[Demonstration of cerebral metabolism using positron emission tomography and magnetic resonance spectroscopy in relation to the pathophysiology of focal cerebral disorders].
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Adult↗
Biomedical subjects
A M Paans
Publications and source records attributed to A M Paans.
Quantification of an 11C-labelled beta-adrenoceptor ligand, S-(-)CGP 12177, in plasma of humans and rats.
beta-Adrenoceptors in human lungs and heart can be imaged with the radioligand 4-[3-[(1,1-dimethylethyl)amino]-2-hydroxypropoxy]-1,3- dihydro-2H-benzimidazol-2-11C-one (CGP 12177, [11C]I). For quantification of receptor density with compartment models by adjustment of rate constants, an 'input function' is required which consists of the integral of the concentration of unmodified ligand in arterial plasma over time. A discrepancy in the literature regarding metabolic stability of [11C]I prompted us to study metabolism in rats by reversed-phase HPLC (RP-HPLC) of trichloroacetic acid extracts of arterial plasma after i.v. injection of [11C]I (> 11.1 TBq/mmol, 11 MBq/kg). Some plasma samples were also directly applied to an internal-surface reversed-phase (ISRP) column. In parallel experiments, tritiated [11C]I was employed and methanol extracts of arterial plasma were analyzed by straight-phase TLC. The three methods were in excellent agreement. Unmodified [11C]I decreased from > 98.5% (3H) or > 99.9% (11C) initially to 57 +/- 7% at 80 min post injection due to formation of two polar metabolites. Using the RP-HPLC method, no metabolism was detectable in humans up to 30 min after injection of [11C]I (1851 MBq). Deproteinization of plasma with acetonitrile resulted in the formation of a radioactive species (artifact) which eluted immediately after the void volume in RP-HPLC and which could be mistakenly interpreted as a metabolite. Plasma protein binding was low (ca. 30%) in both humans and rats.(ABSTRACT TRUNCATED AT 250 WORDS)
Adrenergic beta-Antagonists↗
Localised proton spectroscopy and spectroscopic imaging in cerebral gliomas, with comparison to positron emission tomography.
In 32 patients with gliomas, one- and two-dimensional proton magnetic resonance spectroscopy (1H-MRS) has been conducted, the latter allowing reconstruction of spectroscopic data into a spectroscopic image (MRSI), showing the distribution of the various metabolite concentrations over the cross-sectional plane. For lack of absolute concentrations, the measured concentrations of phosphocholine (CHOL), N-acetyl-L-aspartate (NAA), and lactate (LAC) were conventionally expressed in ratios relative to that of creatine (CREAT). Compared to normal brain tissue, an increased CHOL/CREAT ratio was found in all groups of tumours, in glioblastomas, high-, middle- and low-grade astrocytomas both at the margin and the core of the tumours, but in oligodendrogliomas only at the margin. This is consistent with an increased phosphocholine turnover in relation to membrane biosynthesis by the proliferating cells. The NAA/CREAT ratio was decreased in all groups of tumours, both in the centre and at the margin, reflecting replacement of functioning neurons by neoplastic cells. The LAC/CREAT ratio was elevated in the core of malignant gliomas, which may be the result of a prevailing glycolysis, characteristic of tumours, possibly in conjunction with hypoxia/ischaemia. In the perifocal oedema, there was neither elevation of the CHOL/CREAT ratio nor decrease of the NAA/CREAT ratio; an increased LAC/CREAT ratio therefore rather reflected ischaemia/hypoxia probably due to locally elevated pressure and compromised regional perfusion. In the normal brain, the metabolite ratios of grey matter did not differ from those of white matter. The frontal lobe and basal ganglia showed lower NAA/CREAT ratios than the other cerebral areas.(ABSTRACT TRUNCATED AT 250 WORDS)
Aspartic Acid↗
Brain tumors: L-[1-C-11]tyrosine PET for visualization and quantification of protein synthesis rate.
