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Prostate cancer is known for its difficulties in preoperative staging of pelvic lymph nodes by conventional imaging techniques. Thus, a histopathologic examination of the pelvic lymphadenectomy specimen is mandatory for patients at risk for metastatic disease. The aim of this study was to evaluate the strength and accuracy of C-11-choline PET in preoperative noninvasive staging of pelvic lymph nodes in prostate cancer. Methods: In a prospective study we examined 67 consecutive patients with histologically proven prostate cancer with C-11-choline PET. The results of PET were compared with the results of histology of the pelvic lymph nodes and with the follow-up data. Conventional axial imaging was routinely performed using MRI or CT. The sensitivity, specificity, and accuracy of C-11-choline PET were calculated. Results: Fifteen patients had histologically proven lymph node metastases. C-11-Choline PET was true-positive in 12 of 15 patients and false-negative in 3 patients. Fifty-two patients had no lymph node metastases. C-11-Choline PET was true-negative in 50 of 52 patients and false-positive in 2 patients. We calculated a sensitivity of C-11-choline PET for staging metastatic lymph node disease of 80%, a specificity of 96%, and an accuracy of 93%. Next, C-11-choline PET detected solitary extraregional lymph node metastases in 5 of 12 patients with nodal metastases. Conclusion: This study showed that C-11-choline PET is sensitive and accurate in preoperative staging of pelvic lymph nodes in prostate cancer.

Background and Objective: Visualization of prostate cancer with positron emission tomography (PET) using 2-[F-18]2-deoxy-D-glucose (FDG) as radiopharmaceutical is limited by the low uptake of FDG in the tumor and by radioactivity excreted into the bladder. More specific PET radiopharmaceuticals would be welcome. Carbon-11 labeled choline (CHOL) is a new radiopharmaceutical potentially useful for tumor imaging as it is incorporated in the cell membranes as phosphatidylcholine. We prospectively studied the visualization of prostate cancer using CHOL PET. Methods: A total of 25 consecutive patients with histologically proven prostate cancer and five patients with a benign prostate were included. PET images were performed with an ECAT HR+ using 400 MBq CHOL. Data acquisition was started at 5 minutes post-injection. Attenuation-corrected images were evaluated visually. Standardized uptake values (SUV) were calculated of the normal prostate gland and of the prostate tumor tissue. Results: The normal prostate was visualized with a mean SUV of 2.3 (range 1.3-3.2). The primary tumor could be visualized with a mean SUV of 5.0 (range 2.4-9.5). Lymph node metastases>5 mm could be identified. Non-specific uptake of CHOL was noticed in the intestines. Little to no radioactivity in the bladder was observed. Conclusion: Carbon-11-choline is avidly taken up in prostate cancer, both primary tumor and lymph node metastases, in the virtual absence of urinary radioactivity. These results confirm the early results obtained by others and permit further clinical research on the value of CHOL PET as a metabolic imaging technique in areas where conventional imaging have a limited sensitivity. (C) 2002 Elsevier Science B.V. All rights reserved.

The aim of this study was to determine if the brain uptake of 4-(2'-methoxyphenyl)-1-[2'-(N-2"-pyridinyl)-p-[F-18]fluorobenzamido]ethylpiperazine ([F-18]MPPF), a radioligand for the imaging of 5-HT1A receptors, is influenced by the action of P-glycoprotein. Anesthetized male Wistar rats were injected i.v. with the 5-HT1A receptor antagonist [F-18]MPPF (2 MBq, S.A. > 110 TBq/mmol) after treatment with saline (controls) or with the 5-HT1A receptor antagonist 1-(2'-methoxyphenyl)-4-[4-(2-phtalimido)butyl]piperazine (NAN-190) (2.5 mg/kg i.v.). After 60 min, the animals were sacrificed and 13 areas of the brain were dissected for ex vivo gamma counting. The regional distribution of radioactivity was also assessed in brain slices using a storage phosphor system. Modulation of P-glycoprotein was achieved by injection of cyclosporin A (50 mg/kg) 30 min prior to injection of [F-18]MPPF. The distribution of F-18-derived radioactivity corresponded to regional 5-HT1A receptor density as known from autoradiography. Modulation of P-glycoprotein with cyclosporin A caused a 5- to 10-fold increase in the uptake of [F-18]MPPF. Tissue/cerebellum ratios in the brain correlated with receptor densities determined by in vitro autoradiography. Measurements of plasma radioactivity showed that the increased brain uptake of [F-18]MPPF is partially due to a rise in ligand delivery after treatment with cyclosporin A (area under the curve, AUC, increased by a factor of 1.8). Biodistribution experiments in wild type and mdr1a(-/-) knockout mice confirmed that [F-18]MPPF is a substrate for P-glycoprotein. (C) 2000 Elsevier Science B.V. All rights reserved.

