Biomedical subjects

Willem Vaalburg

Publications and source records attributed to Willem Vaalburg.

At least 19 recordsLinked to original sources

PubMed2006

Early FDG-PET assessment in combination with clinical risk scores determines prognosis in recurring lymphoma.

This study was set up to demonstrate whether prognostic classification based on the secondary age-adjusted International Prognostic Index (sAA-IPI) for recurring aggressive non-Hodgkin lymphoma (NHL) or the prognostic score for recurring Hodgkin lymphoma (HL) can be improved by including the midtreatment results of fluorine-18-fluorodeoxy-glucose-positron emission tomography (FDG-PET). Clinical data on patients with recurring lymphoma who were treated with second-line chemotherapy (DHAP-VIM-DHAP) followed by autologous stem cell transplantation (ASCT) were collected and combined with the results of FDG-PET performed before and after 2 cycles of reinduction chemotherapy. PET responses after 2 courses were scored as complete remission (CR), partial remission (PR), or no response (NR). A multivariate analysis was performed to design a predictive model. The number of patients (101 of 117) included those (78 patients with aggressive NHL and 23 patients with HL) that could be analyzed according to protocol. Of these, 80 patients were chemosensitive and 77 received transplants. Both secondary clinical risk score (P<.001) and FDG-PET response (P<.001) were independent predictive factors for the total evaluable group of patients with lymphoma and for patients with NHL alone. The combined use of the clinical risk score and FDG-PET response after 2 chemotherapy courses identified at least 4 categories of patients with a failure-free survival varying between 5% to 100% after transplantation (P<.001). These data indicate that the secondary clinical risk score in conjunction with FDG-PET response provides a more accurate prognostic instrument for the outcome of second-line treatment at least in patients with recurring NHL.

Adult↗

PubMed2006

The role of serial pre-transplantation positron emission tomography in predicting progressive disease in relapsed lymphoma.

BACKGROUND AND OBJECTIVES: 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) appears to be an excellent tool for evaluating early response to chemotherapy in lymphoma patients. As only chemosensitive patients with relapsed lymphoma may benefit from ablative therapy and autologous stem cell transplantation (ASCT), PET may be used to select patients for ASCT. A prospective study was performed to investigate the optimal time point of pre-transplantation PET, using different PET-parameters. DESIGN AND METHODS: Three serial whole-body attenuation-corrected FDG-PET scans were performed in 39 consecutive patients with relapsed lymphoma (28 with aggressive non-Hodgkin's lymphoma and 11 with Hodgkin's disease) eligible for second-line chemotherapy followed by ASCT: PET1 before treatment, PET2 after two cycles of induction chemotherapy and PET3 after a third cycle of chemotherapy just before ASCT in cases with an abnormal PET2. Visual analysis and standardized uptake value (SUV) parameters were obtained for each scan. The follow-up lasted a minimum of 6 months after ASCT. RESULTS: PET2 normalized in 43% (17/39) of the patients, and PET3 normalized in 27% (6/22). Persistent abnormal FDG-uptake was observed in 41% of the patients: 15% showed partial remission and 26% stable or even progressive abnormalities. With a median follow-up of 22 months (range 6-55) 54% of all patients relapsed after ASCT. The results demonstrated that those patients who showed a complete response after the second and third cycles of chemotherapy had a 2-year progression-free survival of 71% and 58%, respectively, while those who showed no response, all relapsed shortly after ASCT. Analysis of the SUV parameters did not reveal additional information compared to that yielded by the visual assessment. INTERPRETATION AND CONCLUSIONS: Two serial PET scans predict outcome after ASCT more precisely than one interim PET in patients with relapsed lymphoma.

Disease Progression↗

PubMed2006

18F-FEAU as a radiotracer for herpes simplex virus thymidine kinase gene expression: in-vitro comparison with other PET tracers.

