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Biomedical subjects

Andrew T Taylor

Publications and source records attributed to Andrew T Taylor.

6 recordsLinked to original sources
PubMed2005

Re(CO)(3) complexes synthesized via an improved preparation of aqueous fac-[Re(CO)(3)(H(2)O)(3)](+) as an aid in assessing (99m)Tc imaging agents. Structural characterization and solution behavior of complexes with thioether-bearing amino acids as tridentate ligands.

Parallel studies of the preparation of Re and (99m)Tc agents aid in interpreting the nature of tracer (99m)Tc radiopharmaceuticals. Aqueous solutions of the fac-[(99m)Tc(CO)(3)(H(2)O)(3)](+) cation are gaining wide use and are readily prepared, but such solutions of the fac-[Re(CO)(3)(H(2)O)(3)](+) cation (1) are not so easily accessible. Herein we describe a new, reliable, and straightforward preparation of aqueous solutions of 1, characterized by HPLC and ESI-MS. Treatment of solutions of 1 with thioether-bearing amino acids, AAH = S-methyl-l-cysteine (MECYSH), S-propyl-l-cysteine (PRCYSH), and methionine (METH), gave high yields of fac-Re(CO)(3)AA complexes. X-ray crystallographic and NMR analyses indicated that MECYS(-), PRCYS(-), and MET(-) were bound in fac-Re(CO)(3)AA complexes as tridentate monoanionic ligands through amino, thioether, and alpha-carboxyl groups. In CD(3)OD, (1)H NMR spectra have broad signals but have two sets of signals at -10 degrees C, consistent with two isomers with different configurations at the pyramidal sulfur; these interconvert slowly on the NMR time scale at low temperatures. Indeed, the crystal structure of the fac-Re(CO)(3)(PRCYS) reveals a mixture of the two possible diastereoisomers. S-(Carboxymethyl)-l-cysteine (CCMH(2)) and 1 gave two products, 5A (kinetically favored) and 5B (thermodynamically favored). X-ray crystallographic analyses of a crystal of 5B and of a 1:1 cocrystal of 5A and 5B showed that 5A and 5B are diastereoisomers with the CCMH(-) alpha-carboxyl group dangling. In addition to the amino and thioether groups, the S-(carboxymethyl) carboxyl group is coordinated, a feature that slows interconversion of diastereoisomers relative to the other fac-Re(CO)(3)AA complexes because interconversion can now occur only after the rupture of Re-ligand bonds. These N, O, and S tridentate adducts are quite stable, and the grouping has promise in (99m)Tc(CO)(3) tracer development.

Amino Acids↗
PubMed2004

Complexes having the fac-[M(CO)3]+ core (M=Tc, Re) useful in radiopharmaceuticals: X-ray and NMR structural characterization and density functional calculations of species containing two sp3 N donors and one sp3 O donor.

Radiopharmaceuticals containing the "fac-[M(CO)3]+ " core (M=99mTc, 186Re, or 188Re) have potential as diagnostic or therapeutic agents. Complexes with this core with sp3 amine donors have received little attention. We have studied adducts formed by ENDACH2 (HO2CCH2NHCH2CH2NHCH2CO2H) and ENACH (NH2CH2CH2NHCH2CO2H). Re(CO)3(ENDACH)-A (1A) and Re(CO)3(ENDACH)-B (1B) isomers were obtained by the reaction of ENDACH2 with Re(CO)5Cl. Re(CO)3(ENAC) (2) was obtained by the reaction of ENACH with aqueous [Re(CO)3(H2O)3]+. From single-crystal X-ray data, the three new neutral complexes, 1A, 1B, and 2, have a six-coordinate, pseudo-octahedral Re center with facially coordinated carbonyl ligands. ENDACH- and ENAC- bind facially to Re through both amine nitrogens and one carboxyl oxygen, forming two five-membered chelate rings. The Re(CO)3(ENDACH) isomers have an uncoordinated, dangling -CH2CO2H group, which is an ideal coupling site for attachment to biomolecules. The isomers differ by the configuration of the NH center bearing this dangling group. The H atom of the amine (N2) is endo (near the carbonyl ligands in the basal plane) in 1A and exo (away from carbonyl ligands) in isomer 1B. Isomers reach equilibrium (1A:1B, 70:30) after 3 days at high pH. Density functional structure optimizations were performed for isolated molecules of the type Tc(I)/Re(I)(CO)3(N2O): [Re(CO)3(NH3)2(H2O)]+, [Tc(CO)3(NH3)2(H2O)]+, [Re(CO)3(EN)(H2O)]+ (EN, ethylenediamine), [Tc(CO)3(EN)(H2O)]+, and various models for 1A, 1B, and 2. The computed structures are in good agreement with the X-ray structures. The theoretical and experimental Re-N bond distances usually agree within 0.045 A. The total electronic energy values for the computed 1A and 1B models differ by 0.815 kcal mol(-1), giving an isomer ratio of 80:20, in good agreement with the 1A/1B ratio (70:30) found.

