Functional imaging of estrogen receptors with radiolabeled-GAP-EDL in rabbit endometriosis model.
OBJECTIVE
Endometriosis is a common women's health problem. Animal models provide an invaluable tool to study the natural history of endometriosis. We previously have reported that (99m)Tc-labeled glutamate peptide-estradiol ((99m)Tc-GAP-EDL) is a useful agent for imaging functional estrogen receptor (ER) via an ER-mediated process. This study was to evaluate the feasibility of using radiolabeled GAP-EDL to image ER-positive (ER +) endometriosis in nonprimate animal models.


METHODS
3-Aminoethyl estradiol (EDL) was conjugated to glutamate peptide (GAP) to yield GAP-EDL. In vitro cellular uptake studies of (99m)Tc and (68)Ga-GAP-EDL inhibition with cold estrone were conducted in 13,762 rat mammary tumor cells. To create a rabbit model with endometriosis, part of uterine tissue was dissected and grafted in the peritoneal wall. Eight weeks after surgery, scintigraphic images were obtained after intravenous injection of (99m)Tc-GAP-EDL (1 mCi/rabbit, intravenous) at 0.5-2.0 hours, and (68)Ga-GAP-EDL at 45 minutes. We also performed (68)Ga-GAP-EDL blocking study in rabbit model by using tamoxifen. The rabbits were sacrificed and the grafts were excised for histologic examination.


RESULTS
In vitro uptake study of (99m)Tc- and (68)Ga-GAP-EDL in 13,762 rat breast cancer cells showed gradually increasing uptake of both tracers. Accumulation of (68)Ga-GAP-EDL in 13,762 cells was inhibited with cold estrone in a dose-dependent manner. In the endometriosis model, the grafted uterine tissue could be visualized by (99m)Tc-GAP-EDL. Necropsy was performed at 2.5 hours after injection time. Four follicular endometrial lesions in eight implanted endometrial tissues were detected, and all lesions could be detected by (99m)Tc-GAP-EDL. Planar scintigraphy of uterus, ovary and implants of necropsy specimen revealed an increased uptake of (99m)Tc-GAP-EDL in comparison with surrounding abdominal wall tissue. Microscopic examinations support that (99m)Tc-GAP-EDL was accumulated in the microinvasive endometrial tissue. After blocking with tamoxifen, (68)Ga-GAP-EDL accumulation in the endometrial grafts could not be visualized, and endometrial tissue-to-normal tissue count ratios were statistically higher in a nonblocked image than that in the blocked image.


CONCLUSIONS
Endometriosis uptake of radiolabeled GAP-EDL was via an estrogen receptor-mediated process. Radiolabeled-GAP-EDLs are useful agents for imaging endometriosis.
Takahashi
Nobukazu
N
Division of Diagnostic Imaging, Box 57, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
Yang
David J
DJ
Kurihara
Hiroaki
H
Borne
Agatha
A
Kohanim
Saady
S
Oh
Chang-Sok
CS
Mawlawi
Osama
O
Kim
E Edmund
EE
D000818:Animals; D004195:Disease Models, Animal; D004715:Endometriosis / Q000000981:diagnostic imaging* / Q000378:metabolism*; D004717:Endometrium / Q000000981:diagnostic imaging* / Q000378:metabolism*; D004970:Estrone / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D005260:Female; D015609:Organotechnetium Compounds / Q000493:pharmacokinetics*; D011099:Polyglutamic Acid / Q000493:pharmacokinetics*; D011817:Rabbits; D011877:Radionuclide Imaging; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics; D011960:Receptors, Estrogen / Q000378:metabolism*
D015609:Organotechnetium Compounds; D019275:Radiopharmaceuticals; D011960:Receptors, Estrogen; C522235:technetium 99m polyglutamate 3-aminoethyl estradiol; D011099:Polyglutamic Acid; D004970:Estrone