OBJECTIVE: The herpes simplex virus thymidine kinase (HSVtk) gene has frequently been applied as a reporter gene for monitoring transgene expression in animal models. In clinical gene therapy protocols, however, extremely low expression levels of the transferred gene are generally observed. Consequently, sensitive and selective radiotracers for imaging are required. This study describes the in-vitro evaluation of 2'-[18F]fluoro-5-ethyl-1-beta-D-arabinofuranosyluracil (18F-FEAU) as a candidate tracer for HSVtk imaging with positron emission tomography (PET). METHODS: In cellular accumulation experiments, the potential of 18F-FEAU as a PET tracer for HSVtk was compared to the known acyclic guanosine derivatives 9-[(3-[18F]fluoro-1-hydroxy-2-propoxy)methyl]guanine (18F-FHPG) and 9-[4-[18F]fluoro-3-(hydroxymethyl)butyl]guanine (18F-FHBG), and the thymidine derivatives 3'-deoxy-3'-[18F]fluorothymidine (18F-FLT), 2'-deoxy-2'-[18F]fluoro-5-methyl-1-beta-D-arabinofuranosyluracil (18F-FMAU) and 2'-deoxy-2'-[18F]fluoro-5-iodo-1-beta-D-arabinofuranosyluracil (18F-FIAU). For this purpose, C6 control cells and HSVtk-expressing C6tk cells were incubated with the different tracers for various periods of time and cellular uptake and initial uptake rates were analysed. The initial rate of tracer uptake was determined from the slope of the plot of tracer uptake versus incubation time. RESULTS: After 2 h of tracer incubation, the C6tk/C6 accumulation ratio was 1.6 for 18F-FLT, 2.4 for F-FMAU, 5.5 for 18F-FHPG, 10.3 for 18F-FIAU, 40.8 for 18F-FHBG and 84.5 for 18F-FEAU. The initial tracer uptake rate in C6tk cells was in the order FLT>FMAU>FEAU>FIAU>FHBG>FHPG, whereas the initial tracer uptake rate in C6 control cells was FLT>FMAU>FIAU>FEAU approximately = FHBG approximately = FHPG. The highest HSVtk specific uptake was observed for FEAU. CONCLUSION: This study indicates that the high uptake rate of FEAU together with its high selectivity make this tracer an excellent candidate as a PET tracer for HSVtk gene expression.

Animals↗

PubMed2005

Blood-brain barrier dysfunction in parkinsonian midbrain in vivo.

Parkinson's disease (PD) is associated with a loss of neurons from the midbrain. The cause of PD is unknown, but it is established that certain neurotoxins can cause similar syndromes. The brain is normally protected from these noxious blood-borne chemicals by the blood-brain barrier which includes specialized proteins on the inside of blood vessels in the brain. These act as molecular efflux pumps and P-glycoprotein (P-gp) is an abundant representative. Vulnerability to PD appears codetermined by the genotype for the P-gp gene. We hypothesized that PD patients have reduced P-gp function in the blood-brain barrier. We used positron emission tomography to measure brain uptake of [(11)C]-verapamil, which is normally extruded from the brain by P-gp. Here, we show significantly elevated uptake of [(11)C]-verapamil (18%) in the midbrain of PD patients relative to controls. This is the first evidence supporting a dysfunctional blood-brain barrier as a causative mechanism in PD.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2005

New positron emission tomography tracer [(11)C]carvedilol reveals P-glycoprotein modulation kinetics.

Imaging of P-glycoprotein (P-gp) function in the blood-brain barrier (BBB) may support development of strategies, which will improve drug delivery to the brain. [(11)C]verapamil has been developed as a positron emission tomography (PET) tracer, to image P-gp function in vivo. Ideally, for the purpose of brain imaging, tracers should have a log P between 0.9 and 2.5. The beta-receptor antagonist carvedilol is a P-gp substrate with a log P=2.0, and can be labeled with [(11)C]. The aim of this study was to determine whether the P-gp substrate [(11)C]carvedilol can be used as a PET tracer for visualisation and quantification of the P-gp function in the BBB. Cellular [(11)C]carvedilol accumulation in GLC(4), GLC(4)/P-gp, and GLC(4)/Adr cells increased three-fold in the GLC(4)/P-gp cells after pretreatment with cyclosporin A (CsA) whereas no effect of MK571 could be determined in the GLC(4)/Adr cells. Ex vivo [(11)C]carvedilol biodistribution studies showed that [(11)C]carvedilol uptake in the brain was increased by CsA. [(11)C]carvedilol uptake in other organs was not affected by CsA. Autoradiography studies of rat brains showed that [(11)C]carvedilol was homogeneously distributed over the brain and that pretreatment with CsA increased [(11)C]carvedilol uptake. In vivo PET experiments were performed with and without P-gp modulation by CsA. P-gp mediated transport was quantified by Logan analysis of the PET data, calculating the distribution volume (DV) of [(11)C]carvedilol in the brain. Logan analysis resulted in excellent fits, revealing that [(11)C]carvedilol is not trapped in the brain. Brain DV of [(11)C]carvedilol showed a dose-dependent increase of maximal three-fold after CsA pretreatment. Above 15 mg kg(-1), no change in DV was found. Compared to [(11)C]verapamil less CsA was needed to reach maximal DV, suggesting that [(11)C]carvedilol kinetics is a more sensitive tool to in vivo measure P-gp function.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2005

