PET study on mice bearing human colon adenocarcinoma cells using [11C]GF120918, a dual radioligand for P-glycoprotein and breast cancer resistance protein.
OBJECTIVE
To evaluate the functions of P-glycoprotein (Pgp) and breast cancer resistance protein (BCRP) in human colon adenocarcinoma (Caco-2), we carried out an in-vitro study and a small animal positron emission tomography (PET) study using [C]GF120918 (elacridar).


METHODS
[C]GF120918 was synthesized by reacting the desmethyl precursor with [C]CH3I. An in-vitro study using [C]GF120918 was carried out in Caco-2 and Madin-Darby canine kidney cells in the presence or absence of a transporter inhibitor (cyclosporine A and unlabeled GF120918). The biodistribution of radioactivity after the injection of [C]GF120918 was determined in Caco-2-bearing mice using a small animal PET scanner.


RESULTS
In Caco-2 cells expressing Pgp and BCRP, coincubation with unlabeled GF120918 caused an approximately two-fold increase in [C]GF120918 uptake compared with that of the control ([C]GF120918 only). In Caco-2-bearing mice, PET results indicated that [C]GF120918 uptake in the tumor was low, but was significantly increased by treatment with unlabeled GF120918. In metabolite analysis, the radioactive component in the tumor almost corresponded to intact [C]GF120918.


CONCLUSIONS
A PET study combining the administration of [C]GF120918 with unlabeled GF120918 may be a useful tool for evaluating the functions of Pgp and BCRP in tumors.
Yamasaki
Tomoteru
T
Department of Molecular Probes, Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan.
Kawamura
Kazunori
K
Hatori
Akiko
A
Yui
Joji
J
Yanamoto
Kazuhiko
K
Yoshida
Yuichiro
Y
Ogawa
Masanao
M
Nengaki
Nobuki
N
Wakisaka
Hidekatsu
H
Fukumura
Toshimitsu
T
Zhang
Ming-Rong
MR
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism*; D000166:Acridines / Q000378:metabolism*; D000230:Adenocarcinoma / Q000473:pathology*; D000818:Animals; D001692:Biological Transport; D015153:Blotting, Western; D018938:Caco-2 Cells; D002250:Carbon Radioisotopes; D003110:Colonic Neoplasms / Q000473:pathology*; D004285:Dogs; D006801:Humans; D008024:Ligands; D008297:Male; D051379:Mice; D009363:Neoplasm Proteins / Q000378:metabolism*; D049268:Positron-Emission Tomography / Q000379:methods*; D044005:Tetrahydroisoquinolines / Q000378:metabolism*; D015899:Tomography, Emission-Computed, Single-Photon
C116614:ABCG2 protein, human; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D000166:Acridines; D002250:Carbon Radioisotopes; D008024:Ligands; D009363:Neoplasm Proteins; D044005:Tetrahydroisoquinolines; C083501:Elacridar