Formation of fluorine-18 labeled diaryl ureas--labeled VEGFR-2/PDGFR dual inhibitors as molecular imaging agents for angiogenesis.

Urea subunits are common components of various pharmaceuticals' core structure. Since in most cases the design and development of PET biomarkers is based on approved or potential drugs, there is a growing need for a general labeling methodology of urea-containing pharmacophores. As a part of research in the field of molecular imaging of angiogenic processes, we synthesized several highly potent VEGFR-2/PDGFR dual inhibitors as potential PET biomarkers. The structure of these inhibitors is based on the N-phenyl-N'-{4-(4-quinolyloxy)phenyl}urea skeleton. A representative inhibitor was successfully labeled with fluorine-18 by a three-step process. Initially, a two-step radiosynthesis of 4-[(18)F]fluoro-aniline from 1,4-dinitrobenzene (60min, EOB decay corrected yield: 63%) was performed. At the third and final step, the 4-[(18)F]fluoro-aniline synthon reacted for 30min at room temperature with 4-(2-fluoro-4-isocyanato-phenoxy)-6,7-dimethoxy-quinoline to give complete conversion of the labeled synthon to 1-[4-(6,7-dimethoxy-quinolin-4-yloxy)-3-fluoro-phenyl]-3-(4-[(18)F]fluoro-phenyl)-urea. The desired labeled product was obtained after total radiosynthesis time of 3h including HPLC purification with 46+/-1% EOB decay corrected radiochemical yield, 99% radiochemical purity, 99% chemical purity, and a specific activity of 400+/-37GBq/mmol (n=5).

A study investigating the acute dose-response effects of 13 mg and 17 mg Delta 9- tetrahydrocannabinol on cognitive-motor skills, subjective and autonomic measures in regular users of marijuana.

Heavy use of marijuana is claimed to damage critical skills related to short-term memory, visual scanning and attention. Motor skills and driving safety may be compromised by the acute effects of marijuana. The aim of this study was to investigate the acute effects of 13 mg and 17 mg Delta 9-tetrahydrocannabinol (THC) on skills important for coordinated movement and driving and on subjective and autonomic measures in regular users of marijuana. Fourteen regular users of marijuana were enrolled. Each subject was tested on two separate days. On each test day, subjects smoked two low-nicotine cigarettes, one with and the other without THC. Seventeen mg THC was included in the cigarette on one test day and 13 mg on the other day. The sequence of cigarette types was unknown to the subject. During smoking, heart rate and blood pressure were monitored, and the subjects performed a virtual reality maze task requiring attention and motor coordination, followed by 3 other cognitive tasks (Wisconsin Card Sorting Test (WCST), a "gambling" task and estimation of time and distance from an approaching car). After smoking a cigarette with 17 mg THC, regular marijuana users hit the walls more often on the virtual maze task than after smoking cigarettes without THC; this effect was not seen in patients after they smoked cigarettes with 13 mg THC. Performance in the WCST was affected with 17 mg THC and to a lesser extent with the use of 13 mg THC. Decision making in the gambling task was affected after smoking cigarettes with 17 mg THC, but not with 13 m THC. Smoking cigarettes with 13 and 17 mg THC increased subjective ratings of pleasure and satisfaction, drug "effect" and drug "high". These findings imply that smoking of 17 mg THC results in impairment of cognitive-motor skills that could be important for coordinated movement and driving, whereas the lower dose of 13 mg THC appears to cause less impairment of such skills in regular users of marijuana.

An unusual case of rheumatic pneumonia.

A 14-year-old boy developed severe respiratory failure during the course of acute rheumatic fever. The results of all microbiological studies were normal. Rheumatic carditis or left ventricular failure was excluded by routine examinations, catheterization of the right side of the heart, and multiple-gated radionuclide ventriculography. The patient recovered completely after a course of high-dose prednisone. To our knowledge, this is the first well-documented case of rheumatic pneumonia in which the lung disease could be attributed to the rheumatic disease and not to a pathologic heart condition.

Auditory nerve and brain stem responses. Comparison in awake and unconscious subjects.

The recording of auditory nerve and brain stem responses to click stimuli is being used for the diagnosis of several conditions such as suspected hearing loss and suspected neurological disorders. The responses obtained in the patient group (often infants and children) are compared with those obtained in normal subjects of similar age who, for ethical reasons, are not sedated. In this study, recordings were made in normal subjects while they were awake and when they were unconscious in drug-induced sleep (being prepared for dental surgery). No significant difference could be observed between the recordings obtained in the awake state and when unconscious in the same subjects. Therefore, one is justified in using recordings made in awake subjects as controls for recordings made in other unconscious patients.

