolabeled estrogen receptor ligands and Positron Emission Tomography (PET), imaging of estrogen receptor-positive (ER+) breast lesions has been accomplished. Targeting the estrogen and progesterone receptors found in receptor-positive breast cancer provides a means of diagnosing the disease non-invasively. The structure-activity relationship of evaluated fluorine-18 ligands are summarized and design considerations for construction of novel target ligands discussed. The role of the serum protein sex hormone-binding globulin (SHBG) in transport and metabolism of estrogens is related to target tissue uptake. A historical review of fluorine-18 radiolabeled estrogens includes the clinical study of 16 alpha-[18F]fluoroestradiol-17 beta (18FES) for imaging ER+ breast lesions. The success of 18FES in the clinical setting has shown the significance of PET in imaging primary and metastatic breast cancer by allowing for assessment of tumor response to tamoxifen therapy after as little as 7 days of treatment. Advantages of visualizing the tumor through targeting the progesterone receptor (PR) include PET imaging to follow the progress of tamoxifen therapy while the estrogen receptors are blocked. Clinical studies with the PR ligand 21-[18F]fluoro-16 alpha-ethyl-19-norprogesterone (18FENP) were not successful due to high hepatic uptake and poor correlation of tumor uptake with receptor content. Second generation PR ligands with decreased non-specific binding are predicted to be effective imaging agents for human PR+ breast cancer from studies in the immature rat and are ready for clinical evaluation.

Animals↗
PubMed1997

Effect of stereochemistry on the clearance mechanism of 111In(III)-labeled D- or L-benzyldiethylenetriaminepentaacetic acid.

The diethylenetriaminepentaacetic acid (DTPA) derivatives L-Bn-DTPA and D-Bn-DTPA were synthesized and radiolabeled with 111In3+. The uptake and clearance of the compounds were determined through biodistribution and excretion studies in Wistar rats. Both isomers readily cleared from the animal. The D isomer showed relatively high kidney uptake and predominantly renal clearance. The L isomer showed substantial kidney and liver uptake with equal biliary and renal clearance. Clearance was also evaluated in TR- Wistar rats, which are defective in the liver canalicular multispecific organic anion transporter (cMOAT) protein. cMOAT mediates hepatobiliary clearance of many organic anions. Both compounds were excreted through the urine in TR- Wistar rats, suggesting that cMOAT is important in the clearance of the compounds from the liver.

Animals↗
PubMed1997

Hormonal contraception, vitamin A deficiency, and other risk factors for shedding of HIV-1 infected cells from the cervix and vagina.

BACKGROUND: Factors that influence shedding of HIV-1 infected cells in cervical and vaginal secretions may be important determinants of sexual and vertical transmission of the virus. We investigated whether hormonal contraceptive use, vitamin A deficiency, and other variables were risk factors for cervical and vaginal shedding of HIV-infected cells. METHODS: Between December, 1994, and April, 1996, women who attended a municipal sexually transmitted diseases (STDs) clinic in Mombasa, Kenya, and had previously tested positive for HIV-1, were invited to take part in our cross-sectional study. Cervical and vaginal secretions from 318 women were evaluated for the presence of HIV-1 infected cells by PCR amplification of gag DNA sequences. FINDINGS: HIV-1 infected cells were detected in 51% of endocervical and 14% of vaginal-swab specimens. Both cervical and vaginal shedding of HIV-1 infected cells were highly associated with CD4 lymphocyte depletion (p = 0.00001 and p = 0.003, respectively). After adjustment for CD4 count, cervical proviral shedding was significantly associated with use of depot medroxyprogesterone acetate (odds ratio 2.9, 95% CI 1.5-5.7), and with use of low-dose and high-dose oral contraceptive pills (3.8, 1.4-9.9 and 12.3, 1.5-101, respectively). Vitamin A deficiency was highly predictive of vaginal HIV-1 DNA shedding. After adjustment for CD4 count, severe vitamin A deficiency, moderate deficiency, and low normal vitamin A status were associated with 12.9, 8.0, and 4.9-fold increased odds of vaginal shedding, respectively. Gonococcal cervicitis (3.1, 1.1-9.8) and vaginal candidiasis (2.6, 1.2-5.4) were also correlated with significant increases in HIV-1 DNA detection, but Chlamydia trachomatis and Trichomonas vaginalis were not. INTERPRETATION: Our study documents several novel correlates of HIV-1 shedding in cervical and vaginal secretions, most notably hormonal contraceptive use and vitamin A deficiency. These factors may be important determinants of sexual or vertical transmission of HIV-1 and are of public health importance because they are easily modified by simple interventions.

Adolescent↗