ALTROPANE, A SPECT OR PET IMAGING PROBE FOR DOPAMINE NEURONS - I - DOPAMINE TRANSPORTER BINDING IN PRIMATE BRAIN

Increasing evidence suggests that the dopamine transporter is an impor tant marker for physiological and pathological changes in dopamine neu rons. Potent dopamine transport inhibitors of the phenyltropane series (e.g., WIN 35,428 or CFT) are particularly suitable for PET (positron emission tomography) or SPECT (single photon emission computed tomogr aphy) imaging of the dopamine transporter in living brain. We investig ated whether altropane, an N-iodoallyl analog of WIN 35,428 (IACFT:E-N -iodoallyl-2 beta-carbomethoxy-3 beta-(4-fluorophenyl)tropane), displa yed in vitro properties suitable for evaluation as a SPECT imaging age nt. In brain striatum of cynomolgus monkey (Macaca fascicularis), the unlabeled E-isomer (IC50: 6.62 +/- 0.78 nM) was more potent than the Z -isomer (IC50: 52.6 +/- 0.3 mM) and displayed a relatively high dopami ne:serotonin transporter selectivity (28-fold). In radiolabeled form, [I-125]altropane bound to sites in the striatum with a single high aff inity (K-D: 5.33 +/- 0.55 nM) and with a site density (B-MAX: 301 pmol /g original wet tissue weight) that was within the density range repor ted previously for the dopamine transporter in striatum. Drugs inhibit ed [I-125] altropane binding with a rank order of potency that corresp onded closely to their potencies for inhibiting [H-3]WIN 35,428 bindin g (r(2): 0.99; P < 0.0001) to the blocking dopamine transport. The fav orable binding properties of altropane, together with its rapid entry into primate brain and highly localized distribution in dopamine-rich brain regions, suggest it is a suitable iodinated probe for monitoring the dopamine transporter in vitro and in vivo by SPECT or PET imaging . (C) 1998 Wiley-Liss, Inc.