FLUORINATED BENZAMIDE NEUROLEPTICS .3. DEVELOPMENT OF (S)-N-[(1-ALLYL-2-PYRROLIDINYL)METHYL]-5-(3-[F-18] FLUOROPROPYL)-2,3-DIMETHOXYBENZAMIDE AS AN IMPROVED DOPAMINE D-2 RECEPTOR TRACER

被引:182
作者
MUKHERJEE, J
YANG, ZY
DAS, MK
BROWN, T
机构
[1] Franklin McLean Institute, Department of Radiology, University of Chicago, Chicago
来源
NUCLEAR MEDICINE AND BIOLOGY | 1995年 / 22卷 / 03期
关键词
D O I
10.1016/0969-8051(94)00117-3
中图分类号
R8 [特种医学]; R445 [影像诊断学];
学科分类号
1002 ; 100207 ; 1009 ;
摘要
We have prepared five new analogs (n-propyl, iso-propyl, allyl, n-butyl, and iso-butyl) of the dopamine D-2 receptor antagonist, FPMB which result from modifications of the ethyl group at the pyrrolidine nitrogen in FPMB. As expected, all new derivatives showed higher apparent lipophilicity (log k(w)), with iso-butyl being the most lipophilic (log k(w) = 2.52), followed by the allyl derivative (log k(w) = 2.43). The allyl group showed the largest increase in affinity (from 0.26 nM for the ethyl substituent to 0.03 nM for the allyl substituent, almost 10-fold), followed by the n-propyl substituent which showed approximately five-fold better affinity than did the ethyl substituent. Radiosynthesis of (S)-N-[(1-allyl-2-pyrrolidinyl)methyl]-5-(3-[F-18]fluoropropyl)-2,3-dimethoxybenzamide ([F-18]fallypride) was carried out by nucleophilic substitution reaction of (S)-N-[(1-allyl-2-pyrrolidinyl)methyl]-5-(3-tosyloxypropyl)-2,3-dimethoxybenzamide with no carrier added F-18(-). [F-18]Fallypride was obtained in approximately 20-40% yields (EOS/EOB, decay corrected) in specific activities of 900-1700 Ci/mmol after reverse phase HPLC purification in 60 min from EOB. High striatal uptake (upto 2.5% injected dose/g) of [F-18]fallypride in rats was observed with striatal/cerebellar ratios of 17, 42, 63 and 122 at 30, 60, 90 and 120 min post-injection, respectively. PET experiments with [F-18]fallypride in a cebus monkey showed a brain uptake of 0.10% injected dose/cc. In rhesus monkeys [F-18]fallypride showed rapid specific uptake in the striata (0.04-0.06% injected dose/cc) with striata/cerebellum ratios of approx. 3.0 at 14 min, 5.0 at 35 min and 8 at 70 min post-injection. Specifically bound [F-18]fallypride was displaced with haloperidol(1 mg/kg) with a half-life of 18 min in the rhesus monkey.
引用
收藏
页码:283 / 296
页数:14
相关论文
共 37 条
[1]   SYNTHESIS AND INVITRO EVALUATION OF 2,3-DIMETHOXY-5-(FLUOROALKYL)-SUBSTITUTED BENZAMIDES - HIGH-AFFINITY LIGANDS FOR CNS DOPAMINE-D2 RECEPTORS [J].
BISHOP, JE ;
MATHIS, CA ;
GERDES, JM ;
WHITNEY, JM ;
EATON, AM ;
MAILMAN, RB .
JOURNAL OF MEDICINAL CHEMISTRY, 1991, 34 (05) :1612-1624
[2]  
BOYSON SJ, 1986, J NEUROSCI, V6, P3177
[3]  
CHENG Y, 1973, BIOCHEM PHARMACOL, V22, P3099
[4]  
CHIPKIN RE, 1988, J PHARMACOL EXP THER, V247, P1093
[5]   FLUORINATED AND IODINATED DOPAMINE AGENTS - D2 IMAGING AGENTS FOR PET AND SPECT [J].
CHUMPRADIT, S ;
KUNG, MP ;
BILLINGS, J ;
MACH, R ;
KUNG, HF .
JOURNAL OF MEDICINAL CHEMISTRY, 1993, 36 (02) :221-228
[6]   POTENTIAL NEUROLEPTIC AGENTS .3. CHEMISTRY AND ANTIDOPAMINERGIC PROPERTIES OF SUBSTITUTED 6-METHOXYSALICYLAMIDES [J].
DEPAULIS, T ;
KUMAR, Y ;
JOHANSSON, L ;
RAMSBY, S ;
FLORVALL, L ;
HALL, H ;
ANGEBYMOLLER, K ;
OGREN, SO .
JOURNAL OF MEDICINAL CHEMISTRY, 1985, 28 (09) :1263-1269
[7]  
DEPAULIS T, 1991, NEW TRENDS IN RADIOPHARMACEUTICAL SYNTHESIS, QUALITY ASSURANCE, AND REGULATORY CONTROL, P97
[8]   LIPOPHILICITY MEASUREMENTS OF PROTONATED BASIC COMPOUNDS BY REVERSED-PHASE HIGH-PERFORMANCE LIQUID-CHROMATOGRAPHY .1. RELATIONSHIP BETWEEN CAPACITY FACTORS AND THE METHANOL CONCENTRATION IN METHANOL WATER ELUENTS [J].
ELTAYAR, N ;
VANDEWATERBEEMD, H ;
TESTA, B .
JOURNAL OF CHROMATOGRAPHY, 1985, 320 (02) :293-304
[9]  
FANG Y-B, 1992, Journal of Nuclear Medicine, V33, P982
[10]   SYNTHESIS AND BINDING-PROPERTIES OF THE FLUORINATED SUBSTITUTED BENZAMIDE [H-3] NCQ-115, A NEW SELECTIVE DOPAMINE-D2 RECEPTOR LIGAND [J].
HALL, H ;
HOGBERG, T ;
HALLDIN, C ;
BENGTSSON, S ;
WEDEL, I .
EUROPEAN JOURNAL OF PHARMACOLOGY, 1991, 201 (01) :1-10