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Biomedical subjects

M J Welch

Publications and source records attributed to M J Welch.

At least 91 records · Page 5Linked to original sources
PubMed1996

Radioimmunotherapy with a 64Cu-labeled monoclonal antibody: a comparison with 67Cu.

67Cu (t1/2 = 62 h) has demonstrated potential as a radionuclide for radioimmunotherapy, but limited availability severely restricts its widespread use. 64Cu (t1/2 = 12.8 h) has been shown to have comparable effectiveness in vitro and in vivo. The present study was undertaken to examine the therapeutic potential of 64Cu- and 67Cu-bromoacetamidobenzyl-1,4,8,11-tetraazacyclotetradeca ne-N, N',N",N"'-tetraacetic acid (BAT)-2-iminothiolane (2IT)-1A3 (1A3 is a mouse anti-human colorectal cancer mAb) for treatment of GW39 human colon carcinoma carried in hamster thighs. Hamsters were injected with 64Cu- or 67Cu-BAT-2IT-1A3 or Cu-labeled nonspecific IgG (MOPC) or saline. Hamsters were killed 6-7 months after therapy or when tumors were > or = 10 g. Of the hamsters with small tumors (mean weight 0.43 +/- 0.25 g), 87.5% were disease-free 7 months after treatment with 2 mCi (1 Ci = 37 GBq) of 64Cu-BAT-2IT-1A3 or 0.4 MCi of 67Cu-BAT-2IT-1A3. The mean tumor doses at these activities of 64Cu- and 67Cu-BAT-2IT-1A3 were 586 and 1269 rad (1 rad = 0.01 Gy), respectively. In contrast, 76% of hamsters treated with 2 mCi of 64Cu-BAT-2IT-MOPC or 0.4 mCi of 67Cu-BAT-2IT-MOPC had to be killed before 6 months because of tumor regrowth. When hamsters with larger tumors (mean weight 0.66 +/- 0.11 g) were treated with 64Cu- or 67Cu-BAT-2IT-1A3, survival was extended compared with controls, but only one animal remained tumor-free to 6 months. These results demonstrate that 64Cu- and 67Cu-BAT-2IT-1A3 given in a single administered dose can eradicate small tumors without significant host toxicity, but additional strategies to deliver higher tumor doses will be needed for larger tumors.

Animals↗
PubMed1996

Indium (III) and gallium (III) complexes of bis(aminoethanethiol) ligands with different denticities: stabilities, molecular modeling, and in vivo behavior.

Complexes of Ga(III) and In(III) radionuclides are widely used in diagnostic imaging. In this study, the following ligands of denticities 4, 5, and 6 respectively were prepared: N,N'-bis-(2,2-dimethyl-2-mercaptoethyl) ethylenediamine (4SS), 1-carboxy-N-N'-bis(2,2-dimethyl-2- mercaptoethyl)ethylenediamine (5SS), and N,N'-bis(2,2- dimethyl-2-mercaptoethyl)ethylenediamine-N,N'-diacetic acid (6SS). Syntheses of the two new ligands, 5SS and 6SS, are described. Equilibrium constants for their In(III) and Ga(III) complexes were determined by both direct and ligand-competitive potentiometric methods. The formation constant (KML = [ML]/[M][L]) of In(III)--6SS in 0.100 M KNO3 at 25.0 degrees C is 10(39.8), and its pM at physiological pH (7.4 with 100% excess of the ligand) is 30.9. These values are higher than those of any other previous reported ligand for In(III). The stability constants of the complexes of 4SS, 5SS, 6SS, and the analogous ligand EDDASS, N,N'-bis(2-mercaptoethyl) ethylenediamine-N,N'-diacetic acid, which does not contain gem-dimethyl groups, are compared. The thermodynamic stabilities of the In(III) complexes of all ligands except 6SS are greater than those of the corresponding Ga(III) complexes. The presence of the geminal dimethyl groups in 6SS increased the stability of the Ga(III) and In(III) complexes over those of EDDASS. The effects of the gem-dimethyl groups on complex stabilities are explained by molecular modeling. The serum stabilities and biodistributions out to 1 h postinjection of 67/68Ga and 111In chelates of 4SS, 5SS, and 6SS were measured and compared with those of EDDASS. The 67/68Ga- and 111In-ligand complexes with more donor atoms showed were more stable in serum, both in vitro and in vivo. The biodistributions of the 67/68Ga- and 111In-ligand complexes exhibited distinct trends. None of the 67/68Ga- and 111In-chelates demonstrated significant heart or brain uptake. The majority of uptake for all compounds was in the liver and kidney. The degree of clearance through the liver corresponded to the thermodynamic stability of the complex. Correlations between in vivo behavior, molecular modeling data, and thermodynamic stability of the complexes are discussed.

