Imaging of striatal dopamine D(2) receptors with a PET system for small laboratory animals in comparison with storage phosphor autoradiography: a validation study with (18)F-(N-methyl)benperidol. (1/10)

Several groups have developed high-resolution PET systems and shown the feasibility of in vivo studies on small laboratory animals. In this investigation, one of these systems was validated for the performance of receptor imaging studies. For this, the radiotracer concentrations obtained in the same animals with PET and with autoradiography were quantified, and the correspondence between both methods was assessed by means of correlation analysis. METHODS: Striatal radioactivity was measured in 10 Sprague-Dawley rats after injection of 60 +/- 10 MBq of the dopamine D(2) receptor ligand (18)F-(N-methyl)benperidol in 6 time frames of 6 min each. On completion of the scans, animals were killed, and their brains were removed and sectioned using a cryostat microtome. Coronal slices were subjected to storage phosphor autoradiography with BaFBr:Eu(2+)-coated imaging plates. Striatal radioactivity was quantified in both modalities using region-of-interest analysis and activity standards. RESULTS: After partial-volume correction, the median of striatal radioactivity concentration measured with PET was 0.40 MBq/cm(3) (25th percentile, 0.32; 75th percentile, 0.44). Radioactivity concentrations determined by means of storage phosphor autoradiography amounted to 0.42 MBq/cm(3) (25th percentile, 0.24; 75th percentile, 0.51). Correlation of striatal radioactivity values yielded a Pearson correlation coefficient of 0.818 (P = 0.002). Radioactivity accumulation in Harder's glands led to an overestimation of striatal activity concentrations by approximately 5%. The median of striatal radioactivity concentration after spillover correction decreased slightly to 0.38 MBq/cm(3) (25th percentile, 0.30; 75th percentile, 0.43). Correlation of striatal radioactivity values after spillover correction yielded a Pearson correlation coefficient of 0.824 (P = 0.002). CONCLUSION: The results show a significant positive correlation between radioactivity values obtained with PET and storage phosphor autoradiography used as the gold standard. Because we applied a selective dopamine D(2) receptor radioligand and because radioactivity concentrations could be reliably quantified in the target region, we may infer that in vivo receptor binding studies will be possible in small laboratory animals.  (+info)

In vivo measurement of D2 receptor density and affinity for 18F-(3-N-methyl)benperidol in the rat striatum with a PET system for small laboratory animals. (2/10)

A recent investigation showed that intracerebral radioactivity concentrations can reliably be quantified in vivo with a small-animal PET device. The purpose of the current study was to investigate the binding characteristics of the D(2) receptor radioligand (18)F-(3-N-methyl)benperidol ((18)FMB) in rat striatum by determining receptor density (B(max)) and affinity (K(d)) in vivo. For validation, K(d) and B(max) additionally were determined in vitro using storage phosphor autoradiography. METHODS: Striatal radioactivity was measured with PET in 8 Sprague-Dawley rats after injection of (18)FMB in increasing specific activities. Free radioligand concentrations were estimated from cortical radioactivity concentrations and were subtracted from striatal radioactivity concentrations to obtain specific binding. In vitro saturation experiments were performed on 7 further rats according to the isotopic dilution method. Specific binding was determined by both subtraction of (18)FMB binding in the presence of raclopride and subtraction of cortical radioactivity concentrations from total radioligand binding. Saturation binding curves were obtained by plotting specifically bound radioligand concentrations against free radioligand concentrations and were evaluated with regression analysis. RESULTS: PET yielded a K(d) of 6.2 nmol/L and a B(max) of 16 fmol/mg for the striatal D(2) receptor. In vitro, K(d) and B(max) amounted to 4.4 nmol/L and 84.1 fmol/mg (subtraction of (18)FMB binding in the presence of raclopride), respectively, and 7.9 nmol/L and 70.1 fmol/mg (subtraction of cortical radioactivity concentrations), respectively. CONCLUSION: K(d) values measured with PET and autoradiography agreed and corresponded to inhibition constants obtained in previous in vitro studies. B(max) values lay within the same order of magnitude. The results of in vitro saturation binding analyses also agreed, irrespective of the mode of determination of free radioligand concentrations. Thus, B(max) and K(d) may be determined with PET in analogy to the evaluation of in vitro binding data by regression analysis of bound-versus-free ligand concentrations. Our results show that small-animal tomographs are valuable tools for the in vivo characterization of receptor radioligands as an alternative to autoradiography.  (+info)

Radiation dosimetry of N-([11C]methyl)benperidol as determined by whole-body PET imaging of primates. (3/10)