Positron emission tomography studies of human airways using an inhaled beta-adrenoceptor antagonist, S-11C-CGP 12388.

OBJECTIVES: Positron emission tomography (PET) scanning may provide information on changes in the density and affinity of airway beta-adrenoceptors in lung diseases. However, the injection of a radiolabeled beta-blocker results in a pulmonary PET signal that reflects the binding of the ligand in the alveoli and not in the airways. Better discrimination between alveolar and airway beta-adrenoceptors may be possible with an inhaled radioligand. DESIGN: A nebulizer was used to administer the antagonist S-11C-CGP12388 in aerosol form. Eight volunteers inhaled the tracer twice, at baseline and after pretreatment with a beta-adrenergic drug. In both PET scan studies, a dynamic scan of the lungs was followed by a whole-body scan to assess the inhaled dose. Pulmonary uptake was quantified using a region-of-interest-based analysis. SETTING: University hospital. PARTICIPANTS: Healthy volunteers. INTERVENTIONS: Pretreatment consisted either of inhaled salbutamol (400 microg, 20 min before the scan), or orally administered pindolol (3 x 5 mg during a period of 16 h before PET scanning). RESULTS: Drug pretreatment did not affect pulmonary deposition of the radioligand. The agonist salbutamol accelerated the monoexponential washout of 11C not only in the peripheral lung (mainly alveoli), but also in the central lung (mainly airways) and in the main bronchi. An even larger increase of the washout rate was induced by the antagonist pindolol. CONCLUSION: The similar effects of pindolol and salbutamol on tracer kinetics suggest that accelerated washout is due to the blockade of beta-adrenoceptors. Thus, the interaction of drugs with airway beta-adrenoceptors can be visualized using PET scanning and an inhaled radioligand.

Administration, Inhalation↗

PubMed2005

Influence of p53 status on the HSV-Tk/GCV-induced bystander effect in a panel of human ovarian carcinoma cell lines.

The p53 protein is mutated in 50% of all human tumors and plays a key role in apoptosis, cell cycle, and the expression of several genes. We investigated if p53 mutations influence the herpes simplex virus thymidine kinase (HSV-tk)/ganciclovir (GCV)-induced bystander effect (BE). Additionally, we studied some of the underlying mechanisms. GCV sensitivity and BE were studied in a human ovarian carcinoma cell line transfected with an empty vector (A2780/cmv) or a vector containing a p53 hotspot mutation at codon 175 (A2780/m175) or 248 (A2780/m248). In addition, expression levels of two nucleoside analogue transporters, multidrug resistance-related protein 4 and 5 (MRP4/MRP5), were determined. Finally, differences in gap junctional intercellular communication (GJIC) were studied by determining connexin 43 (Cx43) expression and by modulating GJIC with 18-alpha-glycyrrhetinic acid. Our results showed that compared to A2780/cmv, GCV sensitivity was significantly decreased in A2780/m175 and A2780/m248. Additionally, a significant BE (relative increase in cell kill) was found in A2780/cmv and A2780/m248. In contrast, an increased survival was observed in A2780/m175. No MRP4 or MRP5 expression was detected. However, all A2780 cell lines expressed Cx43. Modulating the GJIC significantly decreased the BE in A2780/cmv and A2780/ m248. In conclusion, HSV-tk/GCV-induced BE is influenced by p53 mutations. Differences in GJIC could be one of the underlying mechanisms.

