PubMed Health⌕ Search

Biomedical subjects

M J Welch

Publications and source records attributed to M J Welch.

At least 19 recordsLinked to original sources
PubMed1992

Evaluation of two new gadolinium chelates as contrast agents for MRI.

Two new gadolinium chelates were investigated for potential use as tissue-specific contrast agents for magnetic resonance imaging. In vitro measurements of stability constants, octanol/water partition coefficients and relaxation times in solutions of water and human serum albumin (HSA) were performed with each new chelate and compared with gadolinium-diethylenetriamine pentaacetic acid, Gd(DTPA). Biodistribution studies and magnetic resonance imaging in rats were used to evaluate the new chelates in vivo. The stability constants (log K) of gadolinium-N,N''-bis(3-hydroxy-6-methyl-2- pyridylmethyl)diethylenetriamine-N,N',N''-triacetic acid, Gd(DTTA-HP), and gadolinium-1,7,13-triaza-4,10,16-trioxacyclooctadecane-N,N', N''-triacetic acid, Gd(TTCT), were determined to be 23.65 and 18.07, respectively. These can be compared to a literature value of 22.46 for Gd(DTPA). Octanol/water partition coefficients for both complexes showed they were more lipophilic than Gd(DTPA). Gd(DTTA-HP) exhibited a smaller relaxivity in water but a larger relaxivity in 4% HSA than Gd(DTPA). Gd(TTCT) exhibited a lower relaxivity than Gd(DTPA) in both water and 4% HSA. Both complexes showed similar biodistributions to Gd(DTPA) no carrier-added concentrations. Gd(DTTA-HP) had a greater percent change in signal intensity than Gd(DTPA) on T1-weighted spin-echo images in the heart, liver, and kidney. Percent change in signal intensity for Gd(TTCT) was lower than Gd(DTPA) in heart, liver, and kidney.

Acetates↗
PubMed1992

Preparation and evaluation of 17-ethynyl-substituted 16 alpha-[18F]fluoroestradiols: selective receptor-based PET imaging agents.

We have prepared and studied six new analogs of 16 alpha-fluoroestradiol (FES): 17 alpha- and 17 beta-ethynyl-FES (7 [FEES] and 7a), and the 11 beta-ethyl (8 and 8a) and 11 beta-methoxy (9 and 9a) derivatives, novel estrogen receptor-based PET imaging agents. The relative binding affinity (RBA) for the estrogen receptor (ER) versus FES is increased for 7, 9 and 9a but decreased for 7a, 8 and 8a. All six analogs have been labeled in the 16 alpha position with 18F by the nucleophilic displacement of the corresponding 16 beta-trifluoromethanesulfonate with nBu4N18F. Subsequent ethynylation with lithium trimethylsilylacetylide yielded the FEES analogs (total synthesis time: 120 min; effective specific activity: 200-2400 Ci/mmol). Selective uptake in the uterus was high for [18F]7, [18F]8, [18F]9 and [18F]9a (% ID/g values at 1 h: 11.2, 12.9, 9.9 and 8.3, respectively), while uptake was effectively blocked by coinjection of an excess of unlabeled estradiol. The FEES analogs, [18F]7, [18F]8 and [18F]9, exhibited the highest selectivity, in terms of target (uterus)-to-blood ratios, ever seen amongst estrogen radiopharmaceuticals, 154, 145 and 169, respectively. The analogs [18F]7a and [18F]8a displayed no uptake in the uterus, consistent with their low RBAs. Metabolism studies revealed that most of the uterine activity is unmetabolized while the blood exhibits a rapid and subsequently sustained mixture of metabolites. The muscle shows a metabolic profile intermediate to the uterus and blood. These analogs provide an array of desirable characteristics for the optimal PET imaging of ER-rich target tissues.

Animals↗
PubMed1992

68GaTHM2BED: a potential generator-produced tracer of myocardial perfusion for positron emission tomography.

