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The effect of the tert-alcohol reaction medium for nucleophilic fluorination with alkali metal fluorides is examined by studying various interactions among tert-alcohols, the alkali metal fluoride (CsF) and the sulfonyloxy substrate. The protic environment of the reaction medium, as well as hydrogen bonding between the tert-alcohol and reactive heteroatoms in the substrate, has reduced the side reactions such as eliminations, hydroxylations and intramolecular alkylations.

The synthesis of 2,2-bis-(4-hydroxyphenyl)-cyclopentanone via reductive coupling reaction of 4,4'-dihydroxybenzophenone and cyclobutanone with Ti[Cl.sub.4] and Zn is demonstrated.

Research has been conducted on the progesterone receptor high-affinity ligand, fluoro furanyl norprogesterone. The synthetic route developed for the synthesis of this ligand provides improvement in the yield of the fluoro furanyl norprogesterone.

The article examines a method to improve the diagnosing and staging of breast cancer. Development of imaging radiopharmaceuticals providing a determination of the estrogen receptor status in the tumor cells has been discussed.

The synthesis of 2-((super 18)F)fluoroestradiol, a potential diagnostic imaging compound for breast cancer, was described. The aim was to improve the pharmacokinetics of fluorine-18 labeled estrogens as receptor-based agents for diagnosis and staging of estrogen-receptor-positive breast carcinoma. The preparation of 2-((super 18)F)fluoroestradiol was performed via ((super 18)F)fluoride ion displacement of a trimethylammonium leaving group at the C-2 position of an estrogen.

Synthetic routes to (omega-(super 11)C)palmitic acid were improved through new tracer-level techniques. Three new synthetic approaches to (omega-(super 11)C)palmitic acid gave yields of 75%, 68% and 51% in 45, 55 and 65 min, respectively, from the end of target bombardment. These methods are the cross-coupling of a functionalized alkyl borane with a saturated primaryl alkyl iodide via a Suzuki reaction, the sulfone dianion approach and furan ozonolysis. The former two strategies have distinct advantages, but the Suzuki coupling is more convenient and efficient than the sulfone approach.

The synthesis and evaluation of the spectroscopic properties of two azatetrahydrochrysenes resulting from the inclusion of the (hydroxystyryl)pyridine and (hydroxystyryl)pyrimidine chromophores into the tetrahydrochrysene (THC) ring system, is reported. Absorbance and fluoresence properites relied strongly on solvent polarity and pH, due to the ionizable functionalities. Both systems have potential use as spectroscopic probes.

Oxometal(V) complexes are being developed as high affinity ligands for the estrogen receptor. The complexes could be used as imaging agents for estrogen receptor-positive breast tumors when labeled with technetium-99m, a radionuclide. The synthesis of a tetradentate oxorhenium(V) amino amido thioether thiol (AATT) complex, where metal replaces the CD ring of estradiol, is described. The stability of a new coordination scheme for oxorhenium(V) systems is established.

The syntheses and characterization of three isomeric 1,2-substituted-3,4-dihydronaphthalenes, pyrodine analogs of the antiestrogen desmethylnafoxidine, are presented. The isomers were prepared from alpha-(2-, 3-, and 4-pyridyl)acetophenone precursors. The results showed that all three isomers have high apparent binding affinity for estrogen receptor, and exhibited time-dependent irreversible inactivation.

The synthesis of a bis-bidentate oxorhenium(V) complex, a close structural and stereochemical mimic of the androgen 5(alpha)-dihydrotestosterone, is described. Results of 2D-NMR analysis indicate that the N-methyl and oxo substituents are driven into the steroidal anti configuration (beta-N-methyl, alpha-oxo) by the beta-orientation of the methyl group equivalent to C-18. However, the oxometal mimic exhibited low stability and low lipophilicity, prohibiting its use in vivo.

A number of synthetic routes to alpha- and beta-alkyl enol lactones, which may serve as mechanism-based inhibitors of human neutrophil elastase, are explored. Of these, the Eschenmoser-Tanabe approach proves to be a general method. The zinc-mediated alkylation of 3-ethoxy-2-cyclohexen-1-one is a simple way to give good to excellent yields of primary and secondary alkyl iodides. A four-step alkylation using 1,4-dibromobutane, on the other hand, is the most effective way towards alpha-alkyl-5-hexynoic acids. In subsequent assays, the alpha-alkyls prove to be better inhibitors than the beta-alkyls.

