Fluorine-substituted corticosteroids: Synthesis and evaluation as potential receptor-based imaging agents for positron emission tomography of the brain

Martin Gilbert Pomper, Monica J. Kochanny, Andrea M. Thieme, Kathryn E. Carlson, Henry F. Vanbrocklin, Carla J. Mathias, Michael J. Welch, John A. Katzenellenbogen

Research output: Contribution to journalArticle

Abstract

We have prepared eight fluorine-substituted corticosteroids representing ligands selective for Type I and Type II corticosteroid receptor subtypes as potential imaging agents for corticosteroid receptor-containing regions of the brain. Receptor binding affinity assays show that fluorine substitution for hydroxyl or hydrogen in these steroids generally results in some reduction in affinity, with the result that the absolute affinity of these fluorine-substituted ligands for receptor is less than that typical for steroid hormones that show receptor-based, target selective uptake in vivo. Five of these compounds were prepared in fluorine-18 labeled form by a simple sulfonate ester displacement reaction, and their tissue distribution was studied in the adrenalectomized rat. There is no selective accumulation nor selective retention of the Type I selective corticosteroids (18F-RU 26752, 21-[18F]fluoroprogesterone, 21-[18F]fluoro-11β-hydroxyprogesterone) in either the brain, or other target tissues (pituitary, kidney, liver). The Type II selective corticosteroids (18F-RU 28362, 18F-triamcinolone acetonide) show uptake into the hippocampus which can be partially blocked by a competing ligand; in target tissues outside the brain, the blocking is more complete. All of the 18F-labeled compounds show considerable defluorination, evident as high bone activity levels. These results, coupled with earlier findings in the literature, suggest that radiolabeled corticosteroid receptor ligands with both greater metabolic stability and higher receptor binding affinity and selectivity are needed for imaging corticosteroid receptors in the hippocampus.

Original languageEnglish (US)
Pages (from-to)461-480
Number of pages20
JournalInternational Journal of Radiation Applications and Instrumentation.
Volume19
Issue number4
DOIs
StatePublished - 1992
Externally publishedYes

Fingerprint

Fluorine
Steroid Receptors
Positron-Emission Tomography
Adrenal Cortex Hormones
Ligands
Brain
Hippocampus
Steroids
Triamcinolone Acetonide
Tissue Distribution
Hydroxyl Radical
Hydrogen
Esters
Hormones
Kidney
Bone and Bones
Liver

Cite this

Fluorine-substituted corticosteroids : Synthesis and evaluation as potential receptor-based imaging agents for positron emission tomography of the brain. / Pomper, Martin Gilbert; Kochanny, Monica J.; Thieme, Andrea M.; Carlson, Kathryn E.; Vanbrocklin, Henry F.; Mathias, Carla J.; Welch, Michael J.; Katzenellenbogen, John A.

In: International Journal of Radiation Applications and Instrumentation., Vol. 19, No. 4, 1992, p. 461-480.

Research output: Contribution to journalArticle

Pomper, Martin Gilbert ; Kochanny, Monica J. ; Thieme, Andrea M. ; Carlson, Kathryn E. ; Vanbrocklin, Henry F. ; Mathias, Carla J. ; Welch, Michael J. ; Katzenellenbogen, John A. / Fluorine-substituted corticosteroids : Synthesis and evaluation as potential receptor-based imaging agents for positron emission tomography of the brain. In: International Journal of Radiation Applications and Instrumentation. 1992 ; Vol. 19, No. 4. pp. 461-480.
@article{f9bb44166e7e431cb48b077dae64f68a,
title = "Fluorine-substituted corticosteroids: Synthesis and evaluation as potential receptor-based imaging agents for positron emission tomography of the brain",
abstract = "We have prepared eight fluorine-substituted corticosteroids representing ligands selective for Type I and Type II corticosteroid receptor subtypes as potential imaging agents for corticosteroid receptor-containing regions of the brain. Receptor binding affinity assays show that fluorine substitution for hydroxyl or hydrogen in these steroids generally results in some reduction in affinity, with the result that the absolute affinity of these fluorine-substituted ligands for receptor is less than that typical for steroid hormones that show receptor-based, target selective uptake in vivo. Five of these compounds were prepared in fluorine-18 labeled form by a simple sulfonate ester displacement reaction, and their tissue distribution was studied in the adrenalectomized rat. There is no selective accumulation nor selective retention of the Type I selective corticosteroids (18F-RU 26752, 21-[18F]fluoroprogesterone, 21-[18F]fluoro-11β-hydroxyprogesterone) in either the brain, or other target tissues (pituitary, kidney, liver). The Type II selective corticosteroids (18F-RU 28362, 18F-triamcinolone acetonide) show uptake into the hippocampus which can be partially blocked by a competing ligand; in target tissues outside the brain, the blocking is more complete. All of the 18F-labeled compounds show considerable defluorination, evident as high bone activity levels. These results, coupled with earlier findings in the literature, suggest that radiolabeled corticosteroid receptor ligands with both greater metabolic stability and higher receptor binding affinity and selectivity are needed for imaging corticosteroid receptors in the hippocampus.",
author = "Pomper, {Martin Gilbert} and Kochanny, {Monica J.} and Thieme, {Andrea M.} and Carlson, {Kathryn E.} and Vanbrocklin, {Henry F.} and Mathias, {Carla J.} and Welch, {Michael J.} and Katzenellenbogen, {John A.}",
year = "1992",
doi = "10.1016/0883-2897(92)90161-Q",
language = "English (US)",
volume = "19",
pages = "461--480",
journal = "Nuclear Medicine and Biology",
issn = "0969-8051",
publisher = "Elsevier Inc.",
number = "4",

