Rapid reduction of sigma1-receptor binding and 18F-FDG uptake in rat gliomas after in vivo treatment with doxorubicin.
Sigma-receptors are strongly overexpressed in most rodent and human tumors and are proliferation markers. To evaluate the potential of a radiolabeled sigma1-ligand for therapy monitoring, we compared early changes of 11C-1-(3,4-dimethoxyphenethyl)-4-(3-phenylpropyl)piperazine (11C-SA4503) binding and 18F-FDG uptake in gliomas after in vivo chemotherapy.


METHODS
C6 cells (2.5 x 10(6)) were subcutaneously injected into the right shoulder of male Wistar rats. After 7 d, the tumor volume was 0.60 +/- 0.08 cm3. Animals then received either saline or doxorubicin (8 mg/kg, intraperitoneally). One control and 1 treated rat were imaged simultaneously, 24 or 48 h after treatment, under pentobarbital anesthesia. Rodents (n = 20) were scanned first with 11C-SA4503 (25 MBq, intravenously) followed more than 100 min afterward by 18F-FDG (20 MBq, intravenously), using a dedicated small-animal PET camera (60-min protocol, tumors in the field of view). Tumor homogenates were prepared and subjected to sigma-receptor assays. The biodistribution of 18F-FDG was assessed.


RESULTS
Tumors appeared 4-5 d after inoculation and grew exponentially. No significant reduction of tumor growth was visible within 48 h after doxorubicin treatment. Both PET tracers visualized the tumors and showed reduced uptake after chemotherapy (11C-SA4503: 26.5% +/- 6.5% at 24 h, 26.5% +/- 7.5% at 48 h; 18F-FDG: 22.6% +/- 3.2% at 24 h, 27.4% +/- 3.2% at 48 h; ex vivo 18F-FDG: 22.4% +/- 5.4% at 24 h, 31.7% +/- 12.7% at 48 h). Sigma1-receptor density in treated tumors was also reduced (from 172 +/- 35 to 125 +/- 28 fmol/mg of protein).


CONCLUSIONS
Both 11C-SA4503 binding and 18F-FDG uptake declined in gliomas after chemotherapy. Decreased binding of 11C-SA4503 corresponded to a loss of sigma1-receptors from the tumors. Changes in tracer uptake preceded the morphologic changes by at least 48 h.
van Waarde
Aren
A
Department of Nuclear Medicine and Molecular Imaging, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands. a.van.waarde@pet.umcg.nl
Shiba
Kazuhiro
K
de Jong
Johan R
JR
Ishiwata
Kiichi
K
Dierckx
Rudi A
RA
Elsinga
Philip H
PH
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000627:therapeutic use*; D002250:Carbon Radioisotopes; D004317:Doxorubicin / Q000627:therapeutic use*; D019788:Fluorodeoxyglucose F18 / Q000493:pharmacokinetics*; D005910:Glioma / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D010879:Piperazines / Q000493:pharmacokinetics; D049268:Positron-Emission Tomography; D051381:Rats; D017208:Rats, Wistar; D017480:Receptors, sigma / Q000032:analysis* / Q000378:metabolism; D014018:Tissue Distribution
D000903:Antibiotics, Antineoplastic; D002250:Carbon Radioisotopes; D010879:Piperazines; D017480:Receptors, sigma; C101491:sigma1-binding protein, rat; D019788:Fluorodeoxyglucose F18; D004317:Doxorubicin; C101789:SA 4503