Proton therapy for carcinoma of the nasopharynx: a study in comparative treatment planning.

Radiation therapy for nasopharyngeal carcinoma is technically difficult because of the complexity of the regional anatomy and the natural history of the disease. The results of a study are presented showing how detailed diagnostic information available from MRI is helpful in defining the target volume to be irradiated and the critical normal structures. By using 3-dimensional planning techniques, an assessment was made of the relative merits of proton beam therapy and of X ray treatment for patients with early stage and locally advanced carcinoma of the nasopharynx. For both types of patient, the study suggests that the use of protons for the major part of treatment results in a more even distribution of dose to the tumor and an increase of approximately 5 Gy in median tumor dose with substantial reductions in doses to adjacent normal tissues. The superior dose distributions possible with protons should translate into improved local control and reduced morbidity. The difficulties of proton treatment planning for this site are addressed.

Correlations between uptake of technetium, calcium, phosphate, and mineralization in rat tibial bone repair.

Technetium-99m-(99mTc) phosphates are extensively used for detection of bone formation and resorption. The present is a study of 99mTc incorporation during bone remodeling. Uptake of 99mTc-labeled phosphate was studied in an animal model of primary osteogenesis following tibial marrow injury and incorporation was correlated to that of calcium-47 (47Ca), phosphorus-32 (32P), and with matrix vesicle calcification. Isotope uptake on Day 6 in the whole bone was increased compared to controls. On this day, an increase in vesicular diameter and distance from the calcified front was previously observed. Technetium-99m-labeled phosphates were detected only in the organic phase. Phosphorus-32 and 47Ca were detected in both organic and inorganic phases. It is suggested that 99mTc serves as a specific marker to the anabolic phase of remodeling. Increased incorporation of 99mTc during bone healing indicates enhanced organic matrix formation and not calcification.

Increased cerebral blood flow in depressed patients responding to electroconvulsive therapy.

UNLABELLED: Considerable data support the existence of impaired regional cerebral blood flow (rCBF) in major depression. We compare rCBF in depressed patients before and after electroconvulsive therapy (ECT) to define whether the impairment is a "state"-related property or a trait phenomenon. METHODS: Twenty patients with a major depressive disorder were studied by 99mTc-HMPAO brain SPECT, 2-4 days before and 5-8 days after a course of ECT. Three transaxial brain slices delineating anatomically defined regions of interest at approximately 4, 6 and 7 cm above the orbitomeatal line were used, with the average number of counts for each region of interest normalized to the area of maximal cerebellar uptake. RESULTS: Technetium-99m-HMPAO uptake significantly increased in patients who responded to ECT but remained unchanged in patients who did not respond to the treatment (response defined as a reduction of at least 60% on the Hamilton Depression Rating Scale). An inverse correlation was observed between severity of depression and HMPAO uptake, and clinical improvement was positively correlated with the increase in tracer uptake. CONCLUSIONS: These findings imply that reduced rCBF in depression, as reflected in brain 99mTc-HMPAO uptake, is a "state"-related property and is reversible by successful treatment. Technetium-99m-HMPAO uptake may serve as an objective state marker for depression, an an indicator of the severity of depression and as an objective means of evaluating response to treatment.

Nuclear magnetic resonance imaging of liver hemangiomas.

Nine patients with cavernous hemangioma of the liver were examined by nuclear magnetic resonance imaging (MRI) with a 0.5 T superconductive magnet. Spin-echo technique was used with varying time to echo (TE) and repetition times (TR). Results were compared with 99mTc red blood cell (RBC) scintigraphy, computed tomography (CT), echography, and arteriography. Four illustrated cases are reported. It was possible to establish a pattern for MRI characteristics of cavernous hemangiomas; rounded or smooth lobulated shape, marked increase in T1 and T2 values as compared with normal liver values. It is concluded that, although more experience is necessary to compare the specificity with that of ultrasound and CT, MRI proved to be very sensitive for the diagnosis of liver hemangioma, especially in the case of small ones which may be missed by 99mTc-labeled RBC scintigraphy.

Nuclear magnetic resonance proton imaging of bone pathology.