}

TY - JOUR

T1 - Fluorine-substituted corticosteroids

T2 - Synthesis and evaluation as potential receptor-based imaging agents for positron emission tomography of the brain

AU - Pomper, Martin Gilbert

AU - Kochanny, Monica J.

AU - Thieme, Andrea M.

AU - Carlson, Kathryn E.

AU - Vanbrocklin, Henry F.

AU - Mathias, Carla J.

AU - Welch, Michael J.

AU - Katzenellenbogen, John A.

PY - 1992

Y1 - 1992

N2 - We have prepared eight fluorine-substituted corticosteroids representing ligands selective for Type I and Type II corticosteroid receptor subtypes as potential imaging agents for corticosteroid receptor-containing regions of the brain. Receptor binding affinity assays show that fluorine substitution for hydroxyl or hydrogen in these steroids generally results in some reduction in affinity, with the result that the absolute affinity of these fluorine-substituted ligands for receptor is less than that typical for steroid hormones that show receptor-based, target selective uptake in vivo. Five of these compounds were prepared in fluorine-18 labeled form by a simple sulfonate ester displacement reaction, and their tissue distribution was studied in the adrenalectomized rat. There is no selective accumulation nor selective retention of the Type I selective corticosteroids (18F-RU 26752, 21-[18F]fluoroprogesterone, 21-[18F]fluoro-11β-hydroxyprogesterone) in either the brain, or other target tissues (pituitary, kidney, liver). The Type II selective corticosteroids (18F-RU 28362, 18F-triamcinolone acetonide) show uptake into the hippocampus which can be partially blocked by a competing ligand; in target tissues outside the brain, the blocking is more complete. All of the 18F-labeled compounds show considerable defluorination, evident as high bone activity levels. These results, coupled with earlier findings in the literature, suggest that radiolabeled corticosteroid receptor ligands with both greater metabolic stability and higher receptor binding affinity and selectivity are needed for imaging corticosteroid receptors in the hippocampus.

AB - We have prepared eight fluorine-substituted corticosteroids representing ligands selective for Type I and Type II corticosteroid receptor subtypes as potential imaging agents for corticosteroid receptor-containing regions of the brain. Receptor binding affinity assays show that fluorine substitution for hydroxyl or hydrogen in these steroids generally results in some reduction in affinity, with the result that the absolute affinity of these fluorine-substituted ligands for receptor is less than that typical for steroid hormones that show receptor-based, target selective uptake in vivo. Five of these compounds were prepared in fluorine-18 labeled form by a simple sulfonate ester displacement reaction, and their tissue distribution was studied in the adrenalectomized rat. There is no selective accumulation nor selective retention of the Type I selective corticosteroids (18F-RU 26752, 21-[18F]fluoroprogesterone, 21-[18F]fluoro-11β-hydroxyprogesterone) in either the brain, or other target tissues (pituitary, kidney, liver). The Type II selective corticosteroids (18F-RU 28362, 18F-triamcinolone acetonide) show uptake into the hippocampus which can be partially blocked by a competing ligand; in target tissues outside the brain, the blocking is more complete. All of the 18F-labeled compounds show considerable defluorination, evident as high bone activity levels. These results, coupled with earlier findings in the literature, suggest that radiolabeled corticosteroid receptor ligands with both greater metabolic stability and higher receptor binding affinity and selectivity are needed for imaging corticosteroid receptors in the hippocampus.

UR - http://www.scopus.com/inward/record.url?scp=44049114773&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=44049114773&partnerID=8YFLogxK

U2 - 10.1016/0883-2897(92)90161-Q

DO - 10.1016/0883-2897(92)90161-Q

M3 - Article

C2 - 1526811

AN - SCOPUS:44049114773

VL - 19

SP - 461

EP - 480

JO - Nuclear Medicine and Biology

JF - Nuclear Medicine and Biology

SN - 0969-8051

IS - 4

ER -