Targeted functional imaging of estrogen receptors with 99mTc-GAP-EDL.
OBJECTIVE
To evaluate the feasibility of using (99m)Tc-glutamate peptide-estradiol in functional imaging of estrogen receptor-positive [ER(+)] diseases.


METHODS
3-Aminoethyl estradiol (EDL) was conjugated to glutamate peptide (GAP) to yield GAP-EDL. Cellular uptake studies of (99m)Tc-GAP-EDL were conducted in ER(+) cell lines (MCF-7, 13762 and T47D). To demonstrate whether GAP-EDL increases MAP kinase activation, Western blot analysis of GAP-EDL was performed in 13762 cells. Biodistribution was conducted in nine rats with 13762 breast tumors at 0.5-4 h. Each rat was administered (99m)Tc-GAP-EDL. Two animal models (rats and rabbits) were created to ascertain whether tumor uptake of (99m)Tc-GAP-EDL was via an ER-mediated process. In the tumor model, breast tumor-bearing rats were pretreated with diethylstilbestrol (DES) 1 h prior to receiving (99m)Tc-GAP-EDL. In the endometriosis model, part of the rabbit uterine tissue was dissected and grafted to the peritoneal wall. The rabbit was administered with (99m)Tc-GAP-EDL.


RESULTS
There was a 10-40% reduction in uptake of (99m)Tc-GAP-EDL in cells treated with DES or tamoxifen compared with untreated cells. Western blot analysis showed an ERK1/2 phosphorylation process with GAP-EDL. Biodistribution studies showed that tumor uptake and tumor-to-muscle count density ratio in (99m)Tc-GAP-EDL groups were significantly higher than those in (99m)Tc-GAP groups at 4 h. Among (99m)Tc-GAP-EDL groups, region of interest analysis of images showed that tumor-to muscle ratios were decreased in blocking groups. In the endometriosis model, the grafted uterine tissue could be visualized by (99m)Tc-GAP-EDL.


CONCLUSIONS
Cellular or tumor uptake of (99m)Tc-GAP-EDL occurs via an ER-mediated process. (99m)Tc-GAP-EDL is a useful agent for imaging functional ER(+) disease.
Takahashi
Nobukazu
N
Division of Diagnostic Imaging, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA.
Yang
David J
DJ
Kohanim
Saady
S
Oh
Chang-Sok
CS
Yu
Dong-Fang
DF
Azhdarinia
Ali
A
Kurihara
Hiroaki
H
Zhang
Xiaochun
X
Chang
Joe Y
JY
Kim
E Edmund
EE
D000818:Animals; D014408:Biomarkers, Tumor / Q000378:metabolism; D001943:Breast Neoplasms / Q000000981:diagnostic imaging* / Q000378:metabolism*; D016503:Drug Delivery Systems / Q000379:methods*; D004970:Estrone / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D005260:Female; D006801:Humans; D007089:Image Enhancement / Q000379:methods; D008657:Metabolic Clearance Rate; D009928:Organ Specificity; D015609:Organotechnetium Compounds / Q000493:pharmacokinetics*; D011099:Polyglutamic Acid / Q000493:pharmacokinetics*; D049268:Positron-Emission Tomography / Q000639:trends*; D011817:Rabbits; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics; D051381:Rats; D011916:Rats, Inbred F344; D011960:Receptors, Estrogen / Q000378:metabolism*; D014018:Tissue Distribution
D014408:Biomarkers, Tumor; D015609:Organotechnetium Compounds; D019275:Radiopharmaceuticals; D011960:Receptors, Estrogen; C522235:technetium 99m polyglutamate 3-aminoethyl estradiol; D011099:Polyglutamic Acid; D004970:Estrone