Carbon-11-labeled daunorubicin and verapamil for probing P-glycoprotein in tumors with PET.
One of the mechanisms for multidrug resistance (MDR) of tumors is an overexpression of the P-glycoprotein (P-gp). The cytostatic agent daunorubicin and the modulator verapamil were labeled with 11C to probe P-gp with PET.


METHODS
Carbon-11-daunorubicin was prepared from 11CCH2N2 with an aldehyde precursor, followed by hydrolysis. Carbon-11-verapamil was synthesized by 11C-methylation. Both tracers were evaluated by investigating pharmacokinetics in rats and in vitro cell kinetics using human ovarian carcinoma cells.


RESULTS
Amounts of 111 MBq 11C-daunorubicin were prepared. Biodistribution studies of 11C-daunorubicin in male Wistar rats showed dose-dependent pharmacokinetics, whereas with 11C-verapamil the pharmacokinetics were dose independent. In in vitro experiments with cells, the ratio of accumulation of 11C-daunorubicin in drug sensitive/resistant cell lines was 16. Addition of verapamil resulted in increased accumulation of 11C-daunorubicin in the resistant cell line. The ratios of 11C-verapamil accumulation in drug-sensitive versus the MDR counterpart were 4-5.


CONCLUSIONS
Carbon-11-daunorubicin and 11C-verapamil both have potential for in vivo probing of P-glycoprotein with PET.
Elsinga
P H
PH
PET Center, University Hospital, Groningen, The Netherlands.
Franssen
E J
EJ
Hendrikse
N H
NH
Fluks
L
L
Weemaes
A M
AM
van der Graaf
W T
WT
de Vries
E G
EG
Visser
G M
GM
Vaalburg
W
W
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000032:analysis*; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000493:pharmacokinetics; D002250:Carbon Radioisotopes / Q000493:pharmacokinetics; D003630:Daunorubicin / Q000493:pharmacokinetics; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D008297:Male; D010051:Ovarian Neoplasms; D051381:Rats; D017208:Rats, Wistar; D014018:Tissue Distribution; D014055:Tomography, Emission-Computed; D014407:Tumor Cells, Cultured; D014700:Verapamil / Q000493:pharmacokinetics
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000903:Antibiotics, Antineoplastic; D002250:Carbon Radioisotopes; D014700:Verapamil; D003630:Daunorubicin