REGIONAL BRAIN UPTAKE AND PHARMACOKINETICS OF [I-123] KYL-2-BETA-CARBOXY-3-BETA-(4-IODOPHENYL)NORTROPANE ESTERS IN BABOONS

Four N-omega-fluoroalkyl-2 beta-carboxy-3 beta-(4-iodophenyl)nortropan e esters [N-fluoroethyl, methyl ester (beta-CIT-FE), N-fluoropropyl, m ethyl eater (beta-CIT-FP), N-fluoroethyl, isopropyl ester (IP-beta-CIT -FE), and N-fluoropropyl, isopropyl ester (IP-beta-CIT-FP)] were label ed with I-123 and evaluated in baboons by dynamic SPECT regional brain imaging, measurement of pharmacokinetics in arterial plasma, and whol e body imaging. The labeled tracers were prepared by iododestannylatio n of the corresponding 4-(trimethylstannyl)phenyl compounds in radioch emical yield 63-96% and radiochemical purity >96%. Regional SPECT brai n imaging was carried out over a period of 5 h with a Strichman 810X B rain Imager to assess regional uptake in the striatum and midbrain com pared to reference regions in the occipital cortex and cerebellum; art erial blood samples were taken for analysis of metabolites by solvent extraction and HPLC. The methyl esters showed higher total and specifi c peak uptake in the striatum than the isopropyl esters. Midbrain upta ke was uniformly lower than striatal uptake and washed out more rapidl y. beta-CIT-FE had more rapid striatal kinetics than beta-CIT-FP, with specific striatal washout rates of 10-14 vs 4-6% peak/h. Biodistribut ion of [I-123]beta-CIT-FE and [I-123]beta-CIT-FP measured by whole bod y conjugate imaging demonstrated major uptake in the brain, liver, and GI tract, with excretion occurring through both the renal and hepatob iliary routes. Absorbed radiation dose estimates based on the MIRD sch ema indicated highest dose rates to the urinary bladder wall and lower large intestine wall (0.7 and 0.6 rad/mCi for [I-123]beta-CIT-FE and 0.7 and 0.9 rad/mCi for [I-123]beta-CIT-FP, respectively). The high up take in the striatum and the relative specificity with respect to cort ical, midbrain, and cerebellar areas, suggest that [I-123]beta-CIT-FE and [I-123]beta-CIT-FP may be valuable tracers for studying the dopami ne system in vivo by tomographic imaging.