Here we present a chemical strategy that allows brain-specific mTOR inhibition through the combination of two pharmacological agents: a brain-permeable mTOR inhibitor (RapaLink-1) whose function requires the intracellular protein FK506-binding protein 12 (FKBP12), and a brain-impermeant ligand of FKBP12 (RapaBlock).

If the pharmacological effects of these mTOR inhibitors could be confined to the CNS, their therapeutic window could be substantially widened. Although both allosteric and orthosteric mTOR inhibitors have been investigated in numerous diseases of the central nervous system (CNS) including tuberous sclerosis complex 3, 4, 5, glioblastoma 6, 7, 8, 9 and alcohol use disorder 10, 11, 12, systemic inhibition of mTOR is associated with various dose-limiting adverse effects: immune suppression, metabolic disorders and growth inhibition in children 13, 14. Chemical inhibitors of mTOR provide a case in point. On-target–off-tissue toxicities affect commonly used drugs such as statins (myopathy caused by inhibition of HMG CoA reductase in skeletal muscle) 1 and first-generation antihistamines (drowsiness caused by blockade of the H 1 receptor in the brain) 2 and can sometimes preclude the safe usage of otherwise effective therapeutic agents. Although off-target effects may be mitigated by chemical modifications that improve the specificity of the drug, on-target–off-tissue toxicity represents a unique challenge that requires precise control over tissue partitioning. Administration of a small-molecule drug often leads to systemic pharmacological effects that contribute to both efficacy and toxicity and define its therapeutic index.

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