Development and Preliminary Evaluations of a Novel ¹⁸ F-Labeled Tracer for Detection of BRAF ^V600E Mutant Status in Animal Models of Melanoma

The BRAF^V600E mutation is a well-established oncogenic driver, and several oral inhibitors have achieved clinical success. However, radiolabeled tracers for the non-invasive imaging of this mutation remain limited. <i>N</i>-(2-Chloro-3-((3,5-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)oxy)-5-fluorophenyl)propane-1-sulfonamide (<b>74</b>) is a novel oral inhibitor targeting BRAF^V600E with high inhibitory potency. Here, we report the synthesis of its precursor and the radiosynthesis of its ¹⁸F-labeled version, [¹⁸F]LP-1 ([¹⁸F]<b>74</b>). The tracer exhibited nanomolar cellular binding affinity for BRAF^V600E-positive A375 melanoma cells (IC₅₀ = 31.6 nM) and demonstrated selective uptake in tumor models with distinct BRAF mutation status. Blocking studies with the BRAF^V600E-selective inhibitor vemurafenib further confirmed its specific binding. Our findings highlight the potential of [¹⁸F]LP-1 as a lead structure for the development of PET molecular tracers capable of detecting BRAF^V600E mutation status in vivo and support the development of next-generation radiotracers based on the scaffold.