Animals↗
PubMed1996

Carbon-11-labeled estrogens as potential imaging agents for breast tumors.

We have prepared two estrogens labeled with carbon-11, 17 alpha-[11C] methylestradiol and 11 beta-ethyl-17 alpha-[11C]methylestradiol, at a specific activity of 300-1000 Ci/mmol (11.1-37 TBq/mmol), and we have determined their in vivo biodistribution in immature female rats. Both compounds accumulated selectively in two target tissues, the uterus and ovaries, reaching levels of 3.5-4.9%ID/g at 20 min and 4.6-6.6%ID/g at 40 min; uterus-to-blood ratios reached 12-23. Uterine uptake showed a saturation dependence with the amount of injected mass, and was displaced by unlabeled estradiol, indicating that this uptake was receptor mediated. These results suggest that these compounds may be useful in estrogen receptor-based imaging of breast tumors.

Animals↗
PubMed1996

Inhaled [13N]nitric oxide: a positron emission tomography (PET) study.

Using positron emission tomography (PET) and nitric oxide radiolabeled with nitrogen-13 (half-life 9.97 min) we probed the distribution and kinetics of inhaled nitric oxide in anesthetized dogs. The washout of this gas after inhalation was much slower than that observed for [13N]nitrogen gas, demonstrating its uptake by lung tissue. The small fraction of radioactivity found in the plasma was determined to be in the form of [13N]nitrate. The administered gas contained < 1 ppm of nonradioactive nitric oxide, which is believed to be below the physiologic threshold for vasorelaxation.

Administration, Inhalation↗
PubMed1996

Preclinical evaluation of fluorine-18-labeled androgen receptor ligands in baboons.

UNLABELLED: A noninvasive method for detecting and quantifying androgen receptors (AR) in metastatic prostate cancer may be helpful in choosing the method of treatment and in better understanding the pathophysiology of this disease. Nine previously synthesized fluorinated androgens exhibited high affinity binding to AR and showed AR-mediated uptake in the ventral and dorsal prostate of the rat. Further evaluation of these agents for PET imaging is needed since sex hormone binding globulin (SHBG), a glycoprotein which binds androgens with high affinity, is absent in rat blood but is present at high levels in the blood of primates. We chose to study three of the nine fluoro-androgens by PET in the baboon. METHODS: In this study, 16beta-[18F]fluoro-5 alpha-dihydrotestosterone (I), 16beta-[18F]fluoromibolerone (II) and 20-[18F]fluoromibolerone (III) were synthesized and studied in both a young and old male baboon using PET. Blood samples were withdrawn in three of the 10 studies and analyzed for total radioactivity and percent unmetabolized radioligand. Tissue radioactivity was evaluated semiquantitatively, using prostate absolute, standard and target to nontarget uptake values. RESULTS: Prostate uptake was observed with all three 18F-androgens. At 60 min postinjection, compound I gave the highest prostate to soft tissue ratios in both baboons and prostate uptake was shown to be AR-mediated by blocking uptake through the coadministration of testosterone. Compound I gave the highest level of unmetabolized radioligand present in blood up to 45 min postinjection, and gave a 37-fold greater prostate-to-bone ratio at 2 hr postinjection in baboons compared to rats. The favorable behavior of this compound in the baboon may be related to its high affinity for SHBG. CONCLUSION: All three compounds can be used to determine AR-positive tissue in primates. Compound I was selected for the evaluation of AR in men with prostate cancer using PET.

