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¹¹C-GR103545, a Radiotracer for Imaging-Opioid Receptors In Vivo with PET: Synthesis and Evaluation in Baboons

¹ Department of Psychiatry, Columbia University College of Physicians and Surgeons and the New York State Psychiatric Institute, New York, New York
² Laboratory on the Biology of Addictive Diseases, Rockefeller University, New York, New York
³ Department of Radiology, Columbia University College of Physicians and Surgeons and the New York State Psychiatric Institute, New York, New York

View larger version (19K): [in a new window]   FIGURE 1. Preparation of GR103545 and the chiral precursor 7. Reaction conditions: (a) thionyl chloride (SOCl2), methanol; (b) N-Boc-N-Bz-NBz-glycine, N,N-dicyclohexylcarbodiimide; (c) SOCl2; (d) lithium aluminum hydride; (e) 3,4-dichlorophenylacetyl chloride; (f) dimethyl sulfoxide, oxalyl chloride, morpholine; (g) pyrrolidine, HCl/methanol, pH 6; (h) sodium cyanoboronhydride3; (i) H2/Pd/C; (j) methyl chloroformate.

View larger version (15K): [in a new window]   FIGURE 2. (A) Chiral HPLC separation of optical isomers of compound 7, showing R-(+)-isomer of 7, S-(–)-isomer of 7, and racemic (±) isomers of 7. HPLC conditions: column, Chiralcel OD (250 x 4.6 mm); solvent, 25%:75%:0.01% isopropanol:hexane:diethylamine; flow rate, 2 mL/min. (B) Chiral HPLC separation of optical isomers of GR89695, showing GR103545 (the (–)-isomer) and GR89695 (the racemic isomers). HPLC conditions: column, Chiralcel OD (250 x 4.6 mm); solvent, 20%:80%:0.01% isopropanol:hexane:diethylamine; flow rate, 2 mL/min.

View larger version (72K): [in a new window]   FIGURE 3. (A) Sagittal (left), coronal (middle), and transverse (right) slices of representative baboon PET scan acquired from 40 to 80 min after injection of 11C-GR103545. Activity is concentrated in cingulate, frontal, temporal, and parietal cortices; medial temporal lobe; and striatum. Little activity is seen in brain stem and occipital cortex. Cerebellar uptake appears close to background level. (B) 11C-GR103545 scans (same slices in same baboon over same interval) after pretreatment with naloxone, 1 mg/kg intravenously. Images in A and B are normalized to their respective injected doses of activity and displayed with same intensity range. (C) Coregistered MR images of same baboon.

View larger version (23K): [in a new window]   FIGURE 4. Time–activity curves in selected brain regions from single, representative study after bolus injection of 11C-GR103545: cerebellar (), occipital (), frontal (), parietal (), and cingulate (•). Points are measured values; lines are values fitted to a 2-tissue-compartment model. ID = injected dose.

View larger version (17K): [in a new window]   FIGURE 5. Mean regional V3'' values for 11C-GR103545 at baseline and after pretreatment with naloxone, 1 mg/kg intravenously (n = 3). Error bars = SD. After naloxone, regional V3'' values are significantly reduced (repeated-measures ANOVA, P < 0.001) and approach homogeneous low-to-negligible levels. BSTM = brain stem; THA = thalamus; STR = striatum; MTL = medial temporal lobe; CIN = cingulate cortex; FNT = frontal cortex; TEM = temporal cortex; PAR = parietal cortex; OCC = occipital cortex.

View larger version (32K): [in a new window]   FIGURE 6. Time–activity curves in selected brain regions from 4 experiments performed on baboon A: cerebellar (), occipital (), frontal (), parietal (), and cingulate (•). (A) Racemic 11C-GR89696. (B) 11C-GR89696 after pretreatment with naloxone. (C) The active enantiomer 11C-GR103545. (D) The inactive enantiomer (+)- 11C-GR89696. Points are measured values; lines are values fitted to a 2-tissue-compartment model. ID = injected dose.

View larger version (22K): [in a new window]   FIGURE 7. Comparison between 11C-GR103545 (n = 3) and 11C-carfentanil (n = 9) regional V3'' values in same baboons. BSTM = brain stem; THA = thalamus; STR = striatum; MTL = medial temporal lobe; CIN = cingulate cortex; FNT = frontal cortex; TEM = temporal cortex; PAR = parietal cortex; OCC = occipital cortex.