Development of metabotropic glutamate receptor 1-targeted radiopharmaceuticals for theranostics of melanoma

Background/Aims: Metabotropic glutamate receptor 1 (mGluR1), a key mediator of glutamatergic signaling, is frequently expressed as an oncoprotein and has been an attractive target to overcome most solid tumors, such as melanoma (1). Here, a novel small-molecular radiopharmaceutical pair, 3-iodo-N-[4-[6-(methylamino)pyrimidin-4-yl]-1,3-thiazol-2-yl]-N-[11C]methylbenzamide ([11C]1) and 3-211At-astato-N-[4-[6-(methylamino)pyrimidin-4-yl]-1,3-thiazol-2-yl]-N-methylbenzamide ([211At]1), was designed and developed to target the mGluR1 for theranostics of melanomas. Methods: [ 11C]1 was synthesized by reacting a N-desmethyl precursor with [11C]CH3OTf in the presence of NaOH at room temperature for 5 min. Radiolabeling with [211At]1 was performed by reaction of aryl tin precursor with NCS-containing 211At/MeOH solution according to the method reported by our laboratory (2). The theranostic potentials of the radiopharmaceutical pair were explored for PET imaging and radiotherapy in mGluR1-positive B16F10 melanoma-bearing mice. Results: [ 11C]1 and [211At]1 were obtained with a radiochemical purity of greater than 99% and radiochemical yields of 19 ± 8 % and 46 ± 3%, respectively, based on the total radioactivity of used radionuclides. In vivo PET imaging of [ 11C]1 clearly visualized the targeted melanomas with a good tumor-to-background contrast. Ex vivo biodistribution study verified the persistent increase of [ 11C]1, which reached 12.29 ± 2.44 %ID/g tissue at 90 min in the targeted melanomas, and rapidly cleared from nontarget organs after intravenous injection. In the therapeutic studies, [211At]1 exhibited unequivocal and durable antitumor efficacy with only a single treatment (2.96 MBq) in the melanoma model, compared to the controls (0.31 ± 0.08 cm3 vs. 10.44 ± 1.61 cm3 at 16 days post-therapy). No decrease in body weight and no liver and kidney damage were observed through the examination period in melanoma mice injected with 2.96 MBq of [211At]1. Conclusions: The novel small-molecular radiopharmaceutical pair successfully visualized the mGluR1-positive melanomas by [ 11C]1 with high contrast PET images, and further treated the melanoma by [211At]1 without significant toxicity. The results highlight the good potential of using [ 11C]1 and [211At]1 as theranostic agents for the management of mGluR1-positive tumors and should be further investigated in the theranostic field of oncology in the clinic.
第13回世界核医学会（13th orld Federation of Nuclear Medicine and Biology)