Animals↗
PubMed1996

Regional myocardial perfusion assessed with generator-produced copper-62-PTSM and PET.

UNLABELLED: We have previously demonstrated that myocardial perfusion can be estimated accurately in experimental animals with the generator-produced positron-emitting tracer, 62Cu-pyruvaldehyde bis (N4-methylthio- semicarbazone)(62Cu-PTSM) and PET. This study evaluated the feasibility of quantifying regional myocardial blood flow using 62Cu-PTSM and PET in human subjects. METHODS: Regional perfusion was estimated using a previously described and validated two-compartment model from dynamic PET scans obtained after an intravenous bolus of 62Cu-PTSM in 10 healthy volunteers and in 6 patients with coronary artery disease at rest: and in 9 of the volunteers and 4 of the patients after administration of dipyridamole intravenously. Flow estimates were compared with those obtained using H2(15)O. RESULTS: Contrast was high between myocardium and blood or lung with 62Cu-PTSM, resulting in high-quality myocardial images. Liver uptake was also high. At flows of up to 1.5 ml/g/min, flow estimated with 62Cu-PTSM correlated closely with estimates obtained with H2(15)O (y = 0.71x .21, n = 169 regional comparisons, r = 0.66, p < 0.55), but this relationship was not maintained at higher flows. CONCLUSION: The results demonstrate that quantification of myocardial perfusion with 62Cu-PTSM is feasible in human subjects but cannot be used to estimate hyperemic flows due most likely to the strong binding of the tracer to human serum albumin. Copper-62-PTSM congeners with less avidity for human albumin may prove more suitable for evaluation of hyperemic flows.

Adult↗
PubMed1996

Increased enzyme-linked immunosorbent assay specificity with solubilized simian retrovirus 2-infected cell membranes.

Simian type-D retrovirus (SRV) infection is a health problem in captive and wild-caught macaques; it interferes with acquired immune deficiency syndrome-related research. Because the enzyme-linked immunosorbent assay (ELISA) with gradient-purified SRV-2 virus yields a high percentage of false-positive results, the assay was modified with membrane antigens from SRV-2-infected and uninfected A549 cells. The SRV-2 membrane antigen contains the major proteins detected in positive sera by Western blotting: env proteins gp70 and gp20 and gag proteins p27, p14, p12, and p10. The original purified virus ELISA had a specificity of 74% compared with Western immunoblot. The modified ELISA using the difference in optical density between infected and control cell membrane antigens resulted in a specificity of 100% when the same samples were tested.

Animals↗
PubMed1996

Positron emission tomography with 2-[18F]Fluoro-2-deoxy-D-glucose and 16alpha-[18F]fluoro-17beta-estradiol in breast cancer: correlation with estrogen receptor status and response to systemic therapy.

We assessed the value of positron emission tomography (PET) with 2-[18F]fluoro-2-deoxy-D-glucose (FDG) and 16alpha-[18F]fluoro-17beta-estradiol (FES) in women with breast cancer for predicting response to systemic therapy. Results of FES-PET were correlated with estrogen receptor (ER) status. Forty-three women with locally advanced or metastatic breast cancer underwent FDG-PET and FES-PET prior to institution of systemic therapy. All patients had measurable disease and had tumors submitted for ER determination. Cancers were considered functionally hormone sensitive if the standardized uptake value of the lesion on FES-PET was >/=1.0 (FES+) and hormone resistant if the standardized uptake value was <1.0 (FES-). Information obtained by FES-PET was compared with the results of ER assays. The tumor response to chemotherapy and hormonal therapy was correlated with intensity of uptake by both FDG-PET and FES-PET. The ER status of the breast cancers was negative (ER-) in 20 patients, positive (ER+) in 21 patients, and unknown in 2 patients. All 20 of the ER- tumors were also FES-. However, of the 21 ER+ tumors, 16 were FES+ and 5 were FES-. Thirty patients were treated initially with chemotherapy, and 21 (70%) demonstrated objective responses. We were unable to correlate the response to chemotherapy with information obtained by FDG-PET or FES-PET. Thirteen patients were treated with hormone therapy, and 8 (61%) responded to that therapy. Only 1 of the 5 patients whose tumors were ER+ but FES- received hormone therapy, and this treatment resulted in disease stabilization only. Multiple sites of disease were assessed by FES-PET in 17 patients with metastatic breast cancer. Functional hormone sensitivity, defined by FES-PET, was concordant with multiple lesions in 13 (76%). Ten patients with locally advanced breast cancer developed recurrent disease. The initial site of recurrence was the breast in 5 patients. Of the 5 patients with systemic recurrence, 4 had disease detected at the site of recurrence on the pretreatment FDG-PET study but not detected on pretreatment computed tomography. In our experience, FDG-PET imaging is more sensitive than conventional imaging methods, including computed tomography, in staging women with breast cancer. When compared with the in vitro assay of ER status, FES-PET has an apparent sensitivity of 76% and specificity of 100%. Our finding of a subset of patients who have tumors that are ER+ and FES- suggests that the functional assessment of hormone sensitivity by PET imaging can identify patients with ER+ disease whose tumors are likely to be hormone refractory.