PURPOSE: N-([(11)C]methyl)benperidol ([(11)C]NMB) can be used for positron emission tomography (PET) measurements of D(2)-like dopamine receptor binding in vivo. We report the absorbed radiation dosimetry of i.v.-administered (11)C-NMB, a critical step before applying this radioligand to imaging studies in humans. MATERIALS AND METHODS: Whole-body PET imaging with a CTI/Siemens ECAT 953B scanner was done in a male and a female baboon. After i.v. injection of 444-1221 MBq of (11)C-NMB, sequential images taken from the head to the pelvis were collected for 3 h. Volumes of interest (VOIs) were identified that entirely encompassed small organs (whole brain, striatum, eyes, and myocardium). Large organs (liver, lungs, kidneys, lower large intestine, and urinary bladder) were sampled by drawing representative regions within the organ volume. Time-activity curves for each VOI were extracted from the PET, and organ residence times were calculated by analytical integration of a multi-exponential fit of the time-activity curves. Human radiation doses were estimated using OLINDA/EXM 1.0 and the standard human model. RESULTS: Highest retention was observed in the blood and liver, each with total residence times of 1.5 min. The highest absorbed radiation doses were to the heart (10.5 muGy/MBq) [DOSAGE ERROR CORRECTED] and kidney (9.19 muGy/MBq), [DOSAGE ERROR CORRECTED] making these the critical organs for [(11)C]NMB. A heart absorption of 50 mGy would result from an injected dose of 4,762 MBq [(11)C]NMB. CONCLUSIONS: Thus, this study suggests that up to 4,762 MBq of [(11)C]NMB can be safely administered to human subjects for PET studies. Total body dose and effective dose for [(11)C]NMB are 2.82 muGy/MBq [DOSAGE ERROR CORRECTED] and 3.7 mSv/kBq, respectively.  (+info)

Validation of the reference tissue model for estimation of dopaminergic D2-like receptor binding with [18F](N-methyl)benperidol in humans. (4/10)

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In vivo labeling of the dopamine D2 receptor with N-11C-methyl-benperidol. (5/10)

A new dopamine D2 receptor radiotracer, N-11C-methyl-benperidol (11C-NMB), was prepared and its in vivo biologic behavior in mice and a baboon was studied. Carbon-11-NMB was determined to bind to specific sites characterized as dopamine D2 receptors. The binding was saturable, reversible, and stereospecific. Kinetic studies in the dopamine D2 receptor-rich striatum showed that 11C-NMB was retained five times longer than in receptor-devoid regions, resulting in a high maximum striatal-to-cerebellar ratio of 11:1 at 60 min after injection. From frontal cortex and cortex, on the other hand, the tracer washed out as rapidly as it did from cerebellum, resulting in tissue-to-cerebellar ratios close to one in these regions at any time after injection. Blocking studies confirmed the specificity and selectivity of the 11C-NMB binding to the dopamine D2 receptor. A PET study with 11C-NMB of the baboon brain revealed highly selective labeling of dopamine D2 receptor sites which was blocked by preinjection of raclopride.  (+info)

Characterization of extrastriatal D2 in vivo specific binding of [(1)(8)F](N-methyl)benperidol using PET. (6/10)

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Syntheses and specific activity determinations of no-carrier-added (NCA) F-18-labeled butyrophenone neuroleptics--benperidol, haloperidol, spiroperidol, and pipamperone. (7/10)

A general method for the syntheses of no-carrier-added (NCA) 18F-labeled butyrophenone neuroleptics--benperidol, haloperidol, spiroperidol, and pipamperone is described. These 18F-labeled neuroleptic drugs are synthesized by a multistep synthesis in an overall radiochemical yield of 10-20% at end of bombardment (EOB) in a synthesis time of 90 min from EOB. The sequence involves the synthesis of NCA p-[18F]fluorobenzonitrile from NCA [18F]-fluoride and p-nitrobenzonitrile using the rapidly converted to gamma-chloro-p-[18F]fluorobutyrophenone which is alkylated with appropriate amines to give NCA 18F-labeled benperidol, haloperidol, spiroperidol, and pipamperone. The final product is purified by preparative high performance liquid chromatography (HPLC). The 18F solution used in the synthesis as determined by ion chromatography contains 15.3 +/- 9.0 nmol of stable fluoride. The specific activities of the resulting butyrophenone neuroleptics were determined to be 3 Ci/mumol (at EOB) (range 1-6 Ci/mumol) as determined by radioreceptor assay and HPLC assay.  (+info)

A comparative study of conventional premedication (pethidine, promethazine, and atropine) and neuroleptanalgesia (droperidol and phenoperidine) for peroral endoscopy. (8/10)

A double blind comparison of conventional premedication (pethidine, promethazine, and atropine) and neuroleptanalgesia (droperidol and phenoperidine) failed to demonstrate any difference in either the comfort of the patient or ease of instrumentation in 70 upper gastrointestinal tract endoscopies. Further trials are needed before conventional premedication is abandoned.  (+info)

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