Thirty-two patients with diversified pathology were examined with a supraconductive NMR imager using spin echo with different TR and TE to obtain T1 and T2 weighted images. They included 20 tumors (12 primary, eight metastasis), six osteomyelitis, three fractures, two osteonecrosis, and one diffuse metabolic (Gaucher) disease. In all cases except for the stress fractures, the bone pathology was clearly visualized in spite of the normal lack of signal from the compact cortical bone. Nuclear magnetic resonance (NMR) imaging proved to be at least as sensitive as radionuclide scintigraphy but much more accurate than all other imaging procedures including computed tomography (CT) and angiography to assess the extension of the lesions, especially in tumors extended to soft tissue. This is due both to easy acquisition of sagittal and coronal sections and to different patterns of pathologic modifications of T1 and T2 which are beginning to be defined. It is hoped that more experience in clinical use of these patterns will help to discriminate between tumor extension and soft-tissue edema. We conclude that while radionuclide scintigraphy will probably remain the most sensitive and easy to perform screening test for bone pathology, NMR imaging, among noninvasive diagnostic procedures, appears to be at least as specific as CT. In addition, where the extension of the lesions is concerned, NMR imaging is much more informative than CT. In pathology of the spine, the easy visualization of the spinal cord should decrease the need for myelography.

Transient neurological events during dipyridamole stress test: an arterial steal phenomenon?

Dipyridamole-associated adverse neurological side effects have not been extensively described. We present two cases of dipyridamole-associated transient motor neurological events with no evidence of residual neurological deficits detected clinically or by head CT. The patients showed no evidence of significant extracranial (internal carotid) artery disease. We propose the presence of a regional cerebral perfusion disturbance due to an intracranial vascular steal phenomenon as the mechanism for the above side effects of dipyridamole.

Major salivary gland dysfunction in human acute and chronic graft-versus-host disease (GVHD).

Salivary gland dysfunction is frequently observed in patients suffering from acute (a) and chronic (c) GVHD. We studied the influence of GVHD on the function of major salivary glands in 20 patients with GVHD (cGVHD, 15; aGVHD, 5). A subjective evaluation of salivary function was performed, in which the score ranged from 0-4 where a higher score indicated more oral dryness. Patients with aGVHD scored 4.0 while patients with cGVHD scored 2.1 (P < 0.01). In addition to this subjective evaluation, patient's salivary flow rates were measured and a reduction of 90% and 60% in aGVHD and cGVHD patients respectively, was observed as compared to controls (P < 0.01; P < 0.05). No hyposalivation was observed in patients who underwent bone marrow transplantation but did not develop GVHD as compared to normal individuals. A direct correlation was observed between the degree of hyposalivation and the severity of the GVHD. Hyposalivation was also documented by scintigraphy of the major salivary glands in the GVHD patients. Furthermore, hyposalivation was associated with extensive mucosal atrophy, erythema, tongue surface depapillation, lichenoid lesions of the buccal and labial mucosa as well as lupus-like lesions. Routine assessment of these glands in patients with GVHD could play a role in monitoring response to therapy.

Clinical doses of fluoxetine and cerebral blood flow in healthy volunteers.

RATIONALE: Of the specific serotonin reuptake inhibitors (SSRIs), fluoxetine is perhaps the most widely used. Anecdotal reports, mostly in the non-medical press, have suggested that it may positively affect psychological functioning and enhance quality of life in the absence of overt psychiatric disorder. Such wide-spread use in not supported by scientific data. OBJECTIVE: This prospective single blind study examined the effects of long term administration of clinical doses of fluoxetine on cerebral blood flow (CBF) in healthy volunteers. METHODS: Fifteen healthy subjects were examined by Tc99m HMPAO SPECT after 2 weeks of placebo administration and then after 6 weeks of fluoxetine, administered at 20 mg per day. Blood for fluoxetine and norfluoxetine plasma levels was drawn to ensure compliance. Tc99m HMPAO uptake was analyzed by the region of interest approach, normalized to the cerebellum, and by statistical parametric mapping (SPM). RESULTS: No statistically significant differences between the two conditions were detected by both techniques. Correlation analysis between fluoxetine and norfluoxetine plasma levels and rCBF yielded no statistically significant values. CONCLUSION: Our findings suggest a differential effect of fluoxetine on CBF under the following conditions: (i) mental health versus psychiatric illness; (ii) acute versus long term administration. Our findings further emphasize the importance of longitudinal studies in elucidating the physiology of the normal brain as well as the pathophysiology of psychiatric disorders.

Imaging of lymphoma manifestations in the extracranial head and neck region.