Animals↗

PubMed2005

Synthesis and evaluation of dopamine D3 receptor antagonist 11C-GR218231 as PET tracer for P-glycoprotein.

UNLABELLED: While searching for a PET method to determine the density and occupancy of the dopamine D(3) receptor, we found evidence that suggested that the dopamine D(3) antagonist GR218231 could be a substrate of the P-glycoprotein efflux pump. P-glycoprotein protects the brain against toxic substances and xenobiotics, but it also hampers the delivery of various drugs into the brain. In this study, we aimed to explore whether radiolabeled GR218231 could be applied as a PET tracer for monitoring P-glycoprotein activity in the blood-brain barrier. Such an imaging technique could be useful for the development of new drugs and novel strategies to deliver drugs to the brain and for identification of undesirable drug-drug interactions. METHODS: As a potential PET tracer, GR218231 was labeled with (11)C by reaction of the newly synthesized desmethyl precursor with (11)C-methyl triflate. The biodistribution of (11)C-GR218231 was determined in rats. To assess specific binding to the dopamine D(3) receptor, blocking experiments with unlabeled GR218231 (0.2 and 2.5 mg/kg) were performed. To demonstrate the influence of P-glycoprotein on cerebral uptake of (11)C-GR218231, the efflux pump was modulated with 50 mg/kg cyclosporine A. The sensitivity of (11)C-GR218231 for P-glycoprotein modulation was assessed in dose-response studies, using escalating cyclosporine A dosages. RESULTS: (11)C-GR218231 was prepared in 53% +/- 8% decay-corrected radiochemical yield and had a specific activity of 15 +/- 10 GBq/micromol (mean +/- SD). Biodistribution studies in rats revealed a low and homogeneous uptake in the brain. Pretreatment of the animals with unlabeled GR218231 did not demonstrate any specific binding. Modulation of P-glycoprotein with cyclosporine A caused a 12-fold higher (11)C-GR218231 uptake in the brain, indicating that the low cerebral tracer uptake was caused by the P-glycoprotein efflux pump in the blood-brain barrier. Cyclosporine A dose-escalation studies showed a dose-dependent sigmoidal increase in (11)C-GR218231 uptake in brain and spleen (median effective dose [ED(50)], 23.3 +/- 0.6 and 38.4 +/- 2.4 mg/kg, respectively), whereas a dose-dependent decrease was observed in the pancreas (ED(50), 36.0 +/- 4.4 mg/kg). CONCLUSION: Although (11)C-GR218231 is unsuited for dopamine D(3) receptor imaging with PET, it appears to be an attractive PET tracer for visualization and quantification of P-glycoprotein activity in the blood-brain barrier.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2005

The human norepinephrine transporter in combination with 11C-m-hydroxyephedrine as a reporter gene/reporter probe for PET of gene therapy.

UNLABELLED: Although the herpes simplex virus thymidine kinase gene has been frequently applied as a reporter gene for monitoring gene transfection in animals, it has some intrinsic limitations for use in humans. In our search for a reporter gene that lacks these limitations, we have evaluated the feasibility of the human norepinephrine transporter (hNET) as a reporter gene in combination with the reporter probe 11C-m-hydroxyephedrine (mHED) for PET. METHODS: An adenoviral vector (AdTrack-hNET) containing the hNET gene as reporter gene and the enhanced green fluorescent protein (EGFP) as a substitute for a therapeutic gene was constructed. After COS-7, A2780, and U373 cells were transiently transduced with AdTrack-hNET, hNET protein expression, EGFP fluorescence, and cellular uptake of 11C-mHED were determined. In rats, U373 tumor xenografts were grown and transiently transduced with either AdTrack-hNET or an AdTrack-Luc control adenovirus. Intratumoral accumulation of 11C-mHED was determined by PET and ex vivo biodistribution. The tumors were subsequently examined for EGFP fluorescence. RESULTS: 11C-mHED uptake was positively correlated with AdTrack-hNET viral titer and hNET protein expression. However, large differences in transfection efficiency between cell lines were observed. The highest 11C-mHED uptake was found in hNET transfected U373 cells, in which tracer uptake was >70-fold higher than that in control cells. 11C-mHED accumulation could be inhibited by desipramine, a potent inhibitor of hNET. In all cell lines, 11C-mHED uptake was positively correlated with EGFP fluorescence, implying that imaging of hNET with 11C-mHED would enable monitoring of a coexpressed therapeutic gene. In the animal model, gene transfection efficiencies were very low, as determined by EGFP fluorescence. Still, a significantly higher 11C-mHED uptake in hNET transduced tumors than that in control tumors was demonstrated by ex vivo biodistribution studies. PET with a clinical camera could visualize 1 of 3 hNET transduced tumors, indicating that the transfection efficiency was near the detection limit. CONCLUSION: These results indicate that monitoring of gene therapy using the hNET/11C-mHED reporter gene/probe is feasible, but further investigation with regard to the sensitivity of the technique is required.