The utilization of an acyloin condensation-double cyclization procedure leads to the synthesis of 5,6,11,12-tetrahydrochrysenes from alpha-alkyl m-methoxyhydrocinnamate esters in quantitative amounts. Introduction of substituents at the C-5 and C-11 of the planar stilbene chromophore enhances the receptor binding affinity of the compound. The compounds exhibit a tetracyclic nature which makes them useful as fluorescent ligands for the estrogen receptor.

A racemic synthesis of 5,6-dihydro-5-fluorouracil (5-DHFU) from 5-fluorouracil (5-FU) or uracil by using p-methoxybenzyl protecting groups followed by L-selectride reduction is reported. 5-DHFU compound have a potential to find use in various biological applications.

Two fluoro steroids, 7[alpha]-(fluoromethyl)dihydrotestosterone and 7[alpha]-(fluoromethyl)nortestosterone, are synthesized in order to examine the role of sex hormone binding globulin (SHBG) in prostate tumor uptake of positron emission tomography (PET) imaging agents. These two fluoro steroids are well matched in terms of their site of fluorine labeling, structure and equivalent androgen receptor (AR) and hence they can be used as agents for evaluating the role of SHBG binding in the target tissue uptake of AR PET imaging agents in humans.

Research has been conducted on 2-hydrazinopyridines. The authors have investigated these compounds as ligands for technetium and rhenium via the study of the palladium-catalyzed reactions of halo-pyridine substrates with di-tert-butyl hydrazodiformate.

States that synthesis and spectroscopic characterization of two azatetrahydrochrysenes as potential fluorescent ligands for the estrogen receptor were studied. Objective of study; Indepth look at how study was conducted; Results of study; Reference to experimental section of the study.

Although protic solvents are generally not preferred for nucleophilic displacement reactions because of their partial positive charge and hydrogen-bonding capacity that solvate the nucleophile and reduce its reactivity, we recently reported a remarkably beneficial effect of using tertiary alcohols as a reaction media for nucleophilic fluorination with alkali metal fluorides, as well as fluorine-18 radiolabeling with [18F]fluoride ion for the preparation of PET radiopharmaceuticals. In this work, we investigate further the influence of the tert-alcohol reaction medium for nucleophilic fluorination with alkali metal fluorides by studying various interactions among tert-alcohols, the alkali metal fluoride (CsF), and the sulfonyloxy substrate. Factors such as hydrogen bonding between CsF and the tert-alcohol solvent, the formation of a tert-alcohol solvated fluoride, and hydrogen bonding between the sulfonate leaving group and the tert-alcohol appear to contribute to the dramatic increase in the rate of the nucleophilic fluorination reaction in the absence of any kind of catalyst. We found that fluorination of 1-(2-mesyloxyethyl)naphthalene (5) and N-5-bromopentanoyl-3,4-dimethoxyaniline (8) with Bu(4)N(+)F(-) in a tert-alcohol afforded the corresponding fluoro products in much higher yield than obtained by the conventional methods using dipolar aprotic solvents. The protic medium also suppresses formation of byproducts, such as alkenes, ethers, and cyclic adducts.

2,2-Bis-(4-hydroxyphenyl)-cyclopentanone (3a) was unexpectedly obtained in 76% yield from a reductive coupling reaction of 4,4'-dihydroxybenzophenone (1a) and cyclobutanone with TiCl4 and Zn. Further optimization showed that catechol as an external ligand and a hydroxy group on benzophenone facilitated the generation of a quinonemethide (intermediate II) that is involved in the pinacol-type rearrangement of intermediate I to give the rearranged product.

