EVALUATION OF THE MONOAMINE UPTAKE SITE LIGAND [I-123] METHYL 3-BETA-(4-IODOPHENYL)-TROPANE-2-BETA-CARBOXYLATE ([I-123)BETA-CIT) IN NONHUMAN-PRIMATES - PHARMACOKINETICS, BIODISTRIBUTION AND SPECT BRAIN IMAGING COREGISTERED WITH MRI

The in vivo properties of a new radioiodinated probe of the dopamine and serotonin transporter, [I-123]Methyl 3beta-(4-iodophenyl)tropane-2beta-carboxylate ([I-123]beta-CIT) were evaluated in baboons and vervet monkeys. The labeled product was prepared in 65.2 +/- 2.8% yield (mean +/- SEM; n = 18) by reaction of the tributylstannyl precursor with [I-123]NaI in the presence of peracetic acid followed by high pressure liquid chromatography (HPLC) purification to give a product with radiochemical purity of 97.5 +/- 0.5% and specific activity of 500-1200 Ci/mmol. After intravenous administration, whole brain activity peaked at 6-10% injected dose within 1 h post injection (p.i.) and washed out in a biphasic manner with clearance half-lives of 1-2 and 7-35 h for the rapid and slow components, respectively. Excretion occurred primarily through the hepatobiliary route, with about 30% of the injected dose appearing in the GI tract after 5 h. Estimates of radiation absorbed dose gave 0.01, 0.1, 0.2 and 0.03 mGy/MBq to the brain, gall bladder wall, lower large intestine wall and urinary bladder wall, respectively. High resolution SPECT imaging in a baboon demonstrated high uptake of tracer in the region of the striatum (striatum:cerebellum ratio 4.0), in the hypothalamus (ratio 2.6) and in a midbrain region comprising raphe, substantia nigra and superior colliculus (ratio 2.0), with regional brain uptakes measured at 210 min p.i. of [I-123]beta-CIT. The anatomical locations of the regions on the SPECT image were confirmed by coregistration with MRI. Plasma metabolites and pharmacokinetics were analyzed in baboons and vervets by ethyl acetate extraction and HPLC. The major metabolite was a polar, non-extractable fraction, which increased to > 50% of the plasma activity by 30-45 min p.i. A minor lipophilic (extractable) metabolite was also observed, increasing to about 4% at 2 3 h p.i. The plasma protein bound fraction, determined by ultrafiltration. was 74.8 +/- 1.4% (n = 6). The arterial input function was characterized by the sum of three exponential terms with half-lives of 0.3-1.7, 9.7-24.9 and 77-166 min, respectively, for the concentration of free parent compound. [I-123]beta-CIT promises to be a useful marker for SPECT study of the monoamine uptake system in primate brain.