CT and MRI are the most efficient imaging techniques for diagnosing lymphomas while Gallium-67 scintigraphy is used to assess treatment results. In this review, the imaging aspects of lymphoma are addressed according to anatomical subregions, from the orbit to the trachea, Waldeyer's ring being the most common site, in the head and neck. Lymphomas of this region are not easily distinguished from the more common squamous cell carcinomas; however, multiple extranodal sites, the presence of many non-necrotic lymph nodes and a large nasopharyngeal mass without significant bone destruction should alert one to the possibility of lymphoma.

Phase-contrast imaging of the parotid region.

Standard T1- and T2-weighted spin-echo acquisitions were compared with T1- and T2-weighted phase-contrast techniques in a series of 10 consecutive patients with parotid masses to assess the role of phase-contrast methods in the evaluation of lesions in the parotid fossa. Greater tissue-lesion contrast was obtained with phase-contrast methods in nine of 10 cases, allowing improved lesion visualization; however, an increase in lesion detectability was not observed in this series. Standard MR imaging methods are sufficient for imaging the parotid region in most cases, but can be quite time-consuming. Recommended screening of the parotid fossa that optimizes tissue-lesion contrast, lesion detectability, and imaging time is performed by combining a standard T1-weighted acquisition with a T1- or T2-weighted phase-contrast acquisition. Selection of a T1- or T2-weighted phase-contrast acquisition is determined by the T1 characteristics of the lesion.

Preliminary clinical results with low flip angle spin-echo MR imaging of the head and neck.

A new approach for producing primarily T2- and proton-density-weighted MR images in less time than the conventional long TR, long TE imaging is to reduce the TR of a double spin-echo pulse sequence and to also reduce the RF excitation flip angle to minimize the resulting T1 sensitivity. In preliminary studies with a human volunteer and five patients with various diseases of the head and neck, conventional long TR, long TE and short TR, short TE images were compared with short TR, long TE images with reduced flip angles (45 degrees, 30 degrees), which required only 40% of the imaging time of the long TR images. The latter images showed a similar contrast pattern to the conventional T2-weighted image, and contrast-to-noise measurements indicated an increase in contrast between the lesion and nearby tissue when the flip angle was reduced. Furthermore, the maximum contrast/noise per unit imaging time on the short TR, long TE image was comparable to that on the long TR, long TE image. Optimization of the flip angle with short TR allows a substantial reduction in imaging time but with a reduction in multislice capability. This technique will be most useful in areas of complex anatomy where two or more orthogonal imaging planes are required, such as the head and neck.

The indications of FDG-PET in neck oncology.

FDG-PET imaging in neck oncology has a definite clinical impact in the post-therapy setting, assisting in the management of thyroid cancers and SCC of the neck. Quantitation of FDG uptake in suspicious areas may be helpful but should be regarded cautiously. Overall, wider incorporation of FDG imaging in clinical routine depends also on cost availability issues of FDG and of imaging devices. Dual-coincidence scanners for FDG imaging are much cheaper than dedicated PET scanners and are installed in growing numbers in many centers. These devices have inferior sensitivity; however, series published with these scanners produce encouraging results. Easier and more acceptable clinical application will also be facilitated by the systematic use of coregistration with anatomic images. Both prerequisites might be fulfilled by the emergence on the market of a gamma camera-mounted anatomic X-ray tomograph, which in addition to dual-coincidence scintigraphic imaging provides radiographic images of comparable quality to third-generation CT systems. This type of hybrid gamma camera-CT scanner has great potential in a region of complex anatomy, such as the head and neck.

Potential (18)F-labeled biomarkers for epidermal growth factor receptor tyrosine kinase.

As PET candidate tracers for EGFr-TK, five 4-(anilino)quinazoline derivatives, each fluorinated in the aniline moiety, were prepared. Each was tested in vitro for inhibition of EGFr autophosphorylation in A431 cell line. The leading compounds were then radiolabeled with (18)F and cell binding experiments, biodistribution and PET studies in A431 tumor-bearing mice were performed. Metabolic studies were carried out in a mice control group. From our results, we concluded that while in vitro experiments indicates efficacy of 4-(anilino)quinazoline compounds, kinetic factors and rapid blood clearance make them unsuitable as tracers for nuclear medicine imaging of EGFr-TK.

Role of high-resolution pinhole tomography in the evaluation of thyroid abnormalities.

