Synthesis and Evaluation of 18F-and 11C-Labelled 9,10-Ethanobenzo[b]quinolizinium Derivatives for Imaging of the NMDA Receptor at the TCP-Binding Site

Derivatives of 9,10-ethanobenzo[b]quinolizinium are potent antagonists of the TCP-site of the NMDA receptor. Two fluoroethyl-substituted analogues were labelled with fluorine-18 by displacement of the tosylate with [18F]fluoride, followed by a Diels-Alder reaction. A methoxy-substituted analogue labelled with carbon-11 was obtained by O-methylation of the corresponding hydroxy precursor with [11C]iodomethane. In biodistribution studies in mice with these three radioligands, it was found that they have little ability to penetrate the blood-brain barrier

Synthesis and in vitro characterization of radioiodinatable benzodiazepines selective for type 1 and type 2 cholecystokinin receptors

Radiolabeled antagonists of specific peptide receptors identify a higher number of receptor binding sites than agonists and may thus be preferable for in vivo tumor targeting. In this study, two novel radioiodinated 1,4-benzodiazepines, (S)-1-(3-iodophenyl)-3-(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)urea (9) and (R)-1-(3-iodophenyl)-3-(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)urea (7), were developed. They were characterized in vitro as high affinity selective antagonists at cholecystokinin types 1 and 2 (CCK(1) and CCK(2)) receptors using receptor binding, calcium mobilization, and internalization studies. Their binding to human tumor tissues was assessed with in vitro receptor autoradiography and compared with an established peptidic CCK agonist radioligand. The (125)I-labeled CCK(1) receptor-selective compound 9 often revealed a substantially higher amount of CCK(1) receptor binding sites in tumors than the agonist (125)I-CCK. Conversely, the radioiodinated CCK(2) receptor-selective compound 7 showed generally weaker tumor binding than (125)I-CCK. In conclusion, compound 9 is an excellent radioiodinated nonpeptidic antagonist ligand for direct and selective labeling of CCK(1) receptors in vitro. Moreover, it represents a suitable candidate to test antagonist binding to CCK(1) receptor-expressing tumors in vivo

A role for glutamate in subjective response to smoking and its action on inhibitory control

Rationale Our previous study using memantine in smokers suggests that there may be a differential role for N-methyl-d-aspartate (NMDA) receptors in the subjective and cognitive effects of smoking. Objectives This study was designed to investigate if d-cycloserine (DCS) would modulate the subjective and cognitive effects of limited smoking. Methods Forty-eight habitual smokers abstinent for a minimum of 2 h were randomly allocated to receive either placebo or 50 mg DCS (double-blind) and were subsequently required either to smoke half of one cigarette or to remain abstinent. Subjective and physiological effects of DCS were measured at baseline, 90 min postcapsule, and again after the partial-smoking manipulation, while the effects on sustained attention (rapid visual information processing test—RVIP) and cognitive flexibility (intra–extra dimensional set-shift test—IED) were evaluated only after the partial-smoking manipulation. Results DCS alone did not produce significant subjective effects other than an increase in ratings of “Stimulated”. In combination with partial smoking, however, DCS blocked the smoking-induced increase in “Stimulated” and the decrease in “Relaxed” ratings. Furthermore, in combination with smoking, DCS reduced the number of false alarms during the RVIP test (an index of inhibitory control) and produced a small increase in diastolic blood pressure. DCS failed to modulate IED performance. Conclusions These findings provide further evidence of a role for glutamate release in the subjective effects of smoking but not the effects on attention and cognitive flexibility. Furthermore, our results indicate that glutamate release may also be involved in the effect of smoking on inhibitory control