TY - JOUR
T1 - Comparative breast tumor imaging and comparative in vitro metabolism of 16α-[18F]fluoroestradiol-17β and 16β-[18F]fluoromoxestrol in isolated hepatocytes
AU - Jonson, Stephanie D.
AU - Bonasera, Thomas A.
AU - Dehdashti, Farrokh
AU - Cristel, Michael E.
AU - Katzenellenbogen, John A.
AU - Welch, Michael J.
N1 - Funding Information:
Support was provided by the Department of Energy (DE FG02-84ER60218 to MJW), the National Institutes of Health (PHS 5R01 CA25836 to JAK), the Department of Defense (DAMD17-94-J-4029 to SDJ), and the Education and Research Foundation of The Society of Nuclear Medicine (student fellowship to TAB). We thank Kathryn E. Carlson for effective specific activity measurements, Pamela A. Rocque and Henry F. VanBrocklin for assistance and training at the onset of this project, Elizabeth L. C. Sherman and William Courtney for technical assistance, and Landis K. Griffeth and Barry A. Siegel for reading PET images.
PY - 1999/1
Y1 - 1999/1
N2 - 16β-[18F]Fluoromoxestrol ([18F]βFMOX) is an analog of 16α- [18F]fluoroestradiol-17β ([18F]FES), a radiopharmaceutical known to be an effective positron emission tomography (PET) imaging agent for estrogen receptor-positive (ER+) human breast tumors. Based on comparisons of target tissue uptake efficiency and selectivity in a rat model, [18F][βFMOX was predicted to be as effective an imaging agent as [18F]FES. However' in a preliminary PET imaging study with [18F]βFMOX of 12 patients, 3 of whom had ER+ breast cancer, no tumor localization of [18F]βFMOX was observed. In search for an explanation for the unsuccessful [18F]βFMOX clinical trial, we have examined the rate of metabolism of [18F]βFMOX and [18F]FES in isolated rat, baboon, and human hepatocytes. We have also studied the effect of the serum protein sex hormone-binding globulin (SHBG), which binds [18F]FES better than [18F][βFMOX, on these rates of metabolism. Immature rat hepatocytes were found to metabolize [18F]FES 31 times faster than [18F]βFMOX, whereas mature rat cells metabolized [18F]FES only 3 times faster, and baboon and human hepatocytes only 2 times faster than [18F]βFMOX. In the presence of SHBG, the metabolic consumption rate for [18F]FES in mature rat hepatocytes decreased by 26%. Thus, the very favorable target tissue uptake characteristics of [18F]βFMOX determined in the rat probably result from its comparative resistance to metabolism (vis-a-vis [18F]FES) in this species, an advantage that is strongly reflected in comparative metabolism rates in rat hepatocytes. In the baboon and human, [18F]FES is extensively protein bound and protected from metabolism, an effect that may be reflected to a degree as a decrease in the rate of metabolism of this compound in baboon and human hepatocytes relative to [18F]βFMOX. Thus in primates, SHBG may potentiate the ER-mediated uptake of [18F]FES in ER+ tumors by selectively protecting this ligand from metabolism and ensuring its delivery to receptor-containing cells. In addition to current screening methods for 18F-estrogens that involve evaluating in vivo ER-mediated uptake in the immature female rat, studies comparing the metabolism of the new receptor ligands in isolated hepatocytes, especially those from primates or humans, may assist in predicting the potential of these ligands for human PET imaging.
AB - 16β-[18F]Fluoromoxestrol ([18F]βFMOX) is an analog of 16α- [18F]fluoroestradiol-17β ([18F]FES), a radiopharmaceutical known to be an effective positron emission tomography (PET) imaging agent for estrogen receptor-positive (ER+) human breast tumors. Based on comparisons of target tissue uptake efficiency and selectivity in a rat model, [18F][βFMOX was predicted to be as effective an imaging agent as [18F]FES. However' in a preliminary PET imaging study with [18F]βFMOX of 12 patients, 3 of whom had ER+ breast cancer, no tumor localization of [18F]βFMOX was observed. In search for an explanation for the unsuccessful [18F]βFMOX clinical trial, we have examined the rate of metabolism of [18F]βFMOX and [18F]FES in isolated rat, baboon, and human hepatocytes. We have also studied the effect of the serum protein sex hormone-binding globulin (SHBG), which binds [18F]FES better than [18F][βFMOX, on these rates of metabolism. Immature rat hepatocytes were found to metabolize [18F]FES 31 times faster than [18F]βFMOX, whereas mature rat cells metabolized [18F]FES only 3 times faster, and baboon and human hepatocytes only 2 times faster than [18F]βFMOX. In the presence of SHBG, the metabolic consumption rate for [18F]FES in mature rat hepatocytes decreased by 26%. Thus, the very favorable target tissue uptake characteristics of [18F]βFMOX determined in the rat probably result from its comparative resistance to metabolism (vis-a-vis [18F]FES) in this species, an advantage that is strongly reflected in comparative metabolism rates in rat hepatocytes. In the baboon and human, [18F]FES is extensively protein bound and protected from metabolism, an effect that may be reflected to a degree as a decrease in the rate of metabolism of this compound in baboon and human hepatocytes relative to [18F]βFMOX. Thus in primates, SHBG may potentiate the ER-mediated uptake of [18F]FES in ER+ tumors by selectively protecting this ligand from metabolism and ensuring its delivery to receptor-containing cells. In addition to current screening methods for 18F-estrogens that involve evaluating in vivo ER-mediated uptake in the immature female rat, studies comparing the metabolism of the new receptor ligands in isolated hepatocytes, especially those from primates or humans, may assist in predicting the potential of these ligands for human PET imaging.
KW - Estrogens
KW - Fluorine-18
KW - Fluoroestradiol Metabolism
KW - Fluoromoxestrol
KW - Positron emission tomography
KW - Sex hormone-binding globulin
UR - http://www.scopus.com/inward/record.url?scp=0032916932&partnerID=8YFLogxK
U2 - 10.1016/S0969-8051(98)00079-1
DO - 10.1016/S0969-8051(98)00079-1
M3 - Article
C2 - 10096512
AN - SCOPUS:0032916932
SN - 0969-8051
VL - 26
SP - 123
EP - 130
JO - Nuclear Medicine and Biology
JF - Nuclear Medicine and Biology
IS - 1
ER -