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W Vaalburg

Publications and source records attributed to W Vaalburg.

At least 19 recordsLinked to original sources
PubMed2001

Quantifying drug-related 5-HT1A receptor occupancy with.

RATIONALE: There is an increased interest in measuring the interaction of new or established drugs with their targets, in order to gain a better understanding of their mechanisms of action. PET can provide this information if an appropriate radioligand is available. [18F]MPPF (4-(2'-methoxyphenyl)-1-[2'-(N-2"-pyridinyl)-p-[18F]fluorobenzamido]ethylpiperazine) is a selective radioligand for serotonin 5-HT1A receptors. We have established that the binding potential (BP=Bmax/KD) of [18F]MPPF for cerebral 5-HT1A receptors can be assessed in human brain without arterial sampling. OBJECTIVES: The aim of this study was to assess if 5-HT1A receptor occupancy can be measured through calculation of a drug-related decrease in BP with [18F]MPPF and PET. METHODS: Six volunteers were scanned twice using a Siemens Exact HR+ camera following injection of 70+/-18 MBq [18F]MPPF (baseline and medicated conditions). Before the second scan, volunteers orally received either 3x10 mg pindolol at T=-15.5 h, T=-6.5 h, and T=-1.5 h (n=3) or 10 mg buspirone in a single dose at T=-1.5 h (n=3). Binding potentials were calculated using the simplified reference tissue model with the cerebellum as reference. RESULTS: Administration of 30 mg pindolol led to a significant reduction in [18F]MPPF binding potential of 42+/-17%. In contrast, no significant reduction of [18F]MPPF binding potential was observed following administration of buspirone (5+/-17%). CONCLUSIONS: These results show that [18F]MPPF can be used for measurement of drug-related 5-HT1A receptor occupancy and may be of particular interest in determining the 5-HT1A receptor interaction of new or established drugs in phase 1 and early phase 2 drug trials. Apparently, the 5-HT1A partial agonist buspirone is already clinically effective at low levels of 5-HT1A receptor occupancy.

Adrenergic beta-Antagonists↗
PubMed2001

No difference in cardiac event-free survival between positron emission tomography-guided and single-photon emission computed tomography-guided patient management: a prospective, randomized comparison of patients with suspicion of jeopardized myocardium.

OBJECTIVES: We sought to prospectively compare nitrogen-13 (13N)-ammonia/18fluorodeoxyglucose (18FDG) positron emission tomography (PET)-guided management with stress/rest technetium-99m (99mTc)-sestamibi single-photon emission computed tomography (SPECT)-guided management. BACKGROUND: Patients with evidence of jeopardized (i.e., ischemic or viable) myocardium may benefit from revascularization, whereas patients without it should be treated with drugs. Both PET and SPECT imaging have been proven to delineate jeopardized myocardium. When patient management is based on identification of jeopardized myocardium, it is unknown which technique is most accurate for long-term prognosis. METHODS: In a clinical setting, 103 patients considered for revascularization with left ventricular wall motion abnormalities and suspicion of jeopardized myocardium underwent both PET and SPECT imaging. The imaging results were used in a randomized fashion to determine management (percutaneous transluminal coronary angioplasty [PTCA], coronary artery bypass graft surgery [CABG] or drug treatment). Follow-up for cardiac events (cardiac death, myocardial infarction and revascularization) was recorded for 28 +/- 1 months. The study was designed to have a power of 80% to detect a 20% difference in the event rate between PET- and SPECT-based management. RESULTS: Management decisions in 49 patients randomized to PET (12 who had PTCA, 14 CABG and 23 drug therapy) were comparable with 54 patients randomized to SPECT (15 who had PTCA, 13 CABG and 26 drug therapy). In terms of cardiac event-free survival, no differences between PET and SPECT were observed (11 vs. 13 cardiac events for PET and SPECT, respectively; p = NS by the Kaplan-Meier statistic). CONCLUSIONS: No difference in patient management or cardiac event-free survival was demonstrated between management based on 13N-ammonia/18FDG PET and that based on stress/rest 99mTc-sestamibi SPECT imaging. Both techniques may be used for management of patients considered for revascularization with suspicion of jeopardized myocardium.

