Background:Monocarboxylate transporter 8 (MCT8) deficiency is a rare X-linked disease where patients exhibit peripheral hyperthyroidism and cerebral hypothyroidism, which results in severe neurological impairments. These brain defects arise from a lack of thyroid hormones (TH) during critical stages of human brain development. Treatment options for MCT8-deficient patients are limited and none have been able to prevent or ameliorate effectively the neurological impairments. This study explored the effects of the TH agonist sobetirome and its CNS-selective amide prodrug, Sob-AM2, in the treatment of pregnant dams carrying fetuses lackingMct8and deiodinase type 2 (Mct8/Dio2KO), as a murine model for MCT8 deficiency.Methods:Pregnant dams carryingMct8/Dio2KO fetuses were treated with 1 mg of sobetirome/kg body weight/day, or 0.3 mg of Sob-AM2/kg body weight/day for 7 days, starting at embryonic day 12.5 (E12.5). As controls, pregnant dams carrying wild-type and pregnant dams carryingMct8/Dio2KO fetuses were treated with daily subcutaneous injections of vehicle. Dams TH levels were measured by enzyme-linked immunosorbent assay (ELISA). Samples were extracted at E18.5 and the effect of treatments on the expression of triiodothyronine (T3)-dependent genes was measured in the placenta, fetal liver, and fetal cerebral cortex by real-time polymerase chain reaction.Results:Maternal sobetirome treatment led to spontaneous abortions. Sob-AM2 treatment, however, was able to cross the placental as well as the brain barriers and exert thyromimetic effects inMct8/Dio2KO fetal tissues. Sob-AM2 treatment did not affect the expression of the T3-target genes analyzed in the placenta, but it mediated thyromimetic effects in the fetal liver by increasing the expression ofDio1andDio3genes. Interestingly, Sob-AM2 treatment increased the expression of several T3-dependent genes in the brain such asHr,Shh,Dio3,Kcnj10,Klf9,andFaahinMct8/Dio2KO fetuses.Conclusions:Maternal administration of Sob-AM2 can cross the placental barrier and access the fetal tissues, including the brain, in the absence of MCT8, to exert thyromimetic actions by modulating the expression of T3-dependent genes. Therefore, Sob-AM2 has the potential to address the cerebral hypothyroidism characteristic of MCT8 deficiency from fetal stages and to prevent neurodevelopmental alterations in the MCT8-deficient fetal brain.