¹³¹I-IITM and ²¹¹At-AITM: Two Novel Small-Molecule Radiopharmaceuticals Targeting Oncoprotein Metabotropic Glutamate Receptor 1.

Abstract

Targeted radionuclide therapy (TRT) targeting oncoproteins facilitates the delivery of therapeutic radionuclides to tumor tissues with high precision. Herein, we developed 2 new radiopharmaceuticals, 4-¹³¹I-iodo- and 4-²¹¹At-astato-<i>N</i>-[4-(6-(isopropylamino)pyridine-4-yl)-1,3-thiazol-2-yl]-<i>N</i>-methylbenzamide (¹³¹I-IITM and ²¹¹At-AITM), targeting the ectopic metabotropic glutamate receptor 1 (mGluR1) in melanomas for TRT studies. <b>Methods:</b>¹³¹I-IITM and ²¹¹At-AITM were synthesized by reacting a stannyl precursor with ¹³¹I-NaI and ²¹¹At in the presence of an oxidizing agent. The therapeutic efficacy and safety of the 2 radiopharmaceuticals were investigated using mGluR1-expressing B16F10 melanoma cells and melanoma-bearing mice. <b>Results:</b>¹³¹I-IITM and ²¹¹At-AITM were obtained with a radiochemical purity of greater than 99% and radiochemical yields of 42.7% ± 10.4% and 45.7% ± 6.5%, respectively, based on the total radioactivity of used radionuclides. ¹³¹I-IITM and ²¹¹At-AITM exhibited a maximum uptake of 4.66% ± 0.70 and 7.68% ± 0.71 percentage injected dose per gram (%ID/g) in the targeted melanomas, respectively, and were rapidly cleared from nontarget organs after intravenous injection. Both agents markedly inhibited melanoma growth compared with the controls (61.00% and 95.68%, respectively). In the melanoma model, considerably greater therapeutic efficacy with negligible toxicity was observed using ²¹¹At-AITM. <b>Conclusion:</b> The nontoxic radiopharmaceuticals ¹³¹I-IITM and ²¹¹At-AITM are useful high-precision TRT agents that can be used to target the oncoprotein mGluR1 for melanoma therapy.