RAPID DETECTION OF PARKINSONS DISEASE W/ ALTROPANE

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Parkinson's disease (PD) is a progressive neurological disorder, characterized by degeneration of dopamine neurons and their nerve terminals from specific brain areas, particularly the caudate and putamen. Since dopamine neurons contain the dopamine transporter, the degenerative process can be monitored by the loss of the transporter in presynaptic nerve fibers and terminals. Radioligands that bind to these sites are promising probes for e arly diagnosis of the disease which may allow for intervention with drugs that either prevent disease progression or promote regeneration. Imaging of dopamine terminals can furthermore monitor the effectiveness of therapeutic approaches designed to maintain or improve the viability of dopamine neurons. Based on previous promising research with altropane (see abstracts 1, 2, 3 of Division of Neurochemistry), a Phase I clinical trial with [123I]altropane as a probe of dopamine neurons was approved by the FDA. The objectives were to assess the effectiveness of altropane, a SPECT (or PET) imaging agent, [123I]2 -carbomethoxy-3 -(4-fluorophenyl)-N-(1-iodoprop-1-en-3-yl)nortropane ([123I]altropane) to detect Parkinson's disease. In this study, single photon emission computed tomography (SPECT) with [123I] altropane was used to measure dopamine transporter density in 7 healthy volunteers (5 males, age 37-75 and 2 females ages 26 and 39) and 8 male patients with Parkinson's disease (age 14-79, Hoehn and Yahr stage 1.5-3 (n=5) and 4-5 (n=3). Dynamic SPECT images and arterial blood samples were acquired over 1.5-2 hrs and plasma radioactivity was analyzed chromatographically to obtain metabolite corrected arterial input functions. Binding potential (BP, B'max / KD) for striatal (Str) DAT sites was calculated by 2 methods using occipital cortex (Occ) as a reference. In the first method, tissue time-activity curves (TAC) and metabolite corrected arterial input functions were analyzed by a linear graphical method developed for reversible receptor ligands. In the second method, the expression (StrTAC - OccTAC) was fitted to a gamma variate function and the maximum divided by OccTAC at the same time was used to estimate BP. In 5 of the PD patients the SPECT data were compared with the results of PET with [18F] 6-fluoro DOPA (FD-PET). Plasma analysis indicated that [123I]altropane is rapidly converted to polar metabolites. SPECT images in healthy volunteers showed that [123I]altropane accumulated rapidly and selectively in the striatum and yielded excellent quality images within 1 hr after injection. Both methods of analysis revealed a 7.6%/decade reduction in binding potential and average striatal values (corrected to age 25) were 1.77+0.18 and 2.00+0.16 by methods 1 and 2. In all the Parkinson's diseased patients, striatal accumulation was markedly reduced and the pattern of loss was similar to that reported for dopamine, most profound in the posterior putamen with relative sparing of the caudate nuclei. A comparable pattern was observed with FD-PET. For total striatum, age corrected binding potential was significantly (p<0.001) reduced; 0.92 + 0.05 (method 1), 0.92+0.06 (method 2). Measured by the 2 methods, binding potential values were remarkably similar and highly correlated r2 = 0.88, (p<0.001). These results indicate that [123I]altropane is an excellent SPECT ligand for imaging the dopamine transporter/dopamine neurons in human brain. The high selectivity and rapid striatal accumulation of the ligand allows for accurate quantitation of these sites in less than 2 hrs. The results further demonstrate that [123I]altropane is an effective marker for Parkinson's disease. A Phase I clinical trial is in progress. Bonab AA, Babich JW, Alpert N, Madras BK, Fischman AJ. Comparison of three methods of quantification of dopamine transporters by SPECT with I-123 altropane. Soc. Nucl. Med. 38:949, 1997. Fischman AJ, Babich JW, Bonab AA, Alpert NM, Elmaleh DR, Barrow SA, Graham WA, Meltzer PC, Madras BK. Rapid detection of Parkinson's disease by SPECT with altropane a selective ligand for dopamine transporters. Soc. Nucl. Med.38:219, 1997. Fischman AJ, Bonab AA, Babich JW, Palmer P, Alpert NM, Elmaleh DR, Barrow SA, Graham W, Meltzer PC, Hanson RH, Madras BK.