Crystallography, X-Ray↗
PubMed2004

99mTc-MAEC complexes: new renal radiopharmaceuticals combining characteristics of (99m)Tc-MAG3 and (99m)Tc-EC.

UNLABELLED: 99mTc-Mercaptoacetyltriglycine ((99m)Tc-MAG3) and (99m)Tc-L,L-ethylenedicysteine ((99m)Tc-LL-EC) are useful renal radiopharmaceuticals; however, both agents have renal clearances less than that of (131)I-orthoiodohippurate ((131)I-OIH), and (99m)Tc-LL-EC exists in dianionic and monoanionic forms at physiologic pH. In an effort to develop a superior (99m)Tc agent with a rapid clearance comparable with that of (131)I-OIH, we have designed a new ligand system, mercaptoacetamide-ethylene-cysteine (MAEC), which combines important structural features of both MAG3 and EC. METHODS: Biodistribution and clearance studies were performed on Sprague-Dawley rats using syn- and anti-(99m)Tc-L- and -D-MAEC coinjected with (131)I-OIH. Studies were also performed by coinjecting each isomer ( approximately 74 MBq [ approximately 2 mCi]) and 7.4-11.1 MBq (200-300 micro Ci) of (131)I-OIH in 3 volunteers with dual-isotope imaging performed using a camera system fitted with a high-energy collimator. Blood samples were obtained from 3 to 90 min after injection and urine samples were obtained at 30, 90, and 180 min. RESULTS: In the rats, <10% of the injected dose remained in the blood at 10 min after injection for all isomers, and the urine dose at 60 min ranged from 84% to 99% that of (131)I-OIH. The clearances of syn- and anti-(99m)Tc-L-MAEC in the rats were higher than the clearances for the D-isomers (P <or= 0.02) and were 102% and 105% that of (131)I-OIH, respectively. In humans, the plasma protein binding of the (99m)Tc-MAEC complexes ranged from 82% to 89%. All 4 complexes provided excellent renal images. The (99m)Tc-MAEC complex/(131)I-OIH plasma clearance ratio in humans ranged from 45% (anti-(99m)Tc-L-MAEC) to 74% (syn-(99m)Tc-D-MAEC) with the 180-min urine excretion equivalent to that of (131)I-OIH for all 4 complexes. CONCLUSION: Initial data in humans suggest that syn-(99m)Tc-D-MAEC has a higher clearance than that of (99m)Tc-MAG3; however, none of the (99m)Tc-MAEC tracers have a clearance equivalent to that of (131)I-OIH and further ligand design is needed.

Animals↗
PubMed2002

A Bayesian regression model for plasma clearance.

UNLABELLED: Nonlinear Bayesian regression permits curve fitting to a group of subjects simultaneously rather than individually. We evaluated this approach for interpreting plasma clearance curves with the goal of reducing curve-fitting failures and dealing objectively with problem datasets that may arise in clinical settings. METHODS: (99m)Tc-Diethylenetriaminepentaacetic acid plasma clearance curves from 79 subjects were analyzed. The data typically comprised 7-9 samples obtained from 5-10 to 180-240 min after injection. A 2-compartment model was fitted by Bayesian regression to yield compartmental hyperparameters V1, L21, and L12 corresponding to the volume of the compartment into which tracer was injected and the transfer rates from compartment 1 to compartment 2 and from compartment 2 to compartment 1, respectively. This also yielded a clearance estimate for each subject. RESULTS: Estimated hyperparameters were V1 = 8.9 L, L21 = 0.026 min(-1), and L12 = 0.040 min(-1). Conventional methods led to fitting failures in 2 of the 79 subjects but there were no failures with the Bayesian method. The hyperparameters were used to calculate the glomerular filtration rate for each subject from a single plasma sample with a root-mean-square error of 7.3 mL/min, which was not significantly different from the widely used Christensen-Groth formula. CONCLUSION: Fewer fitting failures were encountered than with conventional methods, offering an objective means of dealing with problem data. This conceptually simple model can be used directly to calculate clearance from a single plasma sample. It requires only the 3 parameters described above, whereas the Christensen-Groth method requires 6 parameters.

Adult↗