Aged↗
PubMed2001

Radiolabeled amino acids: basic aspects and clinical applications in oncology.

As the applications of metabolic imaging are expanding, radiolabeled amino acids may gain increased clinical interest. This review first describes the basic aspects of amino acid metabolism, then continues with basic aspects of radiolabeled amino acids, and finally describes clinical applications, with an emphasis on diagnostic value. A special focus is on (11)C-methionine, (11)C-tyrosine, and (123)I-iodomethyltyrosine, because these have been most used clinically, although their common affinity for the L-transport systems may limit generalization to other classes of amino acids. The theoretic and preclinical background of amino acid imaging is sound and supports clinical applications. The fact that amino acid imaging is less influenced by inflammation may be advantageous in comparison with (18)F-FDG PET imaging, although tumor specificity is not absolute. In brain tumor imaging, the use of radiolabeled amino acids is established, the diagnostic accuracy of amino acid imaging seems adequate, and the diagnostic value seems advantageous. The general feasibility of amino acid imaging in other tumor types has sufficiently been shown, but more research is required in larger patient series and in well-defined clinical settings.

Amino Acids↗
PubMed2001

On the quantification of [18F]MPPF binding to 5-HT1A receptors in the human brain.

UNLABELLED: Previous studies have shown that 4-(2'-methoxyphenyl)-1-[2'-(N-2"-pyridinyl)-p-[(18)F]fluorobenzamido]ethylpiperazine ([(18)F]MPPF) binds with high selectivity to serotonin (5-HT(1A)) receptors in man. However, in these studies, the calculation of the binding potential (BP, which equals receptor density divided by equilibrium dissociation constant) used a metabolite-corrected arterial input. The aim of this study was to determine whether metabolite correction and arterial sampling are essential for the assessment of BP. METHODS: Five analytic methods using full datasets obtained from 6 healthy volunteers were compared. In addition, the clinical applicability of these methods was appraised. Three methods were based on Logan analysis of the dynamic PET data using metabolite-corrected and uncorrected arterial plasma input and cerebellar input. The other 2 methods consisted of a simplified reference tissue model and standard compartmental modeling. RESULTS: A high correlation was found between BP calculated with Logan analysis using the metabolite-corrected plasma input (used as the reference method for this study) and Logan analysis using either the uncorrected arterial plasma input (r(2) = 0.95, slope = 0.85) or cerebellar input (r(2) = 0.98, slope = 0.91). A high correlation was also found between our reference method and the simplified reference tissue model (r(2) = 0.94, slope = 0.92). In contrast, a poor correlation was observed between our reference method and the standard compartmental model (r(2) = 0.45, slope = 1.59). CONCLUSION: These results indicate that neither metabolite analysis nor arterial sampling is necessary for clinical evaluation of BP in the human brain with [(18)F]MPPF. Both the Logan analysis method with cerebellar input and the simplified reference tissue method can be applied clinically.

Adult↗
PubMed2000

Influence of P-glycoprotein on brain uptake of [18F]MPPF in rats.

The aim of this study was to determine if the brain uptake of 4-(2'-methoxyphenyl)-1-[2'-(N-2"-pyridinyl)-p-[18F]fluorobenzamido ]ethylpiperazine ([18F]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 [18F]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-phthalimido)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 [18F]MPPF.The distribution of 18F-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 [18F]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 [18F]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 [18F]MPPF is a substrate for P-glycoprotein.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2000

Preoperative staging of non-small-cell lung cancer with positron-emission tomography.

