First imaging of metabotropic glutamate 1 receptor in melanoma with a positron emission tomography probe 18F-FITM

Objectives It has been reported that high expression of metabotropic glutamate 1 (mGlu1) receptor induced spontaneous melanoma development with 100% penetrance in mice, and about 68-88 % of human melanoma biopsies and cell lines were found with aberrant expression of mGlu1 (1,2). Here, we used a novel PET probe 4-[18F]fluoro-N-[4-[6-(isopropylamino)pyrimidin-4-yl]-1,3-thiazol-2-yl]-N-methylbenzamide (18F-FITM) to map mGlu1 overexpressing in melanomas.

Methods 18F-FITM was synthesized by 18F-fluorination of a nitro precursor with 18F-KF (Fig. 1A). B16F1 and B16F10 melanoma cells with rich mGlu1 expression and Hepa1-6 hepatoma without mGlu1 were used for the 18F-FITM evaluation. Binding and specificity of 18F-FITM to mGlu1 was assessed with and without unlabeled FITM and mGlu1-selective antagonist JNJ16259685. PET with 18F-FITM and biodistribution studies were performed on subcutaneous tumor-bearing mice and pulmonary metastases mice.

Results High cellular uptake of 18F-FITM was determined in both B16F1 and B16F10 melanomas with high mGlu1 expression, not but Hepa1-6 hepatomas without mGlu1 (P < 0.01). This uptake was blocked specifically by co-incubated with JNJ16259685 and unlabeled FITM in B16F1 and B16F10 cells. In tumor-bearing mice, 18F-FITM-PET showed a temporal high uptake of radioactivity in B16F1, B16F10 melanomas compared with the surrounding tissues, whereas little uptake was observed in the Hepa1-6 hepatoma (Fig. 1B). In biodistribution studies with tumor-bearing mice, tumor-to-blood ratios reached a plateau at 3h after injection of 18F-FITM (B16F1 38.53 ± 5.93, B16F10 27.20 ± 2.52 v.s Hepa1-6 1.71 ± 0.07). In pulmonary metastases which are common and most frequent occurrence in melanomas, 18F-FITM-PET showed intense and heterogeneous uptake of radioactivity in the lungs bearing metastases compared with the controls, and without any interfering signals from heart or blood.

Conclusions Our results indicated 18F-FITM is a specific PET probe for imaging mGlu1 in the melanomas.