Adenoviridae↗

PubMed2004

Myocardial beta-adrenoceptor downregulation in idiopathic dilated cardiomyopathy measured in vivo with PET using the new radioligand (S)-[11C]CGP12388.

PURPOSE: The beta-adrenoceptor (beta-AR) plays an important role in heart failure. Recently, the new tracer (S)-[11C]CGP12388 has been developed. It displays excellent properties for investigation of the cardiac beta-ARs in vivo with positron emission tomography (PET). Furthermore, the simple production method allows its use in a routine clinical setting. The aim of this study was to investigate whether decreased myocardial beta-AR density in patients with idiopathic dilated cardiomyopathy (IDC) can be estimated using (S)-[11C]CGP12388 PET. METHODS: Myocardial beta-AR density was investigated in six patients with IDC and six age-matched healthy controls, using (S)-[11C]CGP12388 PET. RESULTS: Beta-AR densities of 5.4+/-1.3 pmol/g (mean +/- SD) were observed in patients; these values were significantly lower than those observed in healthy controls (8.4+/-1.5 pmol/g, p<0.005). CONCLUSION: This study indicates that PET with (S)-[11C]CGP12388 is applicable for the measurement of myocardial beta-AR density in patients. A highly significant reduction in beta-AR density was found in patients with IDC compared with healthy controls.

Adult↗

PubMed2004

Receptor imaging in the thorax with PET.

This review focuses on positron emission tomography (PET)-imaging of receptors in the sympathetic and the parasympathetic systems of heart and lung and highlights the human applications of PET. For the alpha-adrenoceptor, only [11C]GB67 (N2-[6-[(4-amino-6,7-dimethoxy-2-quinazolinyl)(methyl)amino]hexyl]-N2-[11C]methyl-2-furamide hydrochloride) has been developed. Its potential for application in patients needs to be assessed. For both the beta-adrenergic and the muscarinic systems, potent PET radioligands have been prepared and evaluated in patients. It has been possible to measure receptor densities quantitatively in human heart [[11C]MQNB: [11C]methylquinuclidinyl benzilate, [11C]CGP12177: S-(3'-t-butylamino-2'-hydroxypropoxy)-benzimidazol-2-[11C]one and [11C]CGP12388: (S)-4-(3-(2'-[11C]isopropylamino)-2-hydroxypropoxy)-2H-benzimidazol-2-one] and qualitatively in lung [[11C]VC002: N-[11C]-methyl-piperidin-4-yl-2-cyclohexyl-2-hydroxy-2-phenylacetate and [11C]CGP12177]. Besides these subtype nonselective radioligands, the development of compounds that are selective for one subtype are ongoing and have not found successful application in humans yet.

Adrenergic alpha-Agonists↗

PubMed2004

In vivo imaging of hepatobiliary transport function mediated by multidrug resistance associated protein and P-glycoprotein.