PURPOSE: Positron emission tomography (PET) with the amino acid tracer L-[1-C-11]-tyrosine was evaluated in 27 patients with primary and recurrent brain tumors. MATERIALS AND METHODS: Patients underwent either static (n = 14) or dynamic PET (n = 13), with quantification of protein synthesis rate (PSR) and tumor-to-background ratio. Findings were compared with histologic findings. RESULTS: Primary brain tumor was proved in 22 patients histologically, as well as metastatic cancer of unknown origin, primary non-Hodgkin lymphoma, meningioma, atypical infarction, and vasculitis in one patient each. At PET, 20 of 22 primary tumors, the metastasis, and non-Hodgkin lymphoma were correctly depicted. A false-positive finding was obtained with the infarction, and the meningioma and vasculitis were not depicted. The calculated sensitivity was 92%; specificity, 67%; and accuracy, 89%. There were no statistically significant relationships between histologic findings, PSR, and tumor-to-background ratio. CONCLUSION: L-[1-C-11]-tyrosine is a valid tracer for diagnosis of brain tumors and allowed quantification of PSR.
Adult↗
In vivo protein synthesis rate determination in primary or recurrent brain tumors using L-[1-11C]-tyrosine and PET.
UNLABELLED: The applicability of protein synthesis rate (PSR) determination with L-[1-11C]tyrosine (11C-TYR) and PET was assessed in patients suspected of a primary or recurrent brain tumor. METHODS: Simultaneous to intravenous injection of 265 MBq of 11C-TYR, dynamic PET acquisition was started and continued for 50 min. Arterial samples were taken and analyzed for 11C-TYR and metabolites. Based on this data, a model was proposed and the corresponding PSR calculated. RESULTS: Plasma metabolites were 11CO2, 11C-proteins and 11C-L-DOPA, constituting more than 50% of total plasma radioactivity at 40 min postinjection. Plasma 11CO2 reached a plateau of around 25% of total plasma radioactivity at 20 min postinjection. Plasma 11C-protein was not detected before 10 min postinjection, but increased exponentially afterwards to 20% at 40 min postinjection. Plasma 11C-L-DOPA was the only acid-soluble radioactive metabolite detected and was less than 8% at 40 min postinjection. Using a five-compartment model, it was shown that while the net PSR was dependent on the recycling of amino acids from protein, the amino acid incorporation was not, which was thus used for subsequent analysis. It was found that our curve-fitting results were unreliable due to the exchange of 11C-TYR between plasma and erythrocytes whereas the graphical Patlak-Gjedde analysis is hardly influenced by this transport phenomenon. The average amino acid incorporation rate thus calculated was 0.7 nmole/ml.min for nontumor tissue with a tumor versus nontumor average ratio of 1.7. CONCLUSION: The assessment of the PSR with TYR-PET is valuable and relatively simple to implement clinically.
Adult↗
Contribution of magnetic resonance spectroscopic imaging and L-[1-11C]tyrosine positron emission tomography to localization of cerebral gliomas for biopsy.
Proton magnetic resonance spectroscopic imaging (1H-MRSI) and positron emission tomography with the tracer L-[1-11C]tyrosine (11C-TYR) were used to localize gliomas for biopsy or resection. This is especially helpful in cases of low-grade gliomas, if these lesions are not visualized by contrast-enhanced computed tomographic and magnetic resonance imaging scans. The clues to improved localization are provided by changes in tissue metabolite contents, such as elevation of phosphocholine, indicating cellular proliferation; decrease of N-acetylaspartate, denoting loss of neurons (as these are replaced by tumor cells); and elevation of lactate, pointing to the prevalence of glycolysis, as observed in many tumors. These data on tissue metabolite content have been obtained in vivo in the patient by proton magnetic resonance spectroscopy; metabolite maps derived from these data then visualize the distribution of the various metabolites over the section of the brain under investigation. Alternatively, localization of a tumor may be achieved by means of positron emission tomography depicting the pattern of uptake of the amino acid tracer 11C-TYR, as it tends to be incorporated in the process of cellular proliferation and protein biosynthesis. Five cases are presented as examples.
