1997 Fiscal Year Final Research Report Summary
Development of Positron-Labeled Radiotracers for Evaluation of NMDA Receptor Functions
| Project/Area Number |
08457244
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Radiation science
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| Research Institution | KYUSHU UNIVERSITY |
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Principal Investigator |
MAEDA Minoru KYUSHU UNIVERSITY,FACULTY OF PHARMACEUTICAL SCIENCES PROFESSOR, 薬学部, 教授 (70101178)
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| Project Period (FY) |
1996 – 1997
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| Keywords | NMDA Receptor / In-Vivo Ligand / Fluorine-18 / Carbon-11 / Labeling Synthesis / Azoniaanthracene / TCP |
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| Research Abstract |
The object of this research is to develop PFT imaging agents selective for the open state of the NMDA ion-channel complex.We designed a lipophilic TCP analog (MMPTC) having a cis-CH_2OCH_3 group atthe C_2 of the cyclohexyl ring, and two fluorine-substituted analogs of 6,11-ethano-12,12-di(2'-thienyl) -6,11-dihydrobenzo [b]quinolizinium cation (ETDQ) which is a hydrophilic and selective openchannel NMDA receptor antagonist. ^<11>C-Labeled MMPTC was achieved by O-methylation of the hydroxy precursor with ^<11>CH_31. Brain regional distribution of ^<11>C-MMPTC in mice did not show selective accumulation in any tissues, although relatively high brain uptake was observed. The introduction of fluoroethyl substituent at C_5 on the thienyl ring of ETDQ and fluoroethoxy substituent C_8 on the benzoring of ETDQ was designed and the new synthetic routes for the prepararion of these fluorine-containing analogs, methods applicable to ^<18>F-labeling radiosynthesis, were developed. The fluoroethyl analogs showed IC_<C50> values of 47-89nM for the PCP binding site on the NMDA receptor complex, while that of the fluoroethoxy analog was 64nM,as determined by displacement of ^3H-TCP binding to rat brain homogenates. Radiosynthesis was done as a two-step, two-pot reaction sequence following these synthetic strategies. Nucleophilic ^<18>F-fluorination was carried out using the Kryptofix222/K_2CO_3 system. Cycloaddition reaction between azoniaanthracene and ^<18>F-fluorinated dithienycarbinol in CF_3CH_2OH at 80ﾟC for 30min gave the ^<18>F-fluroethyl analog in 0.5% radiochemical yield. The ^<18>F-fluoroethoxy analog wasobtained through ^<18>F-fluoroethoxylation of the hydroxy precursor in 5.5% radiochemical yield with a total synthesis time of 160 min.
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