Multidrug resistance associated proteins (MRPs) and P-glycoprotein (P-gp) are involved in hepatobiliary transport of various compounds. Our aim was (1) to define transporter specificity of the cholescintigraphic agents 99mTc-HIDA and 99mTc-MIBI, which are used clinically for myocardial perfusion measurements; and (2) to deduce MRP and P-gp functions in vivo from hepatic 99mTc kinetics. Accumulation of radioactivity was measured in the human tumor cell lines GLC4, GLC4/ADR150x (MRP1-overexpressing/P-gp-negative) and GLC4/P-gp (P-gp-overexpressing). Bile secretion was quantified in untreated and in glutathione-depleted control and MRP2-deficient (GY/TR-) rats. Hepatobiliary transport was measured using a gamma camera in both types of rats. 99mTc-HIDA accumulated 5.8-fold less in GLC4/ADR150x calls than in GLC4 or GLC4/P-gp cells. In GLC4/ADR150x, the cellular 99mTc-HIDA content was increased 3.4-fold by the MRP1,2 inhibitor MK571 (50 microM), while MK571 had no measurable effect in GLC4 and GLC4/P-gp cells. 99mTc-MIBI accumulated less in GLC4/P-gp and GLC4/ADR150x cells than in GLC4 cells. Bile secretion of 99mTc-HIDA was impaired in GY/TR- compared to control rats and not affected by glutathione depletion in GY/TR- rats. Hepatic secretion of 99mTc-HIDA was slower in GY/TR- (t1/2 40 min) than in control rats (t1/2 7 min). Bile secretion of 99mTc-MIBI was similar in both rat strains and impaired by glutathione depletion in control rats only, indicating compensatory activity of additional transporter(s) in GY/TR- rats. 99mTc-HIDA is transported only by MRP1,2 only, while 99mTc-MIBI is transported by P-gp and MRP1,2. The results indicate that hepatic P-gp and MRP1,2 function can be assessed in vivo by sequential use of both radiopharmaceuticals.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2004

Synthesis and evaluation of a fluorine-18 labeled antisense oligonucleotide as a potential PET tracer for iNOS mRNA expression.

Inducible NO synthase (iNOS) is overexpressed in inflammatory bowel diseases. An antisense oligonucleotide with good hybridization properties for iNOS mRNA was selected using RT-PCR. The oligonucleotide was reliably labeled with fluorine-18 using N-(4-[(18)F]fluorobenzyl)-2-bromoacetamide. Cellular uptake and efflux of oligonucleotide complexed with FuGENE-6 were rapid, unlike naked oligonucleotide, which hardly accumulated. However, neither uptake nor efflux showed any selectivity for iNOS expressing cells. The oligonucleotide showed a high level of non-specific binding, which may have obscured its specific hybridization to iNOS mRNA.

Cell Line, Tumor↗

PubMed2004

PET Studies on P-glycoprotein function in the blood-brain barrier: how it affects uptake and binding of drugs within the CNS.

Permeability of the blood-brain barrier (BBB) is one of the factors determining the bioavailability of therapeutic drugs. The BBB only allows entry of lipophilic compounds with low molecular weights by passive diffusion. However, many lipophilic drugs show negligible brain uptake. They are substrates for transporters such as P-glycoprotein (P-gp), multidrug-resistance associated protein (MRP) and organic anion transporting polypeptides (OATPs). The action of these carrier systems results in rapid efflux of xenobiotics from the central nervous system (CNS). Classification of candidate drugs as substrates or inhibitors of such carrier proteins is of crucial importance in drug development. Positron emission tomography (PET) can play an important role in the screening process by providing in vivo information, after the putative drug has passed in vitro tests. Although radiolabeled probes for MRP and OATP function are not yet available, many radiotracers have been prepared to study P-glycoprotein function in vivo with PET. These include alkaloids ((11)C-colchicine), antineoplastic agents ((11)C-daunorubicin, (18)F-paclitaxel), modulators of L-type calcium channels ((11)C-(+/-)verapamil, (11)C-R(+)-verapamil), beta-adrenoceptor antagonists ((11)C-(S)-carazolol, (18)F-(S)-1'-fluorocarazolol, (11)C-carvedilol), serotonin 5-HT(1A) receptor antagonists ((18)F-MPPF), opioid receptor antagonists ((11)C-loperamide, (11)C-carfentanyl), and various (64)Cu-labeled copper complexes. Studies in experimental animals have indicated that it is possible to assess P-glycoprotein function in the BBB and its effect on the uptake and binding of drugs within the intact CNS, using suitable P-gp modulators labeled with positron emitters. Provided that radiopharmaceuticals (and P-gp modulators) can be developed for human use, several exciting fields of study may be explored, viz. (i) direct evaluation of the effect of modulators on the cerebral uptake of therapeutic drugs; (ii) assessment of mechanisms underlying drug resistance in epilepsy; (iii) examination of the role of the BBB in the pathophysiology of neurodegenerative and affective disorders; and (iv) exploration of the relationship between polymorphisms of transporter genes and the pharmacokinetics of test compounds within the CNS.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2004