Adult↗
Visualization of damaged brain tissue after ischemic stroke with cobalt-55 positron emission tomography.
UNLABELLED: In animal experiments, the radionuclide 55Co2+ has been shown to accumulate in degenerating cerebral tissue similar to Ca2+. METHODS: The potential role of 55Co2+ for in vivo brain PET imaging was investigated in four patients after ischemic stroke. RESULTS: PET showed uptake of 55Co2+ in damaged brain tissue irrespective of blood-brain barrier integrity, as affirmed by CT and MRI. CONCLUSION: Our preliminary results indicate that 55CoCl2 may prove to be a useful and relatively inexpensive PET radiopharmaceutical for visualization of degenerative processes in brain tissue.
Aged↗
Positron emission tomography with fluorine-18-fluorodeoxyglucose for the evaluation of therapeutic isolated regional limb perfusion in a patient with soft-tissue sarcoma.
METHODS: The treatment of a patient with soft-tissue sarcoma was evaluated with FDG-PET. A limb-saving complete remission of a locally advanced liposarcoma of the left thigh was achieved with isolated regional perfusion of the limb with tumor necrosis factor alpha, interferon gamma and melphalan. RESULTS: PET with 18F-FDG before perfusion showed high glucose consumption in the tumor. After perfusion, glucose metabolism in the tumor was absent. Subsequent excision confirmed complete necrosis of the tumor. CONCLUSION: FDG-PET may be useful in evaluating the results of isolateral regional limb perfusion for soft-tissue sarcomas.
Chemotherapy, Cancer, Regional Perfusion↗
[The value of new diagnostic techniques in Alzheimer's disease].
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Alzheimer Disease↗
Uptake of radioligands by rat heart and lung in vivo: CGP 12177 does and CGP 26505 does not reflect binding to beta-adrenoceptors.
The biodistribution of (-)-4-(3-t-butylamino-2-hydroxypropoxy)-[5,7-3H-benzimidazol-2-one (CGP12177, a non-selective beta-adrenoceptor antagonist) and 1-[2-(3-carbamoyl-4-hydroxy)-(5-3H-phenoxy)]-2-propanol methanesulfonate, (CGP26505, a beta 1-adrenoceptor antagonist) was studied in rats pretreated with various alpha- and beta-adrenoceptor blocking drugs (5 min before 3H injection, in dosages at which the drugs demonstrated the expected selectivity). Cardiac and pulmonary radioactivity were measured after 10 min, when specific binding was maximal. Uptake of [3H]CGP12177 was linked to binding to beta-adrenoceptors since it was not affected by prazosin or yohimbine, and was equally well inhibited by propranolol, unlabelled CGP12177 and isoprenaline. Moreover, atenolol and CGP20712A inhibited [3H]CGP12177 uptake in heart (predominantly beta 1-adrenoceptors) more potently than ICI 118,551, while in lungs (predominantly beta 2-adrenoceptors) ICI 118,551 was more potent than atenolol or CGP20712A. In contrast, [3H]CGP26505 uptake in the target organs was equally effectively inhibited by propranolol and ICI 118,551, and significantly lowered by alpha-adrenoceptor antagonists. We conclude that [11C]CGP12177, but not [11C]CGP2605 will be suitable for positron emission tomography imaging of beta-adrenoceptors in animals.
Adrenergic alpha-Antagonists↗
Suitability of CGP-12177 and CGP-26505 for quantitative imaging of beta-adrenoceptors.
