IN-VIVO IMAGING OF BABOON AND HUMAN DOPAMINE TRANSPORTERS BY POSITRONEMISSION TOMOGRAPHY USING [C-11] WIN-35,428

[C-11]WIN 35,428 was evaluated as a specific in vivo radioligand for t he dopamine transporter site by PET scanning in nonhuman primates and humans. In studies with a baboon (Papio anubis), [C-11]WIN 35,428 accu mulated in brain regions containing dopamine transporters, i.e., the s triata. This accumulation was partially blocked by prior administratio n of (-)cocaine (4 mg/kg, i.v.). Placement of a unilateral lesion of d opamine-containing nerve terminals with MPTP resulted in a unilateral reduction in [C-11]WIN 35,428 accumulation in the striatum on the side of the lesion. Imaging of D2 dopamine receptors with [C-11]NMSP in th e same MPTP-treated animals showed much less reduction in the postsyna ptic D2 dopamine receptors as compared to the much larger reduction in the dopamine transporters labeled with [C-11]WIN 35,428. A total of t en normal human volunteers (five males and five females) with ages ran ging from 19 to 81 years were studied. The caudate/cerebellar and puta men/cerebellar ratios ranged from 4.4 to 5.7 90 min after injection of the tracer. Preliminary kinetic modeling with arterial plasma samplin g resulted in an average binding potential (k3/k4) of 4.98 in the caud ate nucleus and 5.13 in putamen. To demonstrate in vivo blockade with dopamine reuptake inhibitors, two subjects received prior oral doses o f 6 mg mazindol. Subject 5 had significant reductions of 29% in the ca udate/cerebellar ratio at 90 min, 35% in the putamen/cerebellar ratio at 90 min, 45% in the caudate k3/k4 ratio from 6.7 to 3.7, and 46% in the putamen k3/k4 from 4.7 to 2.5. Subject 8 had significant reduction s of 20% in both the caudate/cerebellar ratio and the putamen/cerebell ar ratio at 90 min. During the human PET studies, a number of neuropsy chological tests and physiological measurements were performed. No sig nificant changes were found after administration of the [C-11]WIN 35,4 28 alone. Taken together, these data indicate that [C-11]WIN 35,428 is a promising radioligand for future studies of neuropsychiatric disord ers that involve the dopamine transporter site. (C) 1993 Wiley-Liss, I nc.