Adult↗
PubMed1995

Identification of metabolites of 111In-diethylenetriaminepentaacetic acid-monoclonal antibodies and antibody fragments in vivo.

The in vivo fate of various 111In-labeled polypeptides has been the subject of many investigations. Intracellular metabolism has been studied through the use of 111In-labeled glycoproteins that are concentrated in the lysosome by receptor-mediated endocytosis. These studies have indicated that the main lysosomal metabolite is 111In-chelate-epsilon-lysine, both in vitro and in vivo (Y. Arano et al., J. Nucl. Med., 35: 890-898, 1994; F. N. Franano et al., Nucl. Med. Biol., 21: 1023-1034, 1994). Since the vast majority of radiolabeled antibodies do not localize within the target tissue, an understanding of the metabolism of 111In-labeled antibodies in nontarget tissues is important for the rational design of future radiolabeled antibodies. We investigated the in vivo metabolism of 111In-DTPA3-conjugated antibody in female Sprague-Dawley rats using the anticolorectal carcinoma monoclonal antibody (MAb) 1A3 and MAb 1A3-F(ab')2. Livers and kidneys were harvested from rats injected with either intact MAb or MAb fragments and analyzed by gel filtration chromatography. Thirty-five % of the radioactivity from 111In-DTPA-1A3 MAb present in the liver was in the form of a low molecular weight species at 1 through 5 days. In contrast, 111In-DTPA-1A3-F(ab')2 was > 98% degraded to a low molecular weight species in the kidney after 1 day. In each case, the low molecular weight metabolites were collected and further analyzed by silica gel thin-layer chromatography, reversed phase high-performance liquid chromatography, and ion-exchange chromatography and compared to 111In-DTPA and 111In-DTPA-epsilon-lysine standards. In each system, the major metabolite co-eluted with 111In-DTPA-epsilon-lysine, similar to the results obtained with 111In-labeled glycoproteins that are delivered to lysosomes by receptor-mediated endocytosis. A minor metabolite that was more highly charged than 111In-DTPA was also observed. Analysis of urine and feces demonstrated that the main excretory product of both 111In-labeled intact 1A3 and 1A3-F(ab')2 was 111In-DTPA-epsilon-lysine. Based on this data, we propose that 111In-DTPA-antibodies are degraded within lysosomes of nontarget organs such as the liver and kidneys.

Animals↗
PubMed1995

Synthesis of 11 beta-[18F]fluoro-5 alpha-dihydrotestosterone and 11 beta-[18F]fluoro-19-nor-5 alpha-dihydrotestosterone: preparation via halofluorination-reduction, receptor binding, and tissue distribution.