BACKGROUND: Determining the stage of non-small-cell lung cancer often requires multiple preoperative tests and invasive procedures. Whole-body positron-emission tomography (PET) may simplify and improve the evaluation of patients with this tumor. METHODS: We prospectively compared the ability of a standard approach to staging (computed tomography [CT], ultrasonography, bone scanning, and, when indicated, needle biopsies) and one involving PET to detect metastases in mediastinal lymph nodes and at distant sites in 102 patients with resectable non-small-cell lung cancer. The presence of mediastinal metastatic disease was confirmed histopathologically. Distant metastases that were detected by PET were further evaluated by standard imaging tests and biopsies. Patients were followed postoperatively for six months by standard methods to detect occult metastases. Logistic-regression analysis was used to evaluate the ability of PET and CT to identify malignant mediastinal lymph nodes. RESULTS: The sensitivity and specificity of PET for the detection of mediastinal metastases were 91 percent (95 percent confidence interval, 81 to 100 percent) and 86 percent (95 percent confidence interval, 78 to 94 percent), respectively. The corresponding values for CT were 75 percent (95 percent confidence interval, 60 to 90 percent) and 66 percent (95 percent confidence interval, 55 to 77 percent). When the results of PET and CT were adjusted for each other, only PET results were positively correlated with the histopathological findings in mediastinal lymph nodes (P<0.001). PET identified distant metastases that had not been found by standard methods in 11 of 102 patients. The sensitivity and specificity of PET for the detection of both mediastinal and distant metastatic disease were 95 percent (95 percent confidence interval, 88 to 100 percent) and 83 percent (95 percent confidence interval, 74 to 92 percent), respectively. The use of PET to identify the stage of the disease resulted in a different stage from the one determined by standard methods in 62 patients: the stage was lowered in 20 and raised in 42. CONCLUSIONS: PET improves the rate of detection of local and distant metastases in patients with non-small-cell lung cancer.

Adult↗
PubMed2000

Monitoring of herpes simplex virus thymidine kinase enzyme activity using positron emission tomography.

9-[(1-[18F]Fluoro-3-hydroxy-2-propoxy)methyl]guanine ([18F]FHPG) was evaluated as a tracer for noninvasive positron emission tomography (PET) imaging of herpes simplex virus type 1 thymidine kinase (HSV-tk) gene expression. C6 rat glioma cells with and without the HSV-tk gene were incubated with [18F]FHPG for 2 h. The in vitro tracer uptake in HSV-tk-containing C6tk cells was 35 +/- 5 times higher than that in control cells. In nude rats carrying both a C6 and a C6tk tumor, the average ratio of tracer accumulation between the tumors was 15 +/- 5 at 2 h postinjection. The tracer is rapidly cleared from nontarget tissue into the urine because only the HSV-tk-expressing tumor, kidneys, and bladder remained visible on the late PET images. HPLC analysis revealed that three metabolites, tentatively assigned as FHPG mono-, di-, and triphosphate, were formed in the C6tk tumors only. In conclusion, we have demonstrated that [18F]FHPG is a promising tracer for monitoring HSV-tk enzyme activity in vivo with PET.

Animals↗
PubMed2000

Preclinical testing of N-[(11)c]-methyl-piperidin-4-yl 2-cyclohexyl-2-hydroxy-2-phenylacetate, a novel radioligand for detection of cerebral muscarinic receptors using PET.

The muscarinic antagonist N-[(11)C]methyl-piperidin-4-yl 2-cyclohexyl-2-hydroxy-2-phenylacetate (VC-004) 1 was tested for visualization of muscarinic receptors in the brain. The active (R)-isomer (pKb = 10.92) was labeled by reacting [(11)C]-CH(3)I with the secondary amine precursor (40-60% decay-corrected radiochemical yield, specific activity 13.0-34.3 TBq/mmol, 45 min after end of bombardment). Biodistribution studies were performed in male Wistar rats. Brain uptake of (R)-[(11)C]-VC-004 was high, standard uptake values (SUVs) ranging from 1.6 in cerebellum to 3.3 in frontal cortex. In all brain regions, the nonsubtype selective muscarinic antagonist scopolamine (2.5 mg/kg) blocked (R)-[(11)C]-VC-004 binding to the same extent (84.6 +/- 3.3%) as nonlabeled (R)-VC-004 (2.0 mg/kg, 83.2 +/- 4.6%). In contrast, the fraction of [(11)C]VC-004 binding which was blocked by atropine (2.5 mg/kg) was significantly smaller (54 +/- 17%). The reduction of (R)-[(11)C]-VC-004 binding by low-dose atropine (0.5 mg/kg) was not significantly different from that caused by (R)-(-)-QNB (20 microg/kg). The decrease in specific binding of (R)-[(11)C]VC-004 after (R)-(-)-QNB block correlated well with literature values for the percentages of M(2) receptors in the brain regions studied. (R)-[(11)C]VC-004 was rapidly cleared from plasma (92% with a half-life of 0.27 min) and the fraction of total plasma radioactivity representing parent compound decreased from 99% to 42% at 10 min postinjection. Although (R)-[(11)C]VC-004 can visualize muscarinic receptors in the brain, it does not show selectivity for the M(2)-subtype. A low dose (0.5 mg/kg) of atropine seems to preferentially block M(2)-receptors in vivo, as has been reported for (R)-(-)-QNB.

Animals↗
PubMed2000

Enhanced cerebral uptake of receptor ligands by modulation of P-glycoprotein function in the blood-brain barrier.

Low cerebral uptake of some therapeutic drugs can be enhanced by modulation of P-glycoprotein (P-gp), an ATP-driven drug efflux pump at the blood-brain barrier (BBB). We investigated the possibility of increasing cerebral uptake of the beta-adrenergic ligands S-1'-[(18)F]-fluorocarazolol (FCAR) and [(11)C]-carazolol (CAR) in P-gp knockout mice (mdr1a (-/-)) and by modulation of P-gp with cyclosporin A (CsA) in rats. Specific and nonspecific binding of FCAR in the rat brain were doubled by CsA, while target/nontarget ratios and clearance from plasma (area under curve (AUC)) were not affected. Cerebral uptake of CAR in rats was much lower than FCAR and nonspecific. CsA increased this uptake 5-6-fold, not only due to P-gp modulation in the BBB but also to a 2-fold higher plasma AUC. In the CNS of mdr1a (-/-) mice, uptake of FCAR and CAR was, respectively, 2-fold and 3-fold higher than in mdr1a (+/+) mice. These results indicate that the cerebral uptake of beta-adrenoceptor ligands can be increased by administration of P-gp modulators such as CsA without affecting regional distribution in the brain. P-gp modulation could improve the count statistics in PET studies of the CNS.

ATP Binding Cassette Transporter, Subfamily B↗
PubMed2000

Evaluation of dissemination studies with FDG whole-body positron emission tomography in patients with suspected metastatic tumours of brain and spine.

BACKGROUND: In the preoperative diagnosis of malignant brain tumours there is often uncertainty regarding their metastatic or primary nature, requiring dissemination studies. Currently FDG-wbPET is being used for the efficient detection of systemic tumours. It therefore may become a substitute for the conventional dissemination studies if it allows an earlier diagnosis. METHOD: In this descriptive and preliminary study a population of 14 patients with suspected or proven metastatic lesions, [18F]-fluoro-2-deoxy-D-glucose whole body positron emission tomography (FDG-wbPET) was conducted and verified by additional conventional dissemination studies. FINDINGS AND THEIR INTERPRETATION: The entire series of dissemination studies required an average of 30 days with a range of 4-73 days. The FDG-wbPET was corroborated by the other dissemination studies in 10 of the 14 patients. In 7 of these 10 patients both PET and dissemination studies showed systemic abnormal findings, but in one case the presence of high pulmonary activity on the FDG-wbPET and the abnormal findings on the chest X-rays proved to be Aspergillus infection at autopsy. In the other 2 cases the negative PET findings corresponded to the absence of systemic dissemination. In 5 cases there was disagreement of the results of the FDG-wbPET with other evidence, among which there were 2 cases of glioblastoma in which systemic metastases were most unlikely, and the foci of activity on the FDG-wbPET had to be considered as false positives. In the remaining 3 cases the systemic presence of high activity on the FDG-wbPET indicated the systemic presence of tumour, whereas the other dissemination studies disclosed no tumour. CONCLUSION: The results warrant the use of FDG-wbPET as a screening method for the search of metastases, allowing other studies to be focussed on the lesion. But from the cost/benefit point of view this would make the method less suitable as a substitute for dissemination studies in general, although it may speed up the diagnostic process.

Adult↗
PubMed2000

Synthesis and biodistribution of [11c]procaterol, a beta2-adrenoceptor agonist for positron emission tomography.

The potent, subtype-selective radioligand (+/-)-erythro-5-(1-hydroxy-2-[11C]isopropyl-aminobutyl)-8-hydroxy-car bostyril ([11C]procaterol) was synthesized and evaluated for visualization of pulmonary beta2-adrenoceptors with positron emission tomography (PET). Procaterol was labelled by reductive alkylation of the desisopropyl precursor with [11C]acetone under the influence of NaCNBH3 and acetic acid. Synthesis and HPLC purification were performed in 34 min. Specific activities ranged from 26.5-39.3 TBq (about 700-1000 Ci)/mmol and the radiochemical yield was 2.4-8.6% (corrected for decay). Biodistribution studies were performed in male Wistar rats which were either untreated or predosed with (D,L)-propranolol hydrochloride (beta-adrenoceptor antagonist, 2.5 mg/kg), ICI 118551 (beta2-adrenoceptor antagonist, 0.15 mg/kg), CGP 20712A (beta1-adrenoceptor antagonist, 0.15 mg/kg) or isoprenaline (beta1-adrenoceptor agonist, 15 mg/kg). Specific binding was observed in lungs, spleen and red blood cells, tissues known to contain beta2-adrenoceptors. Pulmonary binding was blocked by propranolol, ICI 118551 and isoprenaline, but not by CGP 20712A. This binding pattern is consistent with the beta2 selectivity of the radioligand. The clearance of [11C]procaterol was biphasic, with a rapid distribution phase (t1/2 0.17 min) representing 90% of the injected dose followed by an elimination phase (t1/2 18.1 min). About 45% of the plasma radioactivity was unmetabolized procaterol at 15 min postinjection. In a dynamic PET-study, the lungs of untreated control rats could barely be detected and total/non-specific binding ratios rose to only 1.2 at 20 min postinjection. Although labelling and administration of (-) erythroprocaterol, the most active of 4 stereoisomers, may produce better results, [11C]procaterol seems unsuitable for beta-adrenoceptor imaging.

Adrenergic beta-Agonists↗
PubMed2000

Mutagenic activity of a fluorinated analog of the beta-adrenoceptor ligand carazolol in the Ames test.

S-1'[(18)F]-Fluorocarazolol (FCAR) is a fluorinated analog of the nonmutagenic beta-blocker carazolol (CAR). In former studies FCAR proved to be suitable for quantification of beta-adrenoceptors in vivo with positron emission tomography (PET). We report here that FCAR displays no acute toxicity in either rats or mice. However, FCAR induces a strong dose-related increase in the number of revertants in the Ames test. We conclude that FCAR yields mutagenic activity as measured by the Ames test.

Adrenergic beta-Antagonists↗
PubMed2000

Quantitative imaging of 5-HT(1A) receptor binding in healthy volunteers with [(18)f]p-MPPF.