[3H]CGP-12177, a non-selective beta-adrenoceptor antagonist, and [3H]CGP-26505, a beta 1-selective beta-adrenoceptor antagonist, were intravenously administered to rats. 94-97% of the injected radioactivity disappeared from plasma with t1/2 0.2 and 0.5 min. Total/non-specific binding ratios of 5.4 and 6.9 (CGP-12177) or 2.0 and 2.8 (CGP-26505) were maintained in heart and lung from 10 to 40 min post-injection. Labelled plasma metabolites appeared after greater than 20 min (CGP-12177) or within 2 min (CGP-26505). No metabolites were found in the heart. CGP-12177 binds to blood cells, but CGP-26505 does not. CGP-12177 can be used for PET imaging of total (beta 1 and beta 2) adrenoceptors in the heart and lung of experimental animals, but CGP-26505 is less suitable for in vivo analysis of the beta 1-subpopulation.
Adrenergic beta-Antagonists↗
Radiation-induced inhibition of tumor growth as monitored by PET using L-[1-11C]tyrosine and fluorine-18-fluorodeoxyglucose.
The potential use of PET to monitor radiotherapeutic effects on tumors has been evaluated with L-[1-11C]tyrosine and 18FDG. Single x-ray doses of 10, 30, or 50 Gy have been applied to rhabdomyosarcoma tumors growing in the flank of rats. Dose-dependent reductions of tracer uptake were registered by PET 4 and 12 days after treatment. These later effects on tracer uptake appeared to correlate with changes in tumor volume. Therefore, PET using L-[1-11C]tyrosine and 18FDG is suitable to monitor kinetics of tumor growth and tumor regression after radiotherapy. Direct effect on tracer uptake was not observed within 8 hr after irradiation. This indicates that, using PET, early predictions on the outcome of radiotherapy are not possible. When combining a radiation treatment with hyperthermia, radiation-induced inhibition of tumor growth was clearly enhanced. Tracer uptake remained at the pretreatment value, possibly due to invasion of host cells. From these experiments, it can be concluded that it is difficult to monitor a combined treatment of radiation and hyperthermia by PET.
Animals↗
High central D2-dopamine receptor occupancy as assessed with positron emission tomography in medicated but therapy-resistant schizophrenic patients.
We investigated whether the lack of therapeutic response to long-term and adequate neuroleptic treatment was due to a failure to achieve a blockade of cerebral dopamine receptors. Six chronic schizophrenic and medicated patients (DSM-III-R diagnosis, paranoid or disorganized type) were assessed with the Present State Examination and the Brief Psychiatric Rating Scale. According to the Chouinard Rating Scale there were little extrapyramidal symptoms, although no anticholinergic drugs were given. Plasma levels of the neuroleptics were determined and found in the therapeutic range or higher. Dopamine D2-receptor occupancy was determined with positron emission tomography using 11C-methylspiperone as ligand. There was a more than 95% blockade of the D2 receptors in the striatum. These results indicate that the lack of therapeutic response and extra-pyramidal side effects cannot be attributed to an incomplete blockade of cerebral D2 receptors and that the pathogenetic role of these receptors can be questioned in therapy-resistant schizophrenic patients.
Adult↗
A fluorine-18 labeled progestin as an imaging agent for progestin receptor positive tumors with positron emission tomography.
The potential of the fluorine-18 labeled progestin 21-[18F]fluoro- 16 alpha-ethyl-19-norpregn-4-ene-3,20-dione [( 18F]FENP) as an imaging agent for the in vivo assessment of progestin receptor (PR) positive neoplasms with positron emission tomography has been investigated. Tissue distribution studies in immature estrogen primed female rats revealed high uptake of radioactivity, expressed as the differential absorption ratio, by uterine tissue. After simultaneous administration with unlabeled FENP, a significant decrease (83%) in uterine uptake was observed 60 min after injection. Uterine uptake was highly selective. The ratio of uptake of radioactivity by uterine tissue to that by blood was 39 at 180 min. In mice bearing transplanted Grunder strain mammary carcinomas tissue, distribution studies demonstrated a selective uptake of [18F]FENP by PR positive tumors. Pretreatment with unlabeled FENP caused a significant decrease (66%) in tumor uptake. Uptake by other tissues was not affected by the presence of unlabeled progestin. The ratio of uptake of radioactivity by tumor tissue to that by blood was 4.7 at 180 min. For FENP pretreated mice and mice bearing PR negative tumors, this ratio was 1.7 and 1.1, respectively. It is concluded that the uptake of [18F]FENP by uterine and by PR positive mammary tumor tissue in vivo is primarily receptor related, presumably to the PR. Furthermore, [18F]FENP appears to be suitable for imaging of PR positive human neoplasms with positron emission tomography.
