18F-labeled benzamides for studying the dopamine D2 receptor with positron emission tomography.
Two series of (N-benzylpiperidin-4-yl)- and (9-azabicyclo[3.3.1]nonan- 3 beta-yl)benzamides were prepared, and in vitro binding assays were used to measure the affinity of these compounds for dopamine D2, dopamine D3, serotonin 5-HT2, and alpha 2-adrenergic receptors. The results of these studies indicated compounds 23, 26b, and 34 have the selectivity needed for in vivo studies of the D2 (and possibly D3) receptors. 18F-Labeled analogues of 23, 26b and 34 were prepared by N-alkylation of the corresponding desbenzyl precursors with [18F]-4-fluorobenzyl iodide. Preliminary in vivo studies demonstrated that [18F]-23 and [18F]-26b are suitable candidates for further evaluation in positron emission tomography imaging studies. The slow rate of washout of [18F]-34 from nondopaminergic regions and its comparatively high lipophilicity indicates that this compound may not be suitable for imaging studies because of a high level of nonspecific binding.
Mach
R H
RH
Cerebrovascular Research Center, University of Pennsylvania, Philadelphia 19104.
Luedtke
R R
RR
Unsworth
C D
CD
Boundy
V A
VA
Nowak
P A
PA
Scripko
J G
JG
Elder
S T
ST
Jackson
J R
JR
Hoffman
P L
PL
Evora
P H
PH
D000818:Animals; D016367:Baculoviridae / Q000235:genetics; D001549:Benzamides / Q000138:chemical synthesis* / Q000378:metabolism; D001643:Bridged Bicyclo Compounds / Q000138:chemical synthesis* / Q000378:metabolism; D019086:Bridged Bicyclo Compounds, Heterocyclic; D005462:Fluorine Radioisotopes; D015394:Molecular Structure; D009036:Moths; D010880:Piperidines / Q000138:chemical synthesis* / Q000378:metabolism; D010911:Pituitary Neoplasms / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011942:Receptors, Adrenergic, alpha / Q000378:metabolism; D011954:Receptors, Dopamine / Q000235:genetics / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000378:metabolism*; D050637:Receptors, Dopamine D3; D011985:Receptors, Serotonin / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D013329:Structure-Activity Relationship; D014055:Tomography, Emission-Computed; D014407:Tumor Cells, Cultured
D001549:Benzamides; D001643:Bridged Bicyclo Compounds; D019086:Bridged Bicyclo Compounds, Heterocyclic; C493595:Drd3 protein, rat; D005462:Fluorine Radioisotopes; D010880:Piperidines; D011942:Receptors, Adrenergic, alpha; D011954:Receptors, Dopamine; D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3; D011985:Receptors, Serotonin; D011994:Recombinant Proteins; C084477:2,3-dimethoxy-N-(1-(4-fluorobenzyl)piperidin-4-yl)benzamide; C084478:2,3-dimethoxy-N-(9-(4-fluorobenzyl)-9-azabicyclo(3.3.1)nonan-3-yl)benzamide