The development of (99m)Tc-estradiol radiopharmaceuticals would be advantageous for the detection of estrogen receptor-positive breast tumors. Estradiol derivatives conjugated to organometallic tricarbonyl-Tc(I) and related Re(I) complexes are capable of achieving high receptor binding affinity, but effective methods for synthesizing radiolabeled complexes in water are not available. Our interest in the synthesis of 2-hydrazinopyridines as ligands for Tc and Re led us to investigate Pd-catalyzed amination reactions of halo-pyridine substrates with di-tert-butyl hydrazodiformate. Both 2- and 4-substituted halo-pyridine substrates undergo C-N coupling with di-tert-butyl hydrazodiformate to produce Boc-protected pyridine hydrazine derivatives. Only highly electrophilic 3-pyridine halides were converted to the hydrazine. The Boc-protected 5-bromopyridin-2-yl hydrazine substrate 3 was prepared by regioselective substitution at the 2-position of 2,5-dibromopyridine. This bifunctional chelate was attached to ethynyl or vinyl groups at the 17alpha position of estradiol, using Sonogashira and Suzuki/Miyaura coupling reactions to synthesize 1 and 2 in high yields, respectively. Deprotection of 1 under acidic conditions provided the hydrazine hydrochloride salt 25. The 17alpha-estradiol-tricarbonylrhenium(I) complex 4 was synthesized by labeling 25 with fac-[Re(OH(2))(3)(CO)(3)](+) in aqueous ethanol. This complex exhibited excellent stability and high receptor binding affinity for the estrogen receptor, and it is a promising model for evaluation of the analogous Tc-99m complexes as diagnostic imaging agents for breast tumors.

Two different synthetic routes were explored for the synthesis of fluoro furanyl norprogesterone (FFNP) 1, a high-affinity ligand for the progesterone receptor (PgR) that is being developed as a PET imaging agent for PgR-positive breast cancer. Both approaches proceed through a key intermediate, triol 5. The first approach, starting from keto-ketal 2, employed a dioxenyl group as a synthon for installing a corticosteroid side chain in keto-alcohol 4. The second approach, starting from propargylic acetate 12b, involved the application of a two-step method, a Pd(II)-catalyzed oxidative rearrangement followed by a base-catalyzed acetate rearrangement of the intermediate unsaturated acetate 13b, to generate the requisite corticosteroid side chain in keto-acetate 14b. This intermediate was further elaborated to the final product 1 via efficient dihydroxylation with potassium permangnate, furan acetalization with scandium triflate, and mesylation and fluorination reactions. The palladium-catalyzed route is considerably more efficient than the dioxene approach for the synthesis of key intermediate triol 5, and the scandium triflate-catalyzed acetalization, in particular, led to a considerable improvement in the overall yield of the endo furan acetal alcohol 16a. This route provides a major improvement in the overall yield of the final progestin target, FFNP 1.

The diagnosis and staging of breast cancer could be improved by the development of imaging radiopharmaceuticals that provide a noninvasive determination of the estrogen receptor status in the tumor cells. Toward this goal, we have synthesized a number of novel Re-containing 7alpha-substituted estradiol complexes. The introduction of the 7alpha side chain involves the alkylation of tetrahydropyranyloxy-protected 6-keto estradiol. The methods used to introduce the rhenium metal involve "3 + 1" and "4 + 1" mixed ligand complexes (2a-c and 5, respectively), tricarbonyl dithioether complexes (3), and the cyclopentadienyltricarbonylmetal organometallic system (4ab, 6, 7). These complexes showed binding affinities for the estrogen receptor (as high as 45% for the "3 + 1" complex 2c) when compared to the native ligand estradiol. The polarity of some complexes (4ab) was modified to improve biodistribution properties by introducing (poly)ether linkages into the 7alpha side chain (6, 7). These complexes provide a further refinement of our understanding of ligand structure-binding affinity correlations for the estrogen receptor, and they furnish the synthetic groundwork for the synthesis of the analogous Tc-99m complexes for evaluation as breast tumor imaging agents.

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.

We have prepared a series of bis-bidentate complexes of rhenium that mimic the size, shape, and peripheral functionality of steroidal androgens. In a model system, we used 2D NMR and X-ray crystallographic analysis to show that adjacent N-methyl and oxo substitutents adopt an anti configuration during the coordination reaction. We have synthesized a bis-bidentate oxorhenium(V) complex whose structure and peripheral functionality mimic 5alpha-dihydrotestosterone. 2D-NMR analysis indicates that the N-methyl and oxo substituents are driven into the steroidal anti configuration (beta-N-methyl, alpha-oxo) by the beta-orientation of the methyl group equivalent to C-18. Thus, this metal complex provides a remarkable structural and stereochemical mimic of a steroid. Its in vivo stability, however, appears to be limited.