THM2BED [N,N,N',N'-tetrakis-(2-hydroxy-3,5-dimethylbenzyl)ethylenediamine] is a new hexadentate ligand which has been synthesized and complexed with gallium isotopes. A conditional stability constant of 22.3 and a pM value of 20.7 have been determined for GaTHM2BED at physiological pH. Hexachelated and pentachelated complexes of GaTHM2BED have been isolated via preparatory HPLC and evaluated individually. The hexachelated isomer of 68GaTHM2BED clears slowly from the myocardium of rats and at 1 h post-injection the heart-to-blood ratio is 1.65. The data ratio indicates that this radiotracer may be capable of measuring blood flow in the heart. The ability of 68GaTHM2BED to delineate myocardial tissue in a dog has been evaluated and good images were obtained using hexachelated 68GaTHM2BED. There is evidence that this complex penetrates the blood-brain barrier.

Animals↗
PubMed1992

Fluorine-substituted corticosteroids: synthesis and evaluation as potential receptor-based imaging agents for positron emission tomography of the brain.

We have prepared eight fluorine-substituted corticosteroids representing ligands selective for Type I and Type II corticosteroid receptor subtypes as potential imaging agents for corticosteroid receptor-containing regions of the brain. Receptor binding affinity assays show that fluorine substitution for hydroxyl or hydrogen in these steroids generally results in some reduction in affinity, with the result that the absolute affinity of these fluorine-substituted ligands for receptor is less than that typical for steroid hormones that show receptor-based, target selective uptake in vivo. Five of these compounds were prepared in fluorine-18 labeled form by a simple sulfonate ester displacement reaction, and their tissue distribution was studied in the adrenalectomized rat. There is no selective accumulation nor selective retention of the Type I selective corticosteroids (18F-RU 26752, 21-[18F]fluoroprogesterone, 21-[18F]fluoro-11 beta-hydroxyprogesterone) in either the brain, or other target tissues (pituitary, kidney, liver). The Type II selective corticosteroids (18F-RU 28362, 18F-triamcinolone acetonide) show uptake into the hippocampus which can be partially blocked by a competing ligand; in target tissues outside the brain, the blocking is more complete. All of the 18F-labeled compounds show considerable defluorination, evident as high bone activity levels. These results, coupled with earlier findings in the literature, suggest that radiolabeled corticosteroid receptor ligands with both greater metabolic stability and higher receptor binding affinity and selectivity are needed for imaging corticosteroid receptors in the hippocampus.

Adrenal Cortex Hormones↗
PubMed1992

Estrogen platinum-diamine complexes: preparation of a non-steroidal estrogen platinum-diamine complex labeled with platinum-191 and a study of its binding to the estrogen receptor in vitro and its tissue distribution in vivo.

We have prepared in radiolabeled form (platinum-191) a non-steroidal estrogen platinum-diamine complex (Pt-diamine complex) that is reported to have selective cytostatic activity in estrogen receptor positive mouse mammary tumors. We then studied the interaction of this metal radiolabeled complex with the estrogen receptor in vitro and its distribution in immature rats in vivo. The radiolabeled complex was prepared by incubation of the non-steroidal estrogen diamine with [191Pt](II)Cl(-2)4 (t 1/2 = 2.96 days, sp. act. 7.54 Ci/mmol) in dimethylformamide (DMF)/H2O, followed by purification by HPLC. The final radiolabeled product coeluted with an authentic standard of the unlabeled Pt-diamine complex, with a retention time distinct from those of the precursor diamine and chloroplatinate. In competitive radiometric receptor binding assays with rat uterine estrogen receptor, samples of the unlabeled diamine and Pt-diamine complex have apparent binding affinities of 53 +/- 3% and 32 +/- 11%, respectively, relative to estradiol (RBA = 100% as standard). However, attempts to observe the binding of the 191Pt-diamine complex with the estrogen receptor were complicated by a very high level of non-receptor binding, an irreversible binding to proteins in the receptor preparation, and a degradation of the platinum complex that, in part, releases the diamine. As a result, it is difficult to be certain whether the binding affinity measured for the Pt-diamine complex in the competitive binding assays is due to the complex itself, or whether it arises from diamine released upon degradation of the complex. In tissue distribution studies in immature female rats, much of the 191Pt-diamine complex was deposited in the liver; there was no evidence of selective uptake of this compound by estrogen target tissues. Thus, it is not clear, from these studies, that the observed bioactivity of this complex arises from the interaction of the Pt complex or the diamine ligand with the estrogen receptor.

