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1.
Julia Müllauer Rudolf Karch Jens P. Bankstahl Marion Bankstahl Johann Stanek Thomas Wanek Severin Mairinger Markus Müller Wolfgang Löscher Oliver Langer Claudia Kuntner 《Nuclear medicine and biology》2013,40(6):755-763
IntroductionThe adenosine triphosphate-binding cassette (ABC) transporter P-glycoprotein (Pgp) protects the brain from accumulation of lipophilic compounds by active efflux transport across the blood–brain barrier. Changes in Pgp function/expression may occur in neurological disorders, such as epilepsy, Alzheimer’s or Parkinson’s disease. In this work we investigated the suitability of the radiolabeled Pgp inhibitors [11C]elacridar and [11C]tariquidar to visualize Pgp density in rat brain with PET.MethodsRats underwent a first PET scan with [11C]elacridar (n = 5) or [11C]tariquidar (n = 6) followed by a second scan with the Pgp substrate (R)-[11C]verapamil after administration of unlabeled tariquidar at a dose which half-maximally inhibits cerebral Pgp (3 mg/kg). Compartmental modeling using an arterial input function and Logan graphical analysis were used to estimate rate constants and volumes of distribution (VT) of radiotracers in different brain regions.ResultsBrain PET signals of [11C]elacridar and [11C]tariquidar were very low (~ 0.5 standardized uptake value, SUV). There was a significant negative correlation between VT and K1 (i.e. influx rate constant from plasma into brain) values of [11C]elacridar or [11C]tariquidar and VT and K1 values of (R)-[11C]verapamil in different brain regions which was consistent with binding of [11C]inhibitors to Pgp and efflux of (R)-[11C]verapamil by Pgp.ConclusionThe small Pgp binding signals obtained with [11C]elacridar and [11C]tariquidar limit the applicability of these tracers to measure cerebral Pgp density. PET tracers with higher (i.e. subnanomolar) binding affinities will be needed to visualize the low density of Pgp in brain. 相似文献
2.
Claudia Kuntner Jens P. Bankstahl Marion Bankstahl Johann Stanek Thomas Wanek Gloria Stundner Rudolf Karch Rebecca Brauner Martin Meier Xiaoqi Ding Markus Müller Wolfgang Löscher Oliver Langer 《European journal of nuclear medicine and molecular imaging》2010,37(5):942-953
Purpose
Overactivity of the multidrug efflux transporter P-glycoprotein (P-gp) at the blood-brain barrier (BBB) is believed to play an important role in resistance to central nervous system drug treatment. (R)-[11C]verapamil (VPM) PET can be used to measure the function of P-gp at the BBB, but low brain uptake of VPM hampers the mapping of regional differences in cerebral P-gp function and expression. The aim of this study was to evaluate the dose-response relationship of two potent P-gp inhibitors and to investigate if increased brain uptake of VPM mediated by P-gp inhibition can be used to assess regional differences in P-gp activity.Methods
Two groups of Sprague-Dawley rats (n?=?12) underwent single VPM PET scans at 120 min after administration of different doses of the P-gp inhibitors tariquidar and elacridar. In an additional six rats, paired VPