Synthesis and biological evaluation in mice of (2-[11C]methoxy)-6',7'-dihydrorotenol, a second generation rotenoid for marking mitochondrial complex I activity.

Evidence has accumulated suggesting that impairment of the function of the complexes of the mitochondrial respiratory chain might be involved in the pathology of neurological diseases including Parkinson's and Huntington's diseases. Recently we reported the synthesis of (2-[11C]methoxy)rotenone ([11C]ROT) as a tool for in vivo studies of complex I. In an effort to develop a complex I imaging radiotracer which might be easier to synthesize and less likely to be metabolized, we prepared (2-[11C]methoxy)-6',7'-dihydrorotenol ([11C]DHROT). The radiotracer was synthesized by [11C]methylation of 2-O-desmethyl-6',7'-dihydrorotenol under basic [11C]alkylation conditions. (2-[11C]Methoxy)-6',7'-dihydrorotenol was produced in 30-35% radiochemical yields (decay corrected), with synthesis times shorter than 35 min. Radiochemical purities were over 95% and specific activities averaged 1000 Ci/mmol. The brain distributions of [11C]ROT and [11C]DHROT were investigated in mice after intravenous injections. For both radiotracers, distribution of radioactivity was similar in all brain regions examined. However, significantly higher uptake was observed with [11C]DHROT than with [11C]ROT, indicating that the alterations introduced in the structure of rotenone during the design of [11C]DHROT resulted in a tracer with greater brain barrier permeability.