Animals↗
PubMed1992

Method for detection of simian immunodeficiency virus neutralizing antibodies using a noncommercial antigen capture enzyme-linked immunosorbent assay.

A neutralization test (NT) using a noncommercial antigen capture enzyme-linked immunosorbent assay (ELISA) to detect simian immunodeficiency virus (SIV) growth in vitro was developed. The capture antibody was a mixture of purified macaque anti-SIV immunoglobulin G (IgG) and a monoclonal antibody to SIV p27. Captured antigens were detected by using purified macaque anti-SIV IgG conjugated to horseradish peroxidase. The NT reliably and sensitively detected differences when various amounts of SIV were used with positive and negative control macaque sera. Dilutions of sequential sera from a macaque (Macaca nemestrina) that had been experimentally infected with SIV were tested for neutralizing antibody with 300 50% tissue culture infective doses of SIV. In this macaque, neutralizing activity and anti-SIV IgG levels in serum (detected by ELISA) increased with time after SIV inoculation, and high IgG titers were required in serum before neutralization occurred in vitro. This simple NT, which detects the presence of SIV serum neutralizing antibodies at a low cost, will be useful for investigating the role of neutralizing antibodies in the SIV-infected macaque model for AIDS.

Animals↗
PubMed1992

Adrenal function in adult asthmatics during long-term daily treatment with 800, 1,200, and 1,600 micrograms triamcinolone acetonide. Multicenter study.

A study to assess the effect of the long-term use of triamcinolone acetonide (TA) on adrenal function was conducted with 143 male and female patients with asthma who were randomly assigned to receive 800, 1200, or 1,600 micrograms of TA daily for six months. Adrenal function was assessed prior to treatment and after two weeks and one, three, and six months of TA use. The effect of TA was evaluated by measuring plasma cortisol levels just prior to and 30 min after a bolus IV injection of 0.25 mg cosyntropin. Adrenal suppression was assumed if the plasma concentration of cortisol did not increase by at least 7 micrograms/dl from the prestimulation value, and remained below 18 micrograms/dl 30 min after the cosyntropin injection. Urine collected for 24 h prior to each cosyntropin stimulation was assayed for free cortisol and related metabolites to confirm suppression. Although all treatment regimens caused some reduction in the 24-h excretion of corticosteroid products, none of the mean values was below the normal ranges. The mean data indicate that TA had no significant effect on adrenal function at any dose or at any time for the patients overall. Individually, three patients exhibited some reduction in adrenal function.

17-Hydroxycorticosteroids↗
PubMed1992

Copper-64-labeled antibodies for PET imaging.

In the imaging of tumors using radiolabeled monoclonal antibodies, the use of PET gives increased sensitivity over conventional gamma camera imaging techniques. Copper-64, a positron-emitting radionuclide, has been labeled to 1A3, an anticolorectal carcinoma monoclonal antibody, and its fragments 1A3-F(ab')2 utilizing the bifunctional chelate Br-benzyl-TETA. The 64Cu-labeled intact 1A3 and 1A3-F(ab')2 have been evaluated as potential imaging agents for PET. Biodistribution studies of 64Cu-benzyl-TETA-1A3 and 64Cu-benzyl-TETA-1A3-F(ab')2 in tumor-bearing hamsters were compared with those of 111In-Br phi HBED-1A3, 111In-Br phi HBED-1A3-F(ab')2 and 125I-labeled intact 1A3 and 1A3-F(ab')2. Tumor uptake of 64Cu-labeled intact 1A3 and fragments in the hamster model was superior to both 111In- and 125I-labeled intact 1A3 and fragments. Human dosimetry data for 64Cu- and 123I-labeled 1A3 and 1A3-F(ab')2 were calculated from biodistribution data in rats. High kidney uptake of 64Cu-benzyl-TETA-1A3-F(ab')2 precludes clinical study at this time; however, the data shows that 64Cu-benzyl-TETA-1A3 would be suitable for positron tomography imaging of colorectal cancer in patients.