We have prepared 11 beta-fluoro-5 alpha-dihydrotestosterone (11 beta-F-DHT, 1) and 11 beta-fluoro-19-nor-5 alpha-dihydrotestosterone (11 beta-F-19-nor-DHT, 2) in order to investigate the properties of these new androgens labeled with fluorine-18 as potential androgen receptor (AR)-based imaging agents for prostate cancer. These compounds were synthesized in 6 steps from hydrocortisone and in 13 steps from 1,4-androstadiene-3,11,17-trione, respectively. Relative binding affinities (RBA) of 11 beta-F-DHT and 11 beta-F-19-nor-DHT to AR are 53.1 and 75.3 (R1881 = 100), respectively, the latter being the highest reported among fluorine-substituted androgens. The fluorination step, which involves addition of halogen fluoride across the 9(11)-double bond, followed by reductive dehalogenation at the 9 alpha-position has been adapted to introduce a fluorine-18-label at the 11 beta-position of DHT and 19-nor-DHT. The two high-affinity F-18-labeled ligands [18F]-1 and [18F]-2 were evaluated in vivo, in tissue distribution studies using diethylstilbestrol-pretreated mature male rats. 11 beta-F-DHT shows high prostate uptake and selective prostate to blood and prostate to muscle uptake ratios, the latter two ratios increasing from 5 and 8 at 1 h to 12 and 19 at 4 h postinjection. Moreover, this compound has low uptake in bone, displaying the lowest in vivo defluorination among all androgens labeled with fluorine-18 tested so far. The in vivo properties of 11 beta-F-DHT in rats are thus favorable for imaging of prostate cancer. On the other hand, 11 beta-F-19-nor-DHT shows low prostate uptake with low selectivity and high uptake in liver, kidney, and bladder. Even though this ligand has the highest RBA and undergoes little metabolic defluorination, it appears to suffer from rapid metabolism in vivo. Therefore, it is apparent that the biodistribution properties of androgens are affected by their structure and metabolism as well as by their RBA.

Animals↗
PubMed1995

Fluorine-18-labeled progestin 16 alpha, 17 alpha-dioxolanes: development of high-affinity ligands for the progesterone receptor with high in vivo target site selectivity.

We describe the synthesis and tissue biodistribution of two 21-[fluoro-18F]progestin 16 alpha, 17 alpha-furanyl ketals, potential agents for imaging progesterone receptor (PR)-positive breast tumors in humans, using positron emission tomography. 21-Fluro-16 alpha, 17 alpha-[(R)-(1'-alpha-furylmethylidene)dioxy]-19- norpregn-4-ene-3,20-dione (endo-10a) and 21-fluoro-16 alpha, 17 alpha-[(R)-(1'-alpha-furylethylidene)dioxy]-19- norpregn-4-ene-3,20-dione (endo-10b) were chosen for radiochemical synthesis from a series of seven novel progestin 16 alpha, 17 alpha-(furanyldioxolanes) on the basis of their high relative binding affinity to PR (190% and 173%, respectively, relative to R5020 = 100%), their low nonspecific binding (NSB) (log P o/w = 3.87 and 4.13, respectively), and their resulting high binding selectivity indices (BSI; i.e., the ratio of their PR binding affinity to nonspecific binding). Radiochemical synthesis of these two species in high radiochemical purity and at high effective specific activity was accomplished by treatment of the corresponding diastereomerically pure 21-trifluoromethanesulfonates with fluorine-18 anion. In tissue biodistribution studies in estrogen-primed immature female Sprague-Dawley rats, both [18F]-endo-10a and [18F]endo-10b demonstrated high PR-selective uptake in the principal target tissues, the uterus and the ovaries, and relatively low uptake in fat and bone. The metabolism at the 21-position in these progestins (as monitored by in vivo defluorination) appears to be less than that in other 21-fluoroprogestins; this may reflect steric inhibition of metabolism at this site due to the bulk of the furan-substituted dioxolane ring at the 16 alpha, 17 alpha-position. Comparison with other fluorine-18-labeled progestins shows that the PR-specific uptake in uterine tissue correlates with the BSI of the ligand and that the fat uptake correlates with the NSB of the ligand at high levels of statistical significance. These two dioxolanes may prove to be useful as breast tumor-imaging agents in humans.

Animals↗
PubMed1995

Biodistribution and metabolism of targeted and nontargeted protein-chelate-gadolinium complexes: evidence for gadolinium dissociation in vitro and in vivo.