Animal experiments have shown that 4-(2'-methoxyphenyl)-1-[2'-(N-2"-pyridinyl)-p-[(18)F]fluorobenzamido+ ++] ethylpiperazine ([(18)F]p-MPPF) can be used for 5-hydroxytryptamine(1A) (5-HT(1A)) receptor imaging. The aim of this study was to develop a method for the quantitative imaging of 5-HT(1A) receptors in healthy volunteers with [(18)F]p-MPPF. After injection of [(18)F]p-MPPF radioactivity was rapidly taken up in the brain, with the highest accumulation in the medial temporal cortex. Low levels of radioactivity were found in cerebellum and basal ganglia. Plasma clearance and metabolism of [(18)F]p-MPPF resulted in only about 1% of the radioactivity in plasma as parent radioligand after 10 min. Using a linear graphical method (Logan-Patlak), binding potentials were calculated in several brain areas. A good correlation (r = 0.95) was found between the obtained binding potentials and literature values for 5-HT(1A) receptor densities. A good correlation (r = 0.96) was also found between the body weight-corrected region/cerebellum ratios and the respective binding potentials. Moreover, a blocking experiment with pindolol (n = 3) showed a decrease of 40% in the region/cerebellum ratios of the target areas. Compared to those of [carbonyl-(11)C]WAY-100635, the binding potentials were four to six times lower, indicating that [(18)F]p-MPPF has a lower in vivo affinity for 5-HT(1A) receptors. In conclusion, [(18)F]p-MPPF can be used for the quantitative analysis of 5-HT(1A) receptor distribution in human brain.

Adult↗
PubMed2000

[(11)C]FMAU and [(18)F]FHPG as PET tracers for herpes simplex virus thymidine kinase enzyme activity and human cytomegalovirus infections.

[(11)C]-2'-Fluoro-5-methyl-1-beta-D-arabinofuranosyluracil ([(11)C]FMAU) and [(18)F]-9-[(3-fluoro-1-hydroxy-2-propoxy)methyl]guanine ([(18)F]FHPG), radiolabeled representatives of two classes of antiviral agents, were evaluated as tracers for measuring herpes simplex virus thymidine kinase (HSV-tk) enzyme activity after gene transfer and as tracers for localization of active human cytomegalovirus (HCMV) infections. In vitro accumulation experiments revealed that both [(11)C]FMAU and [(18)F]FHPG accumulated significantly more in HSV-tk expressing cells than they did in control cells. [(18)F]FHPG uptake in HSV-tk expressing cells, however, was found to depend strongly on the cell line used, which might be due to cell type dependent membrane transport or cell type dependent substrate specific susceptibility of the enzyme. In vitro, both tracers exhibited a good selectivity for accumulation in HCMV-infected human umbilical vein endothelial cells over uninfected cells. In contrast to [(18)F]FHPG, [(11)C]FMAU uptake in control cells was relatively high due to phosphorylation of the tracer by host kinases. Therefore, [(18)F]FHPG appears to be the more selective tracer not only to predict HSV-tk gene therapy outcome, but also to localize active HCMV infections with PET.

Antiviral Agents↗
PubMed2000

The blood-brain barrier and oncology: new insights into function and modulation.