Animals↗
PubMed1992

Technetium- and rhenium-labeled progestins: synthesis, receptor binding and in vivo distribution of an 11 beta-substituted progestin labeled with technetium-99 and rhenium-186.

In an effort to develop radiopharmaceuticals useful for the diagnostic imaging of steroid receptor-positive breast tumors, we have radiolabeled an analog of the antiprogestin RU486 (mifepristone), modified to incorporate an N2S2 chelate system in the 11 beta-position, with 99Tc, 99mTc, and 186Re. For the 99Tc-labeled analogs (3), a syn pair and two individual antidiastereomers (linker methylene versus metal-oxo, relative to the N2S2 plane) were isolated. In competitive radiometric binding assays, the syn pair (3syn1,2) had affinity for the progesterone receptor that was 25% that of (promegestone) R5020 (or 161% that of progesterone), and the individual anti-diastereomers had affinities of 47% (3anti1) and 7% (3anti2) that of R5020 (or 303% and 45% that of progesterone). The specific-to-nonspecific binding ratio of the 99mTc (4) and 186Re (5) 11 beta-linked syn systems are 75/25 and 54/46, respectively. In vivo, conjugates 4 and 5 showed progesterone receptor-mediated uptake in rat uterus, but also high uptake in non-target tissues, presumably because of the high lipophilicity of the metal complexes. Modified systems may be useful in vivo as receptor-directed agents for diagnostic imaging or treatment of steroid receptor-positive tumors.

Animals↗
PubMed1992

Fluorine-18-labeled androgens: radiochemical synthesis and tissue distribution studies on six fluorine-substituted androgens, potential imaging agents for prostatic cancer.

We have synthesized six androgens labeled with 18F as potential imaging agents for prostatic cancer. These include 16 beta-fluorine-substituted testosterone, dihydrotestosterone and mibolerone, 16 alpha- and 16 beta-fluorine substituted 7 alpha-methyl-19-nortestosterone, and 20-fluoro-R1881 (metribolone). All of the radiochemical preparations proceeded in satisfactory yield, giving material with adequately high effective specific activity for the in vivo studies. In the tissue distribution studies in diethylstilbestrol-treated male rats, high selective uptake by the prostate was observed that ranged from 0.39% to 1.21% injected dose (ID)/g at 1 hr and 0.20 to 0.47 at 4 hr, with prostate-to-blood and prostate-to-muscle ratios ranging from 3.28 to 9.45, respectively, at 1 hr and 4.06 to 35.0, respectively, at 4 hr. Those compounds that are likely to be metabolized rapidly showed lower prostate uptake but higher uptake selectivity at 4 hr; at earlier times, uptake selectivities were more comparable. Compounds with a 16 beta-fluorine substituent showed extensive metabolic defluorination, resulting in ca. 50% of the dose being deposited in bone at 4 hr. This is consistent with a 16 alpha-hydroxylation process that may proceed rapidly with these compounds, but would be retarded by a 17 alpha-methylation, blocked by inversion of stereochemistry at C-16, and would not affect fluorine at the C-20 position. These fluoroandrogens, together with 20-fluoromibolerone described previously, are the first positron-emitting androgens to show high affinity and selective uptake by androgen target tissues in vivo, and they may be useful as in vivo prostate imaging agents in man.

Animals↗
PubMed1991

Efficacy of HSV-1 ISCOM vaccine in the guinea-pig model of HSV-2 infection.

