SYNTHESIS AND CHARACTERIZATION OF RADIOIODINATED -BETA-CARBOMETHOXY-3-BETA-(4-CHLOROPHENYL)TROPANES - POTENTIAL DOPAMINE REUPTAKE SITE IMAGING AGENTS

Methods have been developed for the preparation of radioiodinated N-su bstituted 2 beta-carbomethoxy-3 beta-(4-chlorophenyl)tropanes. The syn theses, physical properties, radiolabeling, and characterization of th e pharmacological properties of N-(3(Z)-iodopropen-1-yl)-2 beta-carbom ethoxy-3 beta-(4-chlorophenyl) tropane (12) and N-(3(E)-iodopropen-1-y l)-2 beta-carbomethoxy-3 beta-(4-chlorophenyl)tropane (13) are describ ed. 2 beta-Carbomethoxy-3 beta-(p-substituted-phenyl)tropanes are pote nt ligands for the dopamine transporter. The radioiodinated derivative s are of interest because of the high uptake and prolonged striatal re tention that may result from specific binding to low-capacity, high-af finity, dopamine reuptake sites. Radioiodine was introduced into the 3 Z and 3E-position of N-(3-iodopropen-1-yl)-2 beta-carbomethoxy-3 beta- (4-chlorophenyl)tropane by iododemetalation of the corresponding 3-(tr i-n-butylstannyl) derivatives. Competition binding data of various dop amine reuptake ligands with rat striatal tissue preparation for either [I-125]-12 Or [I-125]-13 exhibited the following order of potency: E- 13 > 2-12 > GBR 12909 much greater than mazindol >>> (-)-cocaine. Tiss ue distribution studies in rats showed that the E-13 was the best anal ogue. E-13 showed high striatal uptake (60 min, 1.23% dose/g; 120 min, 0.61% dose/g) and high striatal to cerebellum ratios (60 min, 15.9/1; 120 min, 16.5/1). These studies indicate that iodine-123-labeIed E-13 is a potentially useful agent for imaging the dopamine reuptake sites by single-photon-emission computerized tomography.