The intracellular metabolism of receptor-targeted 153Gd-DTPA-glycoproteins was studied in vitro and in vivo. These agents bound to cell surface receptors, underwent receptor mediated endocytosis, and were rapidly degraded to a metabolite which co-migrated with a 153Gd-DTPA-lysine standard on thin layer chromatography. The rates of dissociation of 153Gd and 111In from a glycoprotein-chelate conjugate were determined in vitro. Gadolinium readily dissociated, in a pH-sensitive manner, from glycoprotein-DTPA, and to a lesser degree glycoprotein-MX-DTPA. The biodistribution of targeted and blood pool 153Gd/111In labeled proteins also suggested that gadolinium dissociates from protein-DTPA and protein-MX-DTPA and their metabolites leading to an accumulation of gadolinium in bone. Metal-DTPA-glycoprotein agents targeted to cell surface receptors can still produce very high concentrations of radioactive or paramagnetic metals within the lysosome due to the high rate of accumulation afforded by receptor mediated endocytosis and the low release rate of metabolites such as metal-DTPA-lysine. However, the continued development of gadolinium based macromolecular agents will require improvements in bifunctional chelates.

Animals↗
PubMed1995

N,N'-ethylene-di-L-cysteine (EC) complexes of Ga(III) and In(III): molecular modeling, thermodynamic stability and in vivo studies.

There are several reports in the literature on the evaluation of chelates containing two nitrogens and two sulfurs (N2S2) as four coordinate ligands (in solution) for gallium and indium radiopharmaceuticals. No thermodynamic stability constants of these ligands were reported, and the stability of these complexes in vivo has been questioned. L,L-Ethylenedicysteine (EC) is a N2S2 ligand that also contains two carboxylic acid moieties for complexation of Ga(III) and In(III) in a hexacoordinate environment. The stability constants of Ga- and In-EC have been determined by potentiometric methods. The stability of In-EC was found to be greater than that of Ga-EC, with stability constants (log K's) of 33.0 and 31.5, respectively. A molecular mechanics evaluation of the Ga- and In-EC complexes support the thermodynamic results. 67Ga- and 111In-labeled complexes of EC were prepared and analyzed by thin layer chromatography and electrophoresis. Both complexes were evaluated in biodistribution studies in normal Sprague-Dawley rats. 111In-EC cleared rapidly through the hepatobiliary system, whereas 67Ga-EC remained in the liver at 1 h post-injection. Although 67Ga-EC was retained in the liver, suggesting instability of the complex in vivo. 67Ga-EC was stable in rat plasma in vivo at 2 h post-injection. Because of the high thermodynamic and in vivo stability of In-EC, derivatives of EC may have applications as bifunctional chelates for 111In-labeled proteins and peptides. More lipophilic analogues of 68Ga-EC may also have potential as myocardial PET imaging agents.

Animals↗
PubMed1995

6 alpha-[18F]fluoroprogesterone: synthesis via halofluorination-oxidation, receptor binding and tissue distribution.

We have evaluated 6 alpha-[18F]fluoroprogesterone as a potential imaging agent for progesterone receptor (PgR)-positive breast cancer. 6 alpha-Fluoroprogesterone (1) was obtained via halofluorination of the C-5 double bond in pregnenolone, followed by oxidation of the 3 beta-OH group, elimination of HBr from C-4,5, and epimerization at the C-6 center. The relative binding affinity (RBA) of 6 alpha-fluoroprogesterone (1) to PgR is 11 (R5020 = 100), and its binding selectivity index (BSI, i.e. the ratio of the RBA to the non-specific binding, NSB) is 14.4; these values are similar to those of progesterone. 17 alpha-Acetoxy-6 alpha-fluoroprogesterone (2) was also prepared by the same method, but was not used for fluorine-18 labeling studies because its binding affinity for PgR is very low (0.9). The synthesis of 1 was adapted to fluorine-18 labeling and although the overall radiochemical yield was low (decay-corrected, 0.3%), progestin [18F]1 was obtained in moderately high effective specific activity (147 Ci/mmol). In vivo distribution studies using estrogen-primed immature female rats showed that 6 alpha-fluoroprogesterone ([18F]1) has low uterine uptake, low target tissue selectivity, and high fat uptake, presumably due to its low RBA and BSI. High uptake in bone, which indicates extensive metabolic defluorination, suggests that the C-6 position of steroids may not be a good site for fluorine-18 labeling.