The capability of a herpes simplex virus (HSV)-1 ISCOM vaccine to protect against intravaginal HSV-2 challenge infection in guinea-pigs is described. The protective efficacy of the HSV-1 ISCOM vaccine is compared with that of a purified, aqueous HSV-1 antigen preparation administered using a similar immunization schedule. The results show that female guinea-pigs immunized with two doses of HSV-1 ISCOM vaccine, each consisting of 20 micrograms of protein given 2 weeks apart responded with high ELISA and neutralization antibody titres, and are almost completely protected against the clinical effects of intravaginal challenge with 10(5.2) TCID50 of HSV-2. This cross-protection is significantly greater than that observed in guinea-pigs immunized with a single dose of HSV-1 ISCOM vaccine, two doses of aqueous HSV-1 antigen preparation or two doses of a mock ISCOM vaccine. However, none of the vaccine preparations completely prevented HSV-2 replication following challenge. Western blot and radioimmunoprecipitation of sera from immunized guinea-pigs show the HSV-1 ISCOM vaccine preparation to contain the major HSV-1 glycoproteins. These findings are discussed in relation to the value and potential use of HSV-1 ISCOM vaccine in humans.

Animals↗
PubMed1991

A new procedure for labeling alkylbenzenes with [18F]fluoride.

A new procedure for labeling alkylbenzenes with no-carrier-added (nca) [18F]fluoride is reported. This will allow the use of [18F]-for-nitro aromatic nucleophilic displacement reaction for labeling aromatic compounds with no activating groups on the benzene ring. The new procedure involves (A) the [18F]-for-nitro displacement reaction on nitrophenones, and (B) the reduction of [18F]fluorophenones with triethylsilane and trifluoroacetic acid to alkylfluorobenzenes. The desired 18F-labeled alkylbenzenes were prepared in a synthesis time of 1 h with a radiochemical yield of 20% at end-of-synthesis. The procedure has been successfully applied to the synthesis of 18F-labeled alkylating agents, such as 4-[18F]fluorophenethyl bromide, 4, and 4-[18F]fluorophenbutyl chloride, 5. Using the reaction of piperidine and 4 as a model, the potential use of phenethylbromide 4 for labeling biologically important amines was examined. Initial results indicated that the desired alkylated piperidine was formed in low yields (less than 5%) due to the conversion of halide 4 to [18F]fluorostyrene (greater than 85%) under basic conditions. The new procedure provides an easy method of labeling alkylbenzenes with fluorine-18.

Benzene Derivatives↗
PubMed1991

Investigation of copper-PTSM as a PET tracer for tumor blood flow.

Copper-PTSM has been shown in previous studies to act as a fluid microsphere and to be useful in quantitating blood flow in brain, myocardium, and kidneys. In this study we have evaluated this agent as a PET tumor blood flow agent. 64Cu- or 67Cu-labeled Cu-PTSM was administered (i.v.) to Golden Syrian hamsters with colorectal carcinoma cell implants (GW39). One minute prior to sacrifice (10-60 min after Cu-PTSM was administered) 125I-iodoantipyrine (125I-IAP), an agent known to measure tumor blood flow, was administered intravenously by a 3-stage, 1 min ramp infusion. Following sacrifice, samples of tumor and brain were removed (within 40s) and the tumor and brain levels of Cu-PTSM and iodoantipyrine determined. Since the brain uptake of both Cu-PTSM and IAP is perfusion rate limited, the brain was used as a reference organ to normalize tumor levels of the two tracers. The plot of Cu-PTSM versus 125I-IAP tumor/brain ratios showed a good linear correlation (r value of 0.97), suggesting that Cu-PTSM could be used to quantify tumor blood flow. Since the mechanism of Cu-PTSM trapping is likely to be due to glutathione levels in the tissue, and because tumor tissue glutathione levels might vary, the temporal uptake of Cu-PTSM was investigated by PET imaging both the tumor-bearing hamsters and approximately 300 g Copenhagen rats bearing R3227 prostate tumors. The tumors were clearly visualized and the retained copper radioactivity in the tumor was constant over the 30 min imaging period.

Animals↗
PubMed1991

Antibody fragments labeled with fluorine-18 and gallium-68: in vivo comparison with indium-111 and iodine-125-labeled fragments.

