Pergamon 0969-8051(94)00080-8 Nurl. Med. Biol. Vol. 22, No. I, 31-36. 1995 pp. Copyright 0 1995Else&r ScienceLtd Printed in Great Britain. All rights reserved 0969-8051195 $9.50+ 0.00 Synthesis of a l1 C-labeled NK, Receptor Ligand for PET Studies E. LIVNI’, JOHN W. BABICH’, MANOJ C. DESA13, DENNIS M. GODEK3, ROBERT A. WILKINSON’, ROBERT H. RUBIN’z2 and ALAN J. FISCHMAN’s2* ’ Division of Nuclear Medicine of the Department of Radiology and *The Clinical Investigation Program of the Medical Service, Massachusetts General Hospital and the Departments of Radiology and Medicine, Harvard Medical School, Boston, MA 02114 and ‘Central Research Division, Pfizer Inc., Groton, CT, U.S.A. (Accepted 6 June 1994) Changes in substance P (SP) receptor concentration have been implicated in neuropsychiatric disorders, Parkinson’s disease, arthritis, inflammatory bowel disease and asthma. Since, SP and peptide analogs are rapidly metabolized and do not penetrate into the CNS, they are not useful for PET. Recently, a non-peptide SP antagonist, (+)-(2S,3S)-3-(2-methoxybenzylamino)-2-phenylpiperidine (CP-99,994) was developed. As a prelude to PET studies, this compound was radiolabeled with “C and biodistribution was determined in hamsters. CP-99.994 was radiolabeled by methylation of tert-Boc, desmethyl CP-99,994 with “CH,I followed by deprotection and HPLC purification. The time required for the synthesis was 40min from the end of bombardment. Radiochemical purity of the final product was >95% and specific activity was routinely > 1000 mCi/pmol [EOS]. The biodistribution of “C<P-99,994 was determined in groups of six Syrian hamsters at 5 and 30min after injection. The results of these studies demonstrated that significant concentrations (%ID/g f SEM) of CP-99,994 accumulate in most tissues of the hamster. The highest levels of drug were detected in the lung: 21.04 k 1.26 (5 min) and 13.49 + 1.71 (30 min). Brain accumulation was: 1.44 k 0.06 (5 min), 1.32 f 0.05 (30 min). These results indicate that “C<P-99,994 can be prepared in high purity and specific activity. This new radiopharmaceutical may be useful for studying both central and peripheral SP receptors by PET. Introduction Substance P and its receptors are widely distributed throughout the central and peripheral nervous sys- tems and are involved in a variety of physiological processes (Nicoll et al., 1980; Pernow, 1983; Maggio, 1988),including: vasodilation (Melchiorri et al., 1977; Pernow and Rosell, 1975), smooth muscle contrac- tion (Pernow, 1953) stimulation of salivary secretion (Vogler et al., 1963; Leeman and Hammerschlag, 1967) and leukocyte activation (Payan et al., 1984; Hartung et al., 1986; Lotz et al., 1987;Perianin et al., 1989). In addition, there is significant evidence for a neurotransmitter or neuromodulator function of sub- stance P in pain transmission and in interactions with other neurotransmitters in the brain (Vaught, 1988; Nicoll et al., 1980; Maggio, 1988;Nilsson et al., 1974; Hokfelt et al., 1975; Mantyh et al., 1984; Womack et *All correspondence should be addressed to: Dr Alan J. Fischman, Division of Nuclear Medicine, Department of Radiology, Massachusetts General Hospital, 32 Fruit Street, Boston, MA 02114, U.S.A. al., 1988). Changes in substance P receptor concen- tration have been implicated in a variety of disease states, including: neuropsychiatric disorders, Parkin- son’s disease, arthritis, inflammatory bowel disease and asthma (Payan, 1989; Tenovuo et al., 1990). Clearly, a non-invasive method for studying the role of substance P receptors in the pathophysiology of these conditions would be of significant value. Since substance P and peptide analogs are rapidly metab- olized and do not penetrate the CNS to a significant extent, they are not useful for external imaging of the brain. Recently, two non-peptide substance P antag- onists, [(2S,3S)-cis-2-(diphenylmethyl)-N-[(2- methoxyphenyl) - methyl] - 1 - azabicyclo[2.2.2]octan- 3-amine (CP-96,345) and (+)-(2S,3S)-3-(2-methoxy- benzylamino)-2-phenylpiperidine (CP-99,994) were developed (Snider et al., 1991; Lowe et al., 1991, 1992; Desai et al., 1992). These compounds are metabolically stable, have high affinity for the NK, receptor and minimal binding to NK, and NK, receptors, and can be easily labeled with “C. Auto- radiography with 3 H-labeled CP-96,345 has demon- strated a pattern of distribution of binding sites in NMB **;,-a 31