Synthesis and evaluation of N-methyl and S-methyl 11C-labeled 6-methylthio-2-(4'-N,N-dimethylamino)phenylimidazo[1,2-a]pyridines as radioligands for imaging beta-amyloid plaques in Alzheimer's disease.

6-Thiolato-substituted 2-(4'- N,N-dimethylamino)phenylimidazo[1,2- a]pyridines ( RS-IMPYs; 1- 4) were synthesized as candidates for labeling with carbon-11 ( t 1/2 = 20.4 min) and imaging of A beta plaques in living human brain using positron emission tomography (PET). K i values for binding of these ligands to Alzheimer's disease brain homogenates were measured in vitro against tritium-labeled 6 (Pittsburgh compound B). MeS-IMPY ( 3, K i = 7.93 nM) was labeled with carbon-11 at its S- or N-methyl position to give [ (11)C] 7 or [ (11)C] 8, respectively. After injection into rats, [ (11)C] 7 or [ (11)C] 8 gave moderately high brain uptakes of radioactivity followed by rapid washout to low levels. The ratio of radioactivity at maximal uptake to that at 60 min reached 18.7 for [ (11)C] 7. [ (11)C] 7 behaved similarly in mouse and monkey. [ (11)C] 7 also bound selectively to A beta plaques in post mortem human Alzheimer's disease brain. Although rapidly metabolized in rat by N-demethylation, [ (11)C] 7 was stable in rat brain homogenates. The ex vivo brain radiometabolites observed in rats have a peripheral origin. Overall, [ (11)C] 7 merits further evaluation in human subjects.

Evaluation of anesthesia effects on [18F]FDG uptake in mouse brain and heart using small animal PET.

This study evaluates effects of anesthesia on (18)F-FDG (FDG) uptake in mouse brain and heart to establish the basic conditions of small animal PET imaging. Prior to FDG injection, 12 mice were anesthetized with isoflurane gas; 11 mice were anesthetized with an intraperitoneal injection of a ketamine/xylazine mixture; and 11 mice were awake. In isoflurane and ketamine/xylazine conditions, FDG brain uptake (%ID/g) was significantly lower than in controls. Conversely, in the isoflurane condition, %ID/g in heart was significantly higher than in controls, whereas heart uptake in ketamine/xylazine mice was significantly lower. Results suggest that anesthesia impedes FDG uptake in mouse brain and affects FDG uptake in heart; however, the effects in the brain and heart differ depending on the type of anesthesia used.

Cerebral benzodiazepine receptors in depressed patients measured with [123I]iomazenil SPECT.

BACKGROUND: A recent magnetic resonance spectroscopy (MRS) study revealed low gamma-aminobutyric acid (GABA) levels in the occipital cortex of depressed patients. No in vivo study has been reported to measure postsynaptic GABA receptors in the patients. METHODS: Cortical benzodiazepine (BZ) binding to GABA(A) receptors was measured with [(123)I]iomazenil and single photon emission computed tomography in unmedicated patients with unipolar major depression (n = 13) and healthy subjects (n = 19). Group differences were evaluated by means of statistical parametric mapping (SPM) with partial volume correction for gray matter. Occipital GABA levels were determined by proton MRS in a subgroup (n = 6) of the patients. RESULTS: No evidence of altered BZ binding was found in patients with depression compared with healthy control subjects in the SPM analysis. Although reduction in gray matter volume was observed in the frontal cortex and amygdala of the patients, partial volume correction of the atrophy did not change the result of unaltered BZ binding. GABA levels were found lower in the occipital cortex; however, BZ binding did not show significant relationship to GABA levels. CONCLUSIONS: GABA(A) receptor binding measured in vivo with BZ radioligand binding are not altered in patients with depression.

Changes in human in vivo serotonin and dopamine transporter availabilities during chronic antidepressant administration.

Few studies have demonstrated in vivo alterations of human serotonin and dopamine transporters (SERTS and DATS) during antidepressant treatment. The current study measured these transporter availabilities with [(123)I]beta-CIT single photon emission computed tomography (SPECT) during administration of selective serotonin reuptake inhibitors (SSRIs) or a non-SSRI, bupropion. A total of 17 healthy human subjects were randomly assigned to two different treatment protocols: (1). citalopram (40 mg/day) followed by augmentation with bupropion (100 mg/day) or (2). bupropion (100-200 mg/day) for 16 days. Citalopram significantly inhibited [(123)I]beta-CIT binding to SERT in brainstem (51.4%) and diencephalon (39.4%) after 8 days of administration, which was similarly observed after 16 days. In contrast, citalopram significantly increased striatal DAT binding by 15-17% after 8 and 16 days of administration. Bupropion and its augmentation to citalopram did not have a significant effect on DAT or SERT. In 10 depressed patients who were treated with paroxetine (20 mg/day), a similar increase in DAT and inhibition of SERT were observed during 6 weeks treatment. The results demonstrated the inhibition of SERT by SSRI in human in vivo during the chronic treatment and, unexpectedly, an elevation of DAT. This apparent SSRI-induced modulation of the dopamine system may be associated with the side effects of these agents, including sexual dysfunction.