Synthesis and preclinical evaluation of the radiolabeled P-glycoprotein inhibitor [11C]MC113
Nuclear Medicine and Biology, cilt.39, sa.8, ss.1219-1225, 2012 (SCI-Expanded, Scopus)
- Yayın Türü: Makale / Tam Makale
- Cilt numarası: 39 Sayı: 8
- Basım Tarihi: 2012
- Doi Numarası: 10.1016/j.nucmedbio.2012.08.005
- Dergi Adı: Nuclear Medicine and Biology
- Derginin Tarandığı İndeksler: Science Citation Index Expanded (SCI-EXPANDED), Scopus
- Sayfa Sayıları: ss.1219-1225
- Anahtar Kelimeler: Blood-brain barrier, MC113, MC18, P-glycoprotein, Positron emission tomography, Tariquidar, Tumor
- Maltepe Üniversitesi Adresli: Hayır
Özet
Objectives: With the aim to develop a PET tracer to visualize P-glycoprotein (Pgp) expression levels in different organs, the Pgp inhibitor MC113 was labeled with 11C and evaluated using small-animal PET. Methods: [11C]MC113 was synthesized by reaction of O-desmethyl MC113 with [11C]methyl triflate. Small-animal PET was performed with [11C]MC113 in FVB wild-type and Mdr1a/b(-/-) mice (n=3 per group) and in a mouse model of high (EMT6Ar1.0) and low (EMT6) Pgp expressing tumor grafts (n=5). In the tumor model, PET scans were performed before and after administration of the reference Pgp inhibitor tariquidar (15mg/kg). Results: Brain uptake of [11C]MC113, expressed as area under the time-activity curve from time 0 to 60min (AUC0-60), was moderately but not significantly increased in Mdr1a/b(-/-) compared with wild-type mice (mean±SD AUC0-60, Mdr1a/b(-/-): 88±7min, wild-type: 62±6min, P=0.100, Mann Whitney test). In the tumor model, AUC0-60 values were not significantly different between EMT6Ar1.0 and EMT6 tumors. Neither in brain nor in tumors was activity concentration significantly changed in response to tariquidar administration. Half-maximum effect concentrations (IC50) for inhibition of Pgp-mediated rhodamine 123 efflux from CCRFvcr1000 cells were 375±60nM for MC113 versus 8.5±2.5nM for tariquidar. Conclusion: [11C]MC113 showed higher brain uptake in mice than previously described Pgp PET tracers, suggesting that [11C]MC113 was only to a low extent effluxed by Pgp. However, [11C]MC113 was found unsuitable to visualize Pgp expression levels presumably due to insufficiently high Pgp binding affinity of MC113 in relation to Pgp densities in brain and tumors. © 2012 Elsevier Inc..