Serotonin-1A (5-hydroxytryptamine-1A [5-HT1A]) receptors have been reported to play an important role in the pathophysiology of a variety of psychiatric and neurodegenerative disorders. Animal experiments have shown that 4-(2'-methoxyphenyl)-1-[2'-(N-2 " -pyridinyl)-p-[F-18]fluorobenzamido]ethylpiperazine ([F-18]MPPF) may be suitable for 5-HT1A receptor imaging in humans. The aim of this study was to determine if [F-18]MPPF can be used for the quantitative analysis of 5-HT1A receptor densities in brain regions of healthy human volunteers. Methods: [O-15]H2O perfusion scanning was performed before intravenous injection of [F-18]MPPF to obtain anatomic information. Cerebral radioactivity was monitored using a PET camera. Plasma metabolites of [F-18]MPPF were determined by high-performance liquid chromatography. Binding potentials were calculated using the metabolite-corrected arterial input function and a linear graphic method (Logan-Patlak analysis). Results: The highest levels of radioactivity were observed in the medial temporal cortex, especially in the hippocampal area. In contrast, the cerebellum and basal ganglia showed low uptake of F-18, in accordance with known 5-HT1A receptor distribution. The calculated binding potentials correlated well with literature values for 5-HT1A receptor densities. The binding potentials for [F-18]MPPF were 4-6 times lower than those that have been reported for [carbonyl-C-11]-(N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridyl) cyclohexane-carboxamide (WAY 100635), indicating that [F-18]MPPF has a lower in vivo affinity for 5-HT1A receptors. Conclusion: These results confirm that [F-18]MPPF can be used for the quantitative analysis of 5-HT1A receptor distribution in the living human brain. The:rapid dissociation from the receptor makes this ligand a possible candidate to monitor changes in endogenous serotonin levels.

S-1'-[F-18]fluorocarazolol was administered to healthy volunteers to assess its potential for noninvasive measurement of regional pulmonary and myocardial beta-adrenoceptor densities. Methods: High-specific activity fluorocarazolol was intravenously injected on two separate occasions within a 1-wk interval. The initial injection was without pretreatment, but before the second injection, the volunteers either inhaled salbutamol (2 x 200 mu g aerosol) or they ingested pindolol (3 x 5 mg during a 12-hr interval). Twenty-eight PET time frames of 31 planes were acquired over a period of 60 min after each injection. Blood samples were drawn and analyzed for the presence of fluorocarazolol and radioactive metabolites. Results: Uptake of fluorocarazolol in the target tissues was hardly affected by salbutamol but was strongly depressed by pindolol. Pulmonary and myocardial tissue-to-plasma concentration ratios of fluorocarazolol reached plateau values of 11.6 +/- 0.6 (lungs) and 18.1 +/- 1.0 (heart) at 45-50 min postinjection. These values were reduced to 2.0 +/- 0.4 and 2.0 +/- 0.6 after treatment with pindolol. Conclusion: These data indicate that: 1. Pulmonary and myocardial uptake of radioactivity after intravenous administration of S-1'-[F-18]fluorocarazolol represents radioligand binding to beta-adrenoceptors. 2. Pulmonary binding occurs mainly in alveoli rather than in airway smooth muscle under these conditions. 3. Binding kinetics do not preclude quantification of receptors with compartment models.