Animals↗
PubMed1995

Specific, reversible binding of [18F]benperidol to baboon D2 receptors: PET evaluation of an improved 18F-labeled ligand.

[18F]Benperidol ([18F]BP), a positron-emitting analogue of the dopaminergic D2 antagonist benperidol, was evaluated as a radiopharmaceutical for use with positron emission tomography (PET). PET imaging of baboons after i.v. injection of [18F]BP indicated that the radiofluorinated ligand rapidly localized in vivo within dopaminergic receptor-rich cerebral tissues, and that selective disposition was retained for over 2 h. Pretreatment of an animal with unlabeled receptor-specific antagonists prior to injection of [18F]BP confirmed that the radioligand bound specifically to central D2 receptors in vivo, and not to S2 or D1 receptors. [18F]BP bound to D2 receptors in a reversible manner; unlabeled eticlopride displaced D2 receptor-bound [18F]BP in vivo. The radioligand was metabolized in the periphery to polar metabolites which are not expected to cross the blood-brain barrier. [18F]BP has advantages over other tracers as a radiopharmaceutical for PET study of central D2 receptor activity, and can be applied for noninvasive evaluation of the interaction of unlabeled drugs with central D2 receptor sites.

Animals↗
PubMed1995

New hydroxybenzyl and hydroxypyridylmethyl substituted triazacyclononane ligands for use with gallium(III) and indium(III).

The 67Ga(III) and/or 111In(III) complexes of four new hexadentate ligands have been prepared and evaluated in vitro and in vivo. These substituted triazacyclononane ligands bind the metal ion through three tertiary ring nitrogens and three oxygens from pendant phenolic or hydroxypyridyl arms. The hydroxypyridyl moieties increase the aqueous solubility of the metal complexes while retaining a lipophilic character. As indicated by their large positive partition coefficients, the phenolic ligands proved to be significantly more lipophilic than the hydroxypyridyl ligands. Biodistribution in Sprague-Dawley rats indicated that the more lipophilic phenolic complexes cleared the body primarily through the liver, while the less lipophilic hydroxypyridyl complexes cleared rapidly, primarily through the kidney. To differentiate the clearance characteristics of these radiolabeled compounds, radiochemical purity of selected complexes in vivo was measured. The complexes were evaluated for overall charge in vitro and in vivo, in plasma samples. In addition, plasma and urine were analyzed for possible metabolites. With one exception, each complex was unmetabolized in vivo. All complexes and metabolites formed were neutral in vitro and in vivo. Extended stability in serum of selected radiometal complexes has been measured. Each complex measured was stable to exchange with transferrin, up to 72 h, as expected from the large stability constants of the complexes. The clearance characteristics of the hydroxypyridyl and phenolic ligands, however, were markedly different. The rapid hepatic clearance of the phenolic ligands indicates potential as bifunctional chelates for Ga(III) or In(III).

Animals↗
PubMed1995

In vivo measurements of pulmonary angiotensin-converting enzyme kinetics. I. Theory and error analysis.

We developed a procedure for measuring pulmonary angiotensin-converting enzyme kinetics with fluorine-18 fluorocaptopril and positron emission tomography (PET). The method is based on the application of a compartmental receptor model that represents the kinetics of two species of ligand, presumably the trans and cis conformers of captopril. The input function was characterized and includes corrections for the labeled metabolites of fluorocaptopril. Application of the procedure to lung time-activity data obtained with PET produced estimates of kinetic parameters demonstrating fast kinetics for one conformer and slower kinetics for the other. Simulation studies were performed to evaluate the sensitivity of the estimated parameters to errors in the model assumptions and in measured values for variables required for analysis of the PET data. Estimates for two of the kinetic parameters, the amount of perfused unbound functional enzyme normalized to regional lung volume and the association rate constant for the trans conformer, were relatively stable even with large errors in the input data, varying < 30% from true values for all perturbations. Thus, the procedure produces reliable estimates of the kinetics of the trans conformer of captopril as well as theoretical curves that are close to the observed data.

Animals↗