ALTROPANE, A SPECT OR PET IMAGING PROBE FOR DOPAMINE NEURONS - III - HUMAN DOPAMINE TRANSPORTER IN POSTMORTEM NORMAL AND PARKINSONS DISEASED BRAIN

Increasing evidence suggests that the dopamine transporter is situated almost exclusively on dopamine neurons. Accordingly, it is an valuabl e marker for Parkinson's disease and other pathological states of dopa mine neurons. We previously demonstrated that the potent dopamine tran sport inhibitor [I-125]altropane (IACFT:E-N-iodoallyl-2 beta-carbometh oxy-3 beta-(4-fluorophenyl)tropane) is a high affinity selective probe for the dopamine transporter in monkey brain and an effective SPECT i maging agent in nonhuman primate brain. We now report the binding prop erties of [I-125]altropane in postmortem tissue of normal human brain and compare the findings to Parkinson's diseased brain. In homogenates of human brain putamen, [I-125]altropane bound with high affinity (K- D: 4.96 +/- 0.38 nM, n = 4) and site density (B-MAX: 212 +/- 41.1 pmol /g original wet tissue weight) well within the density range reported previously for the dopamine transporter in this brain region. Drugs in hibited [I-125]altropane binding with a rank order of potency that cor responded closely to their rank order for blocking dopamine transport (r 0.98, P < 0.001). In postmortem Parkinson's diseased brain, bound [ I-125]altropane (1 nM) was markedly reduced (89%, 99% in putamen, depe nding on measures of nonspecific binding) compared with normal aged-ma tched controls (normal putamen: 49.2 +/- 8.1 pmol/g; Parkinson's disea sed putamen: 0.48 +/- 0.33 pmol/g; n = 4). In vitro autoradiography, c onducted in tissue sections at a single plane of the basal ganglia, re vealed high levels of [I-125]altropane binding the caudate nucleus and putamen, but lower levels (73% of the caudate-putamen) in the nucleus accumbens (n = 7). In Parkinson's diseased brains (n = 4), [I-125]alt ropane binding was 13% of the levels detected in normal putamen, 17% o f normal values in the caudate nucleus, and 25% of normal levels in nu cleus accumbens. The association of [I-125]altropane to the dopamine t ransporter in human postmortem tissue, the marked reduction of [I-125] altropane binding in Parkinson's diseased brains, its rapid entry into brain and highly localized distribution in dopamine-rich brain region s, support its use as a probe for monitoring the dopamine transporter in vitro and in vivo by SPECT imaging. (C) 1998 Wiley-Liss, Inc.