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Biomedical subjects

Michael J. Welch

Publications and source records attributed to Michael J. Welch.

5 recordsLinked to original sources
PubMed1999

Synthesis of 2-[(18)F]Fluoroestradiol, a Potential Diagnostic Imaging Agent for Breast Cancer: Strategies to Achieve Nucleophilic Substitution of an Electron-Rich Aromatic Ring with [(18)F]F(-).

To improve the pharmacokinetics of fluorine-18 labeled estrogens to be used as receptor-based imaging agents for the identification and staging of estrogen-receptor-positive breast carcinoma, we wanted to synthesize 2-[(18)F]fluoroestradiol. This compound has high affinity for the estrogen receptor and also binds very well to sex hormone binding globulin, a protein thought to protect estrogens from metabolism and deliver them to target tissues. We anticipated that this compound might have increased tumor uptake and reduced uptake in the liver. The synthesis of a [(18)F]fluoroaryl estrogen at the high specific activity, no-carrier-added level requires the use of [(18)F]F(-) as a precursor. Several strategies were explored for the synthesis of a [(18)F]fluoroaryl estrogen. The synthesis of 2-[(18)F]fluoroestradiol was eventually achieved by [(18)F]fluoride ion displacement of a trimethylammonium leaving group at C-2 of an estrogen, with additional activation being provided by a 6-keto group which was subsequently removed by reduction. Incorporation yields of fluorine-18 were between 20% and 50%. The potential of this new radiopharmaceutical as an imaging agent is being evaluated in an appropriate animal model.

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PubMed1996

Molecular Mechanics Investigation of Gadolinium(III) Complexes.

Parameters for the commercially available modeling package SYBYL have been developed for Gd(3+) complexes allowing these to be studied with molecular mechanics. With these parameters and a technique termed the "coordination scan", the coordination numbers of Gd(III) based complexes can be predicted, and thus the hydration number q determined. Knowledge of q has allowed the prediction of molar relaxivities based on correlations to literature values. In addition, the calculated value DeltaE(coord) was found to successfully predict the thermodynamic stability constants for polyamino carboxylate ligands with Gd(3+). Gadolinium complexes are commonly utilized as MRI contrast agents, and thus the techniques utilized in this work should aid in the development of new contrast agents.

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PubMed1996

Stability and Structure of Activated Macrocycles. Ligands with Biological Applications.

Single p-toluic acid pendant groups were attached to 1,4,7,10,13-pentaazacyclopentadecane (15aneN5) and 1,4,8,11-tetraazacyclotetradecane (cyclam) to prepare bifunctional reagents for radiolabeling monoclonal antibodies with (64,67)Cu. The ligands are 1,4,7,10,13-pentaazacyclopentadecane-1-(alpha-1,4-toluic acid) (PCBA) and 1,4,8,11-tetraazacyclotetradecane-1-(alpha-1,4-toluic acid) (CPTA). For the parent macrocycles and their pendant arm derivatives, the 1:1 Cu(2+) complexes dissociate only below pH 2. At pH 0.0 and 25 degrees C the CPTA-Cu complex has a half-life toward complete dissociation of 24 days. A new approach was developed for the estimation of the Cu(2+) stability constant for the kinetically robust CPTA. All other formation constants were determined at 25.0 degrees C with batch spectrophotometric techniques. Potentiometric titrations were used to determine the protonation constants of the macrocyclic ligands as well as of the metal chelates. The protonation constants, stability constants, and pM's are discussed in terms of both molecular mechanics calculations and the ligands' potential applicability as copper(II) radiopharmaceuticals.

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PubMed1996

N,N'-Ethylenedi-L-cysteine (EC) and Its Metal Complexes: Synthesis, Characterization, Crystal Structures, and Equilibrium Constants.

N,N'-ethylenedi-L-cysteine (EC) and its indium(III) and gallium(III) complexes have been synthesized and characterized. The crystal structures of the ligand and the complexes have been determined by single-crystal X-ray diffraction. EC.2HBr.2H(2)O (C(8)H(22)Br(2)N(2)O(6)S(2)) crystallizes in the orthorhombic space group P2(1)2(1)2 with a = 12.776(3) Å, b = 13.735(2) Å, c = 5.1340 (10) Å, Z = 2, and V = 900.9(3) Å(3). The complexes Na[M(III)EC].2H(2)O (C(8)H(16)MN(2)O(6)S(2)Na) are isostructural for M = In and Ga, crystallizing in the tetragonal space group P4(2)2(1)2 with the following lattice constants for In, (Ga): a = 10.068(2) Å, (9.802(2) Å), b = 10.068(2) Å, (9.802(2) Å), c = 14.932(2) Å, (15.170(11) Å), Z = 4 (4), and V = 1513.6(5) Å(3), (1457.5(11) Å(3)). In both metal complexes, the metal atoms (In and Ga) are coordinated by six donor atoms (N(2)S(2)O(2)) in distorted octahedral coordination geometries in which two sulfur atoms and two nitrogen atoms occupy the equatorial positions, and the axial positions are occupied by two oxygen atoms of two carboxylate groups. The structures of the complexes previously predicted by molecular mechanics are compared with the crystal structures of the Ga(III) and In(III) complexes obtained experimentally. In contrast to the oxygen donors in phenolate-containing ligands, such as 1,2-ethylenebis((o-hydroxyphenyl)glycine) (EHPG) and N,N'-bis(o-hydroxybenzyl)ethylenediamine-N,N'-diacetic acid (HBED), the thiolate donors of EC enhances affinity for In(III) relative to Ga(III). The following stability sequence has been obtained: In(III) > Ga(III) >> Ni(II) > Zn(II) > Cd(II) > Pb(II) > Co(II). Evidence was also obtained for several protonated and hydroxo species of the complexes of both divalent and trivalent metals, where the corresponding protonation constants (K(MHL)) decrease with increasing stability of the chelate, ML(n)(-)(4), where M(n)()(+) represent the metal ion.

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