Although monoclonal antibodies have been radiolabeled with many different radionuclides, the application of positron emission tomography (PET) to the imaging of radiolabeled antibodies has been limited to the investigation of a small number of long-lived radionuclides. In this study, we labeled F(ab')2 fragments of a mouse monoclonal antibody (BB5-G1) specific for a human parathyroid surface antigen with the positron emitting radionuclides, gallium-68 and fluorine-18. The biodistribution of the fragments was evaluated in a nude mice model and the results were compared to those obtained with fragments labeled with iodine-125 and indium-111 using conventional labeling techniques. All labeled fragments bound to human parathyroid tissue implanted in nude mice, with parathyroid-to-muscle ratios reaching as high as 10:1, 4 h after administration. A major difference was observed in the uptake and clearance of the various labeled fragments through the kidney. The halogen activity cleared, but the metal radioactivity was retained in the kidney. The results indicate that the fluorine-18 or gallium-68 labeled fragment may be useful for parathyroid imaging with positron emission tomography.

Albumins↗
PubMed1991

Positron labeled muscarinic acetylcholine receptor antagonist: 2- and 4-[18F]fluorodexetimide. Syntheses and biodistribution.

Two 18F-labeled analogues of dexetimides, 2-[18F]fluorodexetimide (2-FDEX) and 4-[18F]fluorodexetimide (4-FDEX), were prepared and evaluated in vivo as possible agents for the study of the muscarinic acetylcholine receptor (mAChR) with PET. Two synthetic approaches, a 2-step reductive alkylation procedure and a 4-step alkylation approach, were investigated. The alkylation approach with higher overall radiochemical yields was used to prepare 2- and 4-FDEX for biodistribution studies. The overall synthesis time for both compounds was 2.5 h and the overall radiochemical yield at end-of-synthesis was 12%. The specific activity was found to be greater than 600 mCi/mumol. Biodistribution studies of 2-FDEX in rats produced striatum-to-cerebellum and cortex-to-cerebellum ratios of 8.6 +/- 1.1 and 8.4 +/- 1.0 at 1 h after injection, and 12.1 +/- 2.1 and 10.7 +/- 2.2 at 3 h, respectively. Substantial radioactivity detected in bone indicated the in vivo defluorination of 2-FDEX. The striatum-to-cerebellum ratio for 4-FDEX was slightly lower at 1 h (5.9 +/- 0.9) but equally high at 3 h (12.3 +/- 2.0) when compared to 2-FDEX, and there was little bone uptake. The uptake of both 2-FDEX and 4-FDEX into mAChR rich brain regions (e.g. striatum, cortex) was blocked by a dose of dexetimide (5 mg/kg). Our results suggest 4-FDEX is a potential PET agent for study mAChR in vivo.

Acetylcholine↗
PubMed1991

Evaluation of two new bifunctional chelates for radiolabeling a parathyroid-specific monoclonal antibody with In-111.

BB5-G1, a monoclonal antibody specific for human parathyroid cell membrane antigen was conjugated with two new ligands, BrMe2HBED and Br phi HBED and radiolabeled with 111In. We have compared the biodistribution of 111In-labeled BB5 using the new ligands to conventionally labeled (125I-labeled and 111In-DTPA-labeled) BB5 in a nude mouse model. Both 111In-BrMe2HBED-BB5 and 111In-Br phi HBED-BB5 attained high parathyroid-to-blood and parathyroid-to-muscle ratios by 72-96 h. 111In-Br phi HBED-BB5 showed lower %ID/g than 111In-BrMe2HBED-BB5 in the clearance organs, the liver and kidney; renal activity had cleared significantly by 120 h. This work suggests that 111In-Br phi HBED-BB5 offers improved in vitro behavior and may be useful as a radiopharmaceutical for localizing parathyroid tissue.

Animals↗
PubMed1991

TMPHPG: a lipophilic derivative of EHPG for iron, gallium-68 and indium-111 hepatobiliary clearance.

TMPHPG (N,N'-trimethylenebis[2-(2-hydroxy-3,5-dimethylphenyl)glycine]) is a derivative of the ligand EHPG (ethylenebis[2-(o-hydroxyphenyl)glycine]) but is more lipophilic and had been synthesized to increase hepatobiliary clearance. 59Fe(III), 68Ga(III) and 111In(III) complexes of this ligand have been investigated as potential imaging agents for MRI, PET and SPECT, respectively. Metal-dependent differences in blood and liver clearance in mature rats have been evaluated.

Animals↗