Nucl. Med. Biol. Vol. 13, No. 5,pp. 523-526, 1986 ht. J. Radiat. Appl. Instrum. Part B Printed in Great Britain 0883-2897186 $3.00 + 0.00 Pergamon Journals Ltd Biodistribution of N-Alkyl and N-Fluoroalkyl Derivatives of Spiroperidol; Radiopharmaceuticals for PET Studies of Dopamine Receptors MICHAEL J. WELCH, DAE YOON CHI,’ CARLA J. MATHIAS, MICHAEL R. KILBOURN, JAMES W. BRODACK and JOHN A. KATZENELLENBOGEN’ Division of Radiation Sciences, The Edward Mallinckrodt Institute of Radiology, Washington University School of Medicine, 510 South Kingshighway, St Louis, MO 63110 and ‘Department of Chemistry, University of Illinois, 1209 West California Street, Urbana, IL 61801, U.S.A. (Receiued 28 February 1986) There is great interest in the application of positron labeled ligands to map the dopamine receptor in uiuo. A series of fluorine-184abeled N-alkyl and N-fluoroalkyl spiroperidol (SP) derivatives N-methyl[‘*F]SP; N-ethyl[‘*F]SP; N-(2-[‘sF]fluoroethyl)SP; N-propyl[‘*FjSP; N-(3-[‘*F]fluoropropyl)SP; N-(3-fluoro- propyl)[‘*F]SP; N-(2-[r8F]fluoropropyl)SP; N-(2-[r8F]fluorobutyl)SP; N-(2-[‘sF]fluoropentyl)SP; and N- (2-[‘*F]fluorohexyl)SP were synthesized. The lipophilicity of these ligands (log octanol/water partition coefficient) varies from 2.67 to 5.56 and the initial brain uptake in rats, measured at 2 min, was greatest with the methyl, ethyl, propyl, fluoroethyl, and fluoropropyl derivatives. The highest striatum/cerebellum values 1 h after administration were obtained with the N-methyl, N-propyl, and N-3-fluoropropyl derivatives, while that of N-2-fluoroethyl showed the greatest uptake of total activity in the brain at this time. The uptake of all these ligands in the striatum could be blocked by cold SP showing the striatal uptake to be by the dopamine receptors. Introduction Over the last several years there has been great interest in the development of high specific activity, high affinity ligands labeled with positron-emitting radionuclides for the in zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA uivo study of the dopamine receptor. The three ligands that have been studied in greatest detail are fluorine-18-labeled spiroperidol,““’ carbon-l l-labeled N-methyl-spiroperido1,‘s~6’ and fluorine-l&labeled N-methyl-spiroperidol,.(‘l”’ All three of these ligands have drawbacks with either their chemical preparation or their biological behav- ior. Fluorine-18-labeled spiroperidol and fluorine- l&labeled N-methyl-spiroperidol can only be pre- pared reliably using a multi-step chemical reaction; the total reaction time is r2 h, and the overall radiochemical yield is ~10%. The multi-step syn- thesis is difficult to automate, and the low yield means that one preparation is required for each patient study. Both of these compounds have been used to study the dopamine receptor in uiuo.‘3~4*6~8) The advan- tage of fluorine-184abeled spiroperidol is that the binding of spiroperidol has been characterized in vitro and in uiuo,(9-‘2) whereas the N-methyl compound is more lipophilic than spiroperidol and demonstrates a greater uptake in the brain.“’ N-Methyl spiroperidol has been labeled with “C and has been used in PET studies for the dopamine receptor in human brain. (” Since imaging studies of greater than 1 h in length are required in order to properly assess the in viuo behavior of these ligands, there are considerable advantages to ‘*F over “C.‘2.3’ Imaging studies of the [‘*F]spiroperidol in primates have allowed time-activity analysis of the bio- distribution of the compound, from which the do- simetry of the compound can be estimated. The calculated amount of ‘8F-1abe1ed compound that can be administered to achieve a radiation dose of less than 5 rad per critical organ is 7.5 mCi for the ‘*F-labeled ligand and 19.2 mCi for the “C-labeled ligand. If the maximum amount of either the “F or “C-labeled compound were administered, then at 1 h past administration 2.1 times as many counts would be obtained from the “F-labeled ligand; at 2 h, 12.25 times as many counts. In an attempt to prepare other ligands in high radiochemical yield via simple rapid chemical reactions, we,‘13’ and others,‘14’ have investigated techniques to synthesize N-fluoroalkyl derivatives of spiroperidol. This would allow the preparation of much larger amounts of dopaminergic ligands than are currently available and thereby enable increased numbers of patient studies to be 523