PET imaging of beta-adrenoceptors in human brain: a realistic goal or a mirage?

Beta-adrenoceptors are predominantly located in the cerebral cortex, nucleus accumbens and striatum. At lower densities, they are also present in amygdala, hippocampus and cerebellum. Beta-2 sites regulate glial proliferation during ontogenic development, after trauma and in neurodegenerative diseases. The densities of beta-1 adrenoceptors are changed by stress, in several mood disorders (depression, excessive hostility, schizophrenia) and during treatment of patients with antidepressants. A technique for beta-adrenoceptor imaging in the human brain is not yet available. Although 24 (ant)agonists have been labeled with either (11)C or (18)F and some of these are successful myocardial imaging agents, only two (S-1'-(18)F-fluorocarazolol and S-1'-(18)F-fluoroethylcarazolol) could actually visualize beta-adrenoceptors within the central nervous system. Unfortunately, these radiopharmaceuticals showed a positive Ames test. They may be mutagenic and cannot be employed for human studies. Screening of more than 150 beta-blockers described in the literature yields only two compounds (exaprolol and L643,717) which can still be radiolabeled and evaluated for beta-adenoceptor imaging. However, other imaging techniques could be examined. Cerebral beta-adrenoceptors might be labeled after temporary opening of the blood-brain barrier (BBB) and simultaneous administration of a hydrophilic ligand such as S-(11)C-CGP12388. Another approach to target beta-adrenoceptor ligands to the CNS is esterification of a myocardial imaging agent (such as (11)C-CGP12177), resulting in a lipophilic prodrug which can cross the BBB and is split by tissue esterases. BBB opening is not feasible in healthy subjects, but the prodrug approach may be successful and deserves to be explored.

Animals↗

PubMed2004

Comparison of gated PET with MRI for evaluation of left ventricular function in patients with coronary artery disease.

UNLABELLED: The aim of this study was to compare left ventricular (LV) volumes and regional wall motion determined by PET with those determined by the reference technique, cardiovascular MRI. METHODS: LV end-diastolic volume (LVEDV), LV end-systolic volume (LVESV), and LV ejection fraction (LVEF) were measured and regional wall motion was scored in 38 patients with chronic coronary artery disease by both gated (18)F-FDG PET and MRI. A 9-segment model was used for PET and MRI to assess regional wall motion. RESULTS: Good correlations were observed between MRI and gated PET for all parameters (r values ranging from 0.91 to 0.96). With PET, there was a significant but small underestimation of LVEDV and LVEF. Mean +/- SD LVEDV, LVESV, and LVEF for MRI were 131 +/- 57 mL, 91 +/- 12 mL, and 33% +/- 12%, respectively, and those for gated PET were 117 +/- 56 mL, 85 +/- 51 mL, and 30% +/- 11%, respectively. For regional wall motion, an agreement of 85% was found, with a kappa-statistic of 0.79 (95% confidence interval, 0.70-0.89; SE, 0.049). CONCLUSION: LV volumes, LVEF, and regional wall motion can be assessed with gated (18)F-FDG PET and correlate well with these parameters assessed by MRI.

Aged↗

PubMed2004

18F-FLT PET for visualization of laryngeal cancer: comparison with 18F-FDG PET.

