A potential radioiodinated ligand for androgen receptor: 7.alpha.-methyl-17.alpha.-[2'-(E)-iodovinyl]-19-nortestosterone

Abstract

The presence of androgen receptor (AR) in prostate cancer has been linked to the androgen-dependent nature of the tumor and has also been shown to have prognostic significance; it also appears to be a positive prognostic indicator in breast cancer. However, due to the relatively low AR concentrations in most tumors and the inherently low specific activity of tritium, the assay of AR based on available 3H-ligands is not sensitive enough to measure accurately the amount of receptor in small specimens. A 125I-ligand like those available for the estrogen and progesterone receptors would be helpful, but development of such a ligand for AR has not been very successful. Although several androgen analogues containing iodine, bromine, or selenium have been synthesized specifically as potential probes for AR, none have shown any significant affinity or specificity for the receptor. We therefore undertook the synthesis of new potential AR ligands which could be radioiodinated, and determined their affinities for AR (from rat uterus and MCF-7 human breast cancer cells) by using a competition assay. We have examined both 5 alpha-dihydrotestosterone (5 alpha-DHT) and 19-nortestosterone analogues and have identified two such compounds which showed high AR affinity: (17 alpha,20E)-17 beta-hydroxy-21-iodo-5 alpha-pregn-20-en-3-one (17 alpha-[E)-iodovinyl)-5 alpha-DHT, 9) and 17 beta-hydroxy-7 alpha-methyl-(17 alpha,20E)-21-iodo-19-norpregna-4,20-dien-3- one (7 alpha-methyl-17 alpha-[E)-iodovinyl)-19-nortestosterone, 11). In fact, the affinity of the latter for human AR was found to be superior to that of 5 alpha-DHT itself. These iodovinyl analogues could be easily prepared in the radioiodinated form, and should prove to be extremely useful in assaying low levels of AR in small specimens.

Rational Design and Synthesis of Androgen Receptor-Targeted Nonsteroidal Anti-Androgen Ligands for the Tumor-Specific Delivery of a Doxorubicin−Formaldehyde Conjugate

“…Several groups have synthesized various derivatives of DHT, generally modified at the 17 position or by etherification or esterification of the 17-hydroxy group. [40][41][42] With few exceptions, steroidal analogues have been shown to exhibit less than 10% the AR binding affinity of DHT.…”

PET Imaging Agents (FES, FFNP, and FDHT) for Estrogen, Androgen, and Progesterone Receptors to Improve Management of Breast and Prostate Cancers by Functional Imaging

“…Early reports of PET imaging agents for the progesterone receptor (PgR), published in the 1970s and 1980s, described the synthesis of 21-[ 18 F]fluoroprogesterone, a direct analog of the endogenous progestational hormone, progesterone, as well as some analogs of this compound and ones substituted at different sites; however, no PgR binding was reported, and biodistribution and metabolism studies were limited and generally disappointing [ 60 , 61 , 62 ]. High-affinity radioiodinated ligands for PgR, reported at the same time, appeared more promising, especially (Z)-17β-hydroxy-17α-(2-iodovinyl)-4-estren-3-one and the bromo analog [ 63 , 64 , 65 , 66 , 67 ], and these showed some evidence of PgR-specific uptake in the uterus of estrogen-primed immature rats [ 24 , 68 ].…”

“…More recent work on radioiodinated androgens was more promising, and those with 7α-iodo or 17α-iodovinyl groups bound well to AR, although those lacking a C19 methyl group (4-estren-3-one core) begin to resemble synthetic progestins and risked having considerable affinity for PgR. In vivo biodistribution studies of uptake of these compounds in rat prostate were either limited or largely unpromising [ 24 , 64 , 66 , 68 , 106 , 107 ].…”

Steroid reactions and partial synthesis

“…A photochemical double-ring contraction with the extrusion of carbon monoxide has been observeda9 in the conversion of 4ahomo-5a-cholest-3-en-l-one (96) to the cyclobutane (97). The J Product (89) -$p H (97) photosensitized oxidation of the enol of the ring A diketone (98) has been shown to affordg0 the lactol (99). Studies on the photochemical reactivity of the methyl ether of 8,9-didehydroestrone towards singlet oxygen have been reported.g1 The photochemical radical fragmentation of the hemi-acetal (1 00) in the presence of diacetoxyiodobenzene has providedg2 a convenient synthesis of medium-sized lactones ( 101) and (102).…”