Linked Life Data

10354410

Source:http://linkedlifedata.com/resource/pubmed/id/10354410

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
11
pubmed:dateCreated
1999-6-24
pubmed:abstractText
We have synthesized several 7alpha-fluoro (F) and 7alpha-iodo (I) analogues of 5alpha-dihydrotestosterone (5alpha-DHT) and 19-nor-5alpha-dihydrotestosterone (5alpha-NDHT) and tested them for binding to the androgen receptor and for their biological activity in an in vitro assay with cells that have been engineered to respond to androgens. The relative binding affinity to the androgen receptor determined in competition assays showed that in the androstane series the fluoro steroids have the highest affinity and that F-17alpha-CH3-DHT (4) has a higher affinity than 5alpha-DHT. All other steroids were somewhat less potent than 5alpha-DHT with F-DHT (2) = I-17alpha-CH3-DHT (3) >/= F-NDHT (6) > F-17alpha-CH3-NDHT (8) = I-DHT (1) >/= I-NDHT (5) > I-17alpha-CH3-NDHT (7). The relative biological activity in cells transfected with the androgen receptor and an androgen responsive reporter gene is 4 >> 5alpha-DHT > 2 > 6 > 3 >/= 1 >/= 8 >/= 5 > 7. The iodinated compound, I-17alpha-CH3-DHT (3), with the highest binding activity was synthesized labeled with 125I and was shown to bind with high affinity, Ka = 1.9 x 10(10) L/mol, and low nonspecific binding to the androgen receptor in rat prostatic cytosol. However, when radiolabeled [125I]-17alpha-CH3-DHT ([125I]3) was injected into castrated male rats, it showed very poor androgen receptor-mediated uptake into the rat prostate. This was unexpected in light of its superior receptor binding properties and its protection by the 17alpha-methyl group from metabolic oxidation at C-17. However, the biological potency of I-17alpha-CH3-DHT (3) was not as high as would have been expected. When I-DHT (1) and I-17alpha-CH3-DHT (3) were incubated in aqueous media at 37 degrees C they rapidly decomposed, but they were stable at 0 degrees C. The fluorinated analogue 4 treated similarly at 37 degrees C was completely stable. The products of the decomposition reaction of I-DHT (1) at 37 degrees C were identified as iodide and principally 17beta-hydroxy-5alpha-androst-7-en-3-one. The temperature dependence of this elimination reaction explains the inconsistency between the high binding to the androgen receptor (measured at 0 degrees C) and the low biological activity, as well as the poor androgen receptor mediated concentration in vivo. The fluorinated analogue F-17alpha-CH3-DHT (4) has both high affinity for the androgen receptor and high stability in aqueous media. Of the compounds tested, 4 has the highest affinity for the androgen receptor as well as the highest androgenic activity. Thus it is likely that F-17alpha-CH3-DHT 4 labeled with 18F will be an excellent receptor-mediated diagnostic imaging agent.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Jun
pubmed:issn
0022-2623
pubmed:author
pubmed:issnType
Print
pubmed:day
3
pubmed:volume
42
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
2021-34
pubmed:dateRevised
2007-11-14
pubmed:meshHeading
pubmed-meshheading:10354410-Animals, pubmed-meshheading:10354410-Binding, Competitive, pubmed-meshheading:10354410-Cell Line, pubmed-meshheading:10354410-Dihydrotestosterone, pubmed-meshheading:10354410-Drug Stability, pubmed-meshheading:10354410-Fluorine Radioisotopes, pubmed-meshheading:10354410-Haplorhini, pubmed-meshheading:10354410-Humans, pubmed-meshheading:10354410-Iodine Radioisotopes, pubmed-meshheading:10354410-Ligands, pubmed-meshheading:10354410-Male, pubmed-meshheading:10354410-Prostate, pubmed-meshheading:10354410-Radiopharmaceuticals, pubmed-meshheading:10354410-Rats, pubmed-meshheading:10354410-Rats, Sprague-Dawley, pubmed-meshheading:10354410-Receptors, Androgen, pubmed-meshheading:10354410-Solutions, pubmed-meshheading:10354410-Tissue Distribution, pubmed-meshheading:10354410-Transfection
pubmed:year
1999
pubmed:articleTitle
7alpha-Iodo and 7alpha-fluoro steroids as androgen receptor-mediated imaging agents.
pubmed:affiliation
Department of Obstetrics and Gynecology, Yale University School of Medicine, New Haven, Connecticut 06510, USA.
pubmed:publicationType
Journal Article, In Vitro, Research Support, U.S. Gov't, P.H.S.