Designing a Small Molecule for PET Radiotracing: [¹⁸F]MC225 in Human Trials for Early Diagnosis in CNS Pathologies

P-Glycoprotein (P-gp, also known as MDR1 or ABCB1) is an ATP-binding cassette (ABC) transporter that actively effluxes a wide range of structurally and functionally diverse molecules, playing a crucial role in drug absorption, distribution, and excretion. P-gp is highly expressed at key biological barriers, such as the blood-brain barrier (BBB), intestine, liver, and kidneys, and it serves as a gatekeeper against xenobiotics and therapeutics. Its dysregulation is involved in multidrug resistance (MDR), epilepsy, cancer, infectious diseases, and neurodegenerative disorders. Several small molecules were synthesized using SAfIR and SAR, and, among them, [¹⁸F]MC225 showed the most promising results for in vivo human studies, with appropriate pharmacodynamics and pharmacokinetics profiles for in vivo use. [¹⁸F]MC225 is currently being employed in PHASE II human trials at the UMC Groningen, the Netherlands, in patients diagnosed with AD, PD and MCI, as well as PHASE II human trials at the Policlinico Gemelli in Rome Italy to diagnose P-gp resistant depression. Preliminary studies show that [¹⁸F]MC225 radiotracer is behaving according to the initial predictions, that is, it accurately diagnoses the aforementioned pathologies, more so than previously developed small molecules for the same goal.