We evaluated the suitability of fluorocarazolol for in vivo studies of cerebral beta-adrenoceptors because (S)-1'-[F-18]fluorocarazolol has a higher affinity to beta-adrenoceptors than to serotonergic receptors (pK(i) beta(1) 9.4, beta(2) 10.0, 5HT(1A) 7.4, 5HT(1B) 8.1) and rapidly crosses the blood-brain barrier. Methods: The (S)-[F-18]fluorocarazolol (74 MBq, >37 TBq/mmol) was intravenously administered to healthy volunteers on two separate occasions with an interval of at least 1 wk, The initial injection was without pretreatment, but before the second injection, the volunteers received the beta blocker (+/-)-pindolol (3 x 5 mg orally, during 18 hr). The brain was studied with a PET camera in dynamic mode. Results: Uptake of radioactivity delineated gray matter and was particularly high in the posterior cingulate, precuneus and striatum, Low uptake occurred in the thalamus, whereas the lowest uptake was observed in the white matter of the corpus callosum. After pindolol pretreatment, uptake was reduced and its distribution became homogeneous throughout the brain, The ratio of total-to-nonspecific binding was about 2 at 60 min, increasing to 2.5-2.75 at longer intervals. Conclusion: Fluorocarazolol is the first radioligand that can visualize cerebral beta-adrenoceptors and may enable monitoring of these binding sites during disease.

The characterization of pulmonary muscarinic receptors with PET is still in its infancy. Because approximately 70% of the lungs consists of air and pulmonary muscarinic receptor densities are low, ligands with high receptor affinity are required to obtain reasonable signal-to-noise ratios on PET images. Therefore, the potent C-11-labeled muscarinic antagonist N-methyl-piperidin-4-yl 2-cyclohexyl-2-hydroxy-2-phenylacetate methiodide ([R]-VC-002) was developed. We administered this radioligand to four healthy human volunteers to examine its suitability for studying pulmonary muscarinic receptors in vivo. Methods: [C-11]VC-002 (185 MBq, specific activity > 7.4 TBq/mmol) was intravenously injected on 2 separate days, with an interval of at least 1 wk. On the first day the volunteers were not pretreated, but on the second day they received the anticholinergic glycopyrronium bromide (Robinul; 2 x 0.1 mg intravenous) 25 and 30 min before the injection of the radiopharmaceutical. C[O-15]O scans (approximately 740 MBq [20 mCi] by inhalation) were acquired before the receptor scan to calculate pulmonary blood volume. Results: On PET images of the thorax, the lungs were clearly visible. After the volunteer was pretreated with glycopyrronium bromide, pulmonary uptake of the radioligand was reduced to 32% +/- 12% of the control value at 60 min postinjection and the lungs could no longer be seen. (R)-[C-11]-VC-002 was rapidly cleared from plasma and was slowly metabolized during the time course (60 min) of the PET scan. The fraction of radioligand representing parent compound decreased from 99.9% at the time of injection to 82% at 40-60 min postinjection, both in the presence and absence of Robinul. Pulmonary tissue-to-plasma ratios, calculated on a count-per-minute-per-gram basis, reached a plateau value of 17.8 +/- 1.2 at 40-50 min postinjection. Conclusion: [C-11]VC-002 appears to be suitable for in vivo studies of pulmonary cholinoceptors.

For the synthesis of [F-18]Fluoro-Org 6141 via a nucleophilic substitution reaction with F-18(-), the tosyl group was chosen as the leaving group because of its stability and excellent leaving group ability. The biodistribution of the high affinity and moderate lipophilicity (log P = 2.66, calculated value) ligand [F-18]Fluoro-Org 6141 (specific activity 8.2 to 37 TBq/mmol, yield 10% at EOB) was examined in sham adrenalectomized (sADX) and adrenalectomized (ADX) male Wistar rats. Two days after ADX or sADX, the animals were anesthetized acid 0.37 to 1.85 MBq of [F-18]Fluoro-Org 6141 was administered intravenously. Kinetics of F-18 activity uptake were monitored for 3 h using a stationary double-headed positron emission tomography (PET) camera, and the biodistribution was assessed by ex vivo determination of radioactivity in several tissues and different brain areas. One hour after injection of the radioligand, the bladder, kidney, liver, trachea, and bone of sADX animals contained more concentration on a wet weight basis than blood. Three hours post injection, radioactivity was retained in bladder, trachea, and bone. The accumulation of radioactivity in brain corresponded to the concentration of activity in the blood within the first hours after injection. ADX animals showed a higher uptake of F-18 activity in spleen, testes, and brain areas (hippocampus and brainstem) but a lower uptake in bone than sADX rats. PET scans suggested that F-18 activity uptake in the brain had not yet reached a maximum at this interval. Although [F-18]Fluoro-Org 6141 is not useful for PET studies of glucocorticoid receptors (GRs), the results obtained with this compound indicate a synthetic strategy suitable for the synthesis of high-affinity radioligands for GRs.