(−)-6′,7′-[ 11 C]Dihydroroten-12Α-ol ((−)-[ 11 C]DHROL) for in vivo measurement of mitochondrial Complex I

Abstract

Deficits in Complex I (NADH-ubiquinone oxidoreductase) of the electron transport chain may play an important role in the inception and progression of neurodegenerative diseases such as Parkinson's disease. In vivo imaging of Complex I offers a unique method for evaluation of these changes in living human brain. Previous carbon-11 labeled rotenoids showed promising results, but were prepared as mixtures of stereoisomers at the 5′-position. We report here the stereospecific syntheses of (−)-6′,7′-[ 11 C]dihydroroten-12Α-ol ((−)-[ 11 C]DHROL), a modified rotenoid with in vivo affinity for Complex I. O -[ 11 C]methylation of the appropriate desmethyl precursor provided (−)-[ 11 C]DHROL in an average radiochemical yield, corrected to end of bombardment, of 27% (n=4) and >99% radiochemical purity. In mice, (−)-[ 11 C]DHROL gave a high and uniform brain uptake similar to that obtained with prior radiolabeled rotenoids. Further in vivo evaluation of (−)-[ 11 C]DHROL in rats with unilateral quinolinic acid-induced striatal lesions showed significant losses of radioligand binding after neurotoxin treatment (lesion/unlesioned ratio of 0.66). As this reduction of in vivo radioligand binding is very similar to that obtained previously with the mixture of [ 11 C]DHROL isomers, the stereochemistry at the 5′-position of [ 11 C]DHROL does not significantly influence the in vivo applications of this radiotracer. Copyright © 1999 John Wiley & Sons, Ltd.