The efficacy of chemotherapy for malignant primary or metastatic brain tumours is still poor. This is at least partly due to the presence of the blood-brain barrier (BBB). The functionality of the BBB can be explained by physicochemical features and efflux pump mechanisms. An overview of the literature is presented with emphasis on oncology. The BBB consists of capillary endothelial cells that lack fenestrations and are connected together with continuous tight junctions, with a high electrical resistance. Permeability of tight junctions can be increased in vitro by contraction of the cytoskeleton, caused by bradykinin agonists. Different efflux pumps are present in the BBB. Examples are P-glycoprotein (P-gp), organic anion transporters, (OAT) and multidrug-resistance-associated proteins (MRP)(1 and 3). These pumps act as a multi-specific efflux pump for various chemotherapeutic drugs. Experiments have shown that P-gp can be inhibited by different non-chemotherapeutic substrates such as cyclosporin A. The functionality in vivo of P-gp can be measured with positron emission tomography and [(11)C]-verapamil or with single photon emission computer tomography and(99m)Tc-sestamibi. MRP(1)and MRP(3)act as organic anion transporters that in vitro act as efflux pumps for substances that are conjugated or co-transported with glutathione and glucuronide, respectively. Methotrexate has been recently demonstrated to be transported by MRP(1)and MRP(3). Results of studies which demonstrate the clinical relevance and applicability of BBB modulators are eagerly awaited.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2000

Positron emission tomography in drug development and drug evaluation.

Positron Emission Tomography (PET) is an imaging modality which can determine biochemical and physiological processes in vivo in a quantitative way by using radiopharmaceuticals labeled with positron emitting radionuclides as (11)C, (13)N, (15)O and (18)F and by measuring the annihilation radiation using a coincidence technique. This includes also measurement of the pharmacokinetics of labeled drugs and the assessment of the effects of drugs on metabolism. Because only very low amounts of the radiolabeled drug have to be administered, far below toxicity levels, human studies can be carried out even before the drug is entered in Phase I. Such studies can provide cost-effective predictive toxicology data and information on the metabolism and mode of action of drugs. PET is also very useful to study the metabolic consequences of gene expression or gene defects. In the last decade many genetically engineered small animal models have been developed. The study of these animals with high resolution small animal PET cameras provides new opportunities in drug development. Especially valuable is the contribution of PET to bridge the gap between molecular biology, understanding of pathology and to the design of a new generation of drugs.

Drug Evaluation↗
PubMed2000

Imaging of soft-tissue tumors using L-3-[iodine-123]iodo-alpha-methyl-tyrosine single photon emission computed tomography: comparison with proliferative and mitotic activity, cellularity, and vascularity.

The radiolabeled amino acid L-3-[123I]-iodo-alpha-methyltyrosine (IMT) is a new tumor tracer that accumulates in many tumors and is suitable for single photon emission computed tomography (SPECT) imaging. Using IMT SPECT, we studied 32 patients with a soft-tissue tumor suspected to be a soft-tissue sarcoma to determine whether: (a) tumors can be visualized; (b) benign and malignant lesions can be distinguished; and (c) IMT uptake is related to tumor grade and proliferation. Whole-body imaging was performed 15 min after administration of 300 MBq IMT, biopsy, or resection 1-2 weeks later. IMT uptake was quantified using a region-of-interest method resulting in tumor:background (T:B) ratios. These were compared with tumor grade, mitotic index, tumor cellularity, vascularity, and the Ki-67 proliferation index. Eleven patients had a benign tumor, and 21 patients had a soft-tissue sarcoma. Six benign tumors demonstrated minor IMT uptake, and five lipomas had no uptake. All malignant tumors had high uptake and were clearly visualized. T:B ratios in malignant tumors (3.83 +/- 1.16) were higher (P < 0.001) than in benign tumors (1.52 +/- 0.60). Small (<5 mm) metastases in two patients were not detected. Taking the T:B ratio 2.0 as the cutoff level, the sensitivity for detection of malignancy was 100%, and specificity was 88%. IMT uptake correlated with histological grade (r = 0.82; P < 0.001), mitotic index (r = 0.75; P < 0.001), tumor cellularity (r = 0.73; P < 0.01), and with the Ki-67 proliferation index (r = 0.63; P < 0.01). In conclusion, IMT SPECT visualized all soft-tissue sarcomas. Uptake in sarcomas was clearly higher than in benign lesions, yielding 100% sensitivity for detection of malignancy at 88% specificity. Uptake increased with higher tumor grade and higher proliferation rate.

Adolescent↗