UNLABELLED: The feasibility of (18)F-3'-fluoro-3'-deoxy-L-thymidine PET (FLT PET) for detecting laryngeal cancer was investigated and compared with (18)F-FDG PET. METHODS: Eleven patients diagnosed with or strongly suspected of having recurrent laryngeal cancer and 10 patients with histologically proven primary laryngeal cancer underwent attenuation-corrected (18)F-FLT PET imaging 60 min after injection of a median of 213 MBq (range, 175-400 MBq) (18)F-FLT and attenuation-corrected (18)F-FDG PET imaging 90 min after injection of a median of 340 MBq (range, 165-650 MBq) (18)F-FDG. All patients were staged by endoscopy and CT according to the Union Internationale Contre la Cancer TNM staging system. All patients underwent biopsy of the laryngeal area after imaging. Lesions seen on (18)F-FDG PET and (18)F-FLT PET were compared with histopathologic results. Mean SUVs, maximum SUVs, and tumor-to-nontumor (TNT) ratios were calculated for (18)F-FLT and (18)F-FDG. Wilcoxon nonparametric testing was used for comparison of (18)F-FDG with (18)F-FLT uptake. The Spearman correlation coefficient was used to correlate mean SUVs, maximum SUVs, and TNT ratios of (18)F-FDG PET and (18)F-FLT PET. Two-tailed P values < 0.05 were considered significant. RESULTS: (18)F-FDG PET and (18)F-FLT PET detected laryngeal cancer correctly in 15 of 17 patients. One lesion judged as positive on (18)F-FDG PET turned out to be normal tissue. Of 2 lesions judged as positive on (18)F-FLT PET, 1 turned out to be inflammation and the other to be normal tissue. Maximum SUVs were 3.3 (range, 1.9-8.5) for (18)F-FDG and 1.6 (range, 1.0-5.7) for (18)F-FLT (P < 0.001). Mean SUVs were 2.7 (range, 1.5-6.5) for (18)F-FDG and 1.2 (range, 0.8-3.8) for (18)F-FLT (P < 0.001). TNT was 1.9 (range, 1.3-4.7) for (18)F-FDG and 1.5 (range, 1.1-3.5) for (18)F-FLT (P < 0.05). CONCLUSION: The numbers of laryngeal cancers detected with (18)F-FLT PET and (18)F-FDG PET were equal. In laryngeal cancer, the uptake of (18)F-FDG is higher than that of (18)F-FLT.

Aged↗

PubMed2004

Selectivity of 18F-FLT and 18F-FDG for differentiating tumor from inflammation in a rodent model.

UNLABELLED: Increased glucose metabolism of inflammatory tissues is the main source of false-positive (18)F-FDG PET findings in oncology. It has been suggested that radiolabeled nucleosides might be more tumor specific. METHODS: To test this hypothesis, we compared the biodistribution of 3'-deoxy-3'-(18)F-fluorothymidine (FLT) and (18)F-FDG in Wistar rats that bore tumors (C6 rat glioma in the right shoulder) and also had sterile inflammation in the left calf muscle (induced by injection of 0.1 mL of turpentine). Twenty-four hours after turpentine injection, the rats received an intravenous bolus (30 MBq) of either (18)F-FLT (n = 5) or (18)F-FDG (n = 5). Pretreatment of the animals with thymidine phosphorylase (>1,000 U/kg, intravenously) before injection of (18)F-FLT proved to be necessary to reduce the serum levels of endogenous thymidine and achieve satisfactory tumor uptake of radioactivity. RESULTS: Tumor-to-muscle ratios of (18)F-FDG at 2 h after injection (13.2 +/- 3.0) were higher than those of (18)F-FLT (3.8 +/- 1.3). (18)F-FDG showed high physiologic uptake in brain and heart, whereas (18)F-FLT was avidly taken up by bone marrow. (18)F-FDG accumulated in the inflamed muscle, with 4.8 +/- 1.2 times higher uptake in the affected thigh than in the contralateral healthy thigh, in contrast to (18)F-FLT, for which this ratio was not significantly different from unity (1.3 +/- 0.4). CONCLUSION: In (18)F-FDG PET images, both tumor and inflammation were visible, but (18)F-FLT PET showed only the tumor. Thus, the hypothesis that (18)F-FLT has a higher tumor specificity was confirmed in our animal model.

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