Pharmacological evaluation of the peripheral benzodiazepine receptor radioligand [¹²³I]-CLINDE in a breast tumour model

Objectives The aim of this study was to evaluate the peripheral benzodiazepine receptor ligand [^123/125I]-CLINDE in breast tumour bearing rodents.

Methods Balb/c nude mice bearing the MDA-MB-231 human breast adenocarcinoma were administered with [^123/125I]-CLINDE intravenously by the tail vein and biodistribution, competition, metabolite analysis, autoradiography and imaging studies were undertaken 33-36 days after tumour induction. For biodistribution the mice were sacrificed between 0.5 to 24h p.i. Drug competition studies were undertaken with PK11195 and CLINDE. [¹²³I]-CLINDE stability in tissue and plasma were measured by HPLC and Radio-TLC. PBR expression in MDA cells and tumour tissue were assessed by ligand binding assays and RT-PCR. Imaging was performed on an X-SPECT/CT animal imaging system.

Results PBR binding of [¹²⁵I]-CLINDE in tumours indicated high affinity for PBR (Kd ≈1nM) and Bmax of 11 pmol/mg protein. PBR expression in the cells and tumours was confirmed by RT-PCR. Biodistribution indicated uptake of 0.9-1.6%ID/g in tumour. Pre-administration of PK 11195 at a dose of 1mg/Kg reduced the uptake of activity in all organs with PBR expression except in adrenals and tumour. The tumour to blood ratio increased with time reaching 6 at 24h. Autoradiography showed a heterogeneous distribution of the uptake in the tumour. γ-Imaging of [¹²³I]-CLINDE indicated significant contrast in the tumours compared to normal tissue. Metabolite studies indicated that the activity extracted from tumours was the intact [¹²³I]-CLINDE.

Conclusions PBR expression has been confirmed in MDA-MB-231 human breast adenocarcinoma tumours using tracer uptake and RT-PCR studies. The PBR imidazopyridine ligand [^123/125I]-CLINDE is a suitable tracer to study the role and relevance of the PBR in tumours