The present study was undertaken to evaluate the contribution of pinhole-single photon emission computed tomography (P-SPECT) to scintigraphy of the thyroid gland. Thirty-six patients, referred for thyroid scintigraphy because of palpatory or ultrasonographic findings, were studied after intravenous administration of technetium-99m pertechnetate (222 MBq) using a rectilinear scanner and a single-headed rotating gamma camera equipped with a pinhole collimator. P-SPECT study was acquired on a 128 x 128 matrix, in 30 projections over 180 degrees and an acquisition time of 40 seconds per step. After transaxial reconstruction, coronal slices were compared with planar views obtained by the scanner. The size of the thyroid gland obtained by P-SPECT matched the life-size image of a rectilinear scan, and it clearly delineated the shape and borders of two huge multinodular glands. Its major contribution was in its improved resolution. Pinhole-SPECT identified 21 foci not visualized on planar views, 19 cold lesions, and 2 "warm" nodules embedded in normal tissue of 13 patients. Furthermore, it clearly delineated 18 discrete ill-defined nodules of 13 patients, (single in 4 patients and multiple in 9 patients): 16 cold lesions, and 2 hot foci. When a distinct palpable nodule was present, whether cold (22 lesions) or hot (2 foci), SPECT was of no additional diagnostic value. However, when the palpable nodule was a toxic one, the contralateral suppressed lobe was visible on SPECT only. Two ultrasonographic findings, of 3- and 5-mm in diameter, were neither identified on planar views nor on P-SPECT. In conclusion, P-SPECT of the thyroid gland improves delineation of huge multinodular glands and detection of small nodules (within the resolution of the camera) that could otherwise have been overlooked on planar views of a thyroid scanner. It allows for definition of tracer uptake in tiny discrete nodules and in multinodular goiter, and is a better guide to the physician in fine-needle aspiration of the cold areas.

Cerebral hypoperfusion in medication resistant, depressed patients assessed by Tc99m HMPAO SPECT.

Functional imaging studies generally show decreased cerebral metabolism and perfusion in depressed patients relative to normal controls, although the location of the deficits varies. We used Tc99m HMPAO SPECT to compare cerebral blood flow in medication resistant, depressed patients and a normal control group. HMPAO uptake ratios (adjusted for age) were significantly lower in the depressed patients in the transaxial slices 4 cm and 6 cm above the orbitomeatal line (OML) on the left side. Examining individual regions of interest (corrected for age and multiple testing), we found significantly lower perfusion in the left superior temporal, right parietal and bilateral occipital regions in the patient group. These findings are in limited agreement with previous HMPAO SPECT studies. Methodological differences between studies, particularly variability in adjusting data for age, lead to a divergence in findings. Future research should seek to standardize protocols and data analysis in order to generate comparable results.

In vivo assessment of the window of barrier opening after osmotic blood-brain barrier disruption in humans.

OBJECT: Osmotic blood-brain barrier (BBB) disruption induced by intraarterial infusion of mannitol is used in conjunction with chemotherapy to treat human brain tumors. The time course to barrier closure, or the so-called therapeutic window, has been examined in animals but little information is available in humans. The authors, therefore assessed the time course to barrier closure after osmotic BBB disruption in humans. METHODS: Disruption of the BBB was demonstrated using 99mTc-glucoheptonate (TcGH) single-photon emission computerized tomography (SPECT) scanning in 12 patients who were treated monthly with combination chemotherapy in conjunction with BBB disruption. The primary diagnosis was primary central nervous system lymphoma in seven patients and primitive neuroectodermal tumors in five. The TcGH (20 mCi) was injected at 1- to 480-minute intervals after osmotic BBB disruption, and patients underwent SPECT scanning after 4 hours. A total of 38 studies was performed. Good-to-excellent BBB disruption was obtained in 29 procedures and poor-to-moderate disruption was seen in the other nine studies. The TcGH indices correlated with the degree of BBB disruption as measured postprocedure on contrast-enhanced CT scans (r = 0.852). Mean baseline TcGH indices were 1.02+/-0.07. For the group of patients with good-to-excellent disruptions the mean indices at 1 minute postdisruption measured 2.19+/-0.18. After 40 minutes no significant change was noted (mean index 2.13+/-0.2). Then the indices declined more steeply and at 120 minutes after the disruption the index was 1.36+/-0.02. A very slow decline was noted between 120 and 240 minutes after mannitol infusion. At 240 minutes the barrier was still open for all good-to-excellent disruptions (index 1.33+/-0.08) but at 480 minutes the mean indices had returned to the baseline level. CONCLUSIONS: Results of these in vivo human studies indicate that the time course to closure of the disrupted BBB for low-molecular-weight complexes is longer than previously estimated. The barrier is widely open during the first 40 minutes after osmotic BBB disruption and returns to baseline levels only after 6 to 8 hours following the induction of good or excellent disruption. These findings have important clinical implications for the design of therapeutic protocols.