Animals↗
[The use of positron emission tomography in cardiology; a metabolic dimension].
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Coronary Circulation↗
PET studies with L-[1-11C]tyrosine, L-[methyl-11C]methionine and 18F-fluorodeoxyglucose in prolactinomas in relation to bromocryptine treatment.
Aspects of metabolism in prolactinomas were investigated by positron emission tomography using L-[1-11C]tyrosine, L-[methyl-11C]methionine and 18F-fluorodeoxyglucose (18FDG). Using L-[1-11C]tyrosine, four patients were monitored prior to and 18 h after an injection of 50 mg bromocriptine. At 18 h after bromocriptine intervention, L-[1-11C]tyrosine uptake into tumour was reduced with 28% (P less than 0.07). A correlation analysis of the bromocriptine-induced decrease in L-[1-11C]tyrosine uptake and the reduction of serum prolactin levels indicated that the action of bromocriptine on prolactin synthesis and prolactin release is not coupled. In the untreated situation, the four patients were investigated with 18FDG as well, but the prolactinomas could not be visualized. Three untreated patients were studied with L-[methyl-11C]methionine. The tumour-imaging potential of L-[methyl-11C]methionine and L-[1-11C]tyrosine appeared to be nearly equivalent for prolactinomas. Unlike prolactinoma tissue, the salivary glands showed a pronounced preference for L-[1-11C]tyrosine as compared to L-[methyl-11C]methionine. L-[1-11C]tyrosine is a valuable tool to obtain information on the metabolism and treatment of prolactinomas.
Adult↗
A comparative PET study using different 11C-labelled amino acids in Walker 256 carcinosarcoma-bearing rats.
In Walker 256 carcinosarcoma-bearing rats, the dynamic distribution of L-[1-11C]tyrosine, L-[methyl-11C]methionine, L-[1-11C]methionine and D-[1-11C]methionine has been measured by PET. An equivalent tumor-imaging potential was observed for each of the three L-amino acids. Thirty minutes after injection, the tumors accumulated 57% (P less than 0.01) more 11C-activity from L-[1-11C]methionine than from L-[methyl-11C]methionine. At the same point of time, the livers showed a 33% (P less than 0.001) higher 11C-uptake with L-[methyl-11C]methionine than with L-[1-11C]methionine. The dynamic tissue data are in agreement with the findings in experiments with 14C-analogs.
Amino Acids↗
Suitability of rodent tumor models for experimental PET with L-[1-11C]tyrosine and 2-[18F]fluoro-2-deoxy-D-glucose.
The applicability of five different rodent tumors for experimental PET has been investigated. L-[1-11C]Tyrosine was a better indicator for the growth activity of the tumors than [18F]FDG. For experimental PET, the three mice models studied appeared inappropriate; the Lewis lung tumor and the fibrosarcomateous FIO 26 had too low a tyrosine utilization, while the lymphosarcomateous LY showed insufficient tumor-to-background ratios. Of the two rat models, the necrotic Walker 256 carcinosarcoma was less suitable. By using L-[1-11C]tyrosine, the solid, rhabdomyosarcoma tumor offers good possibilities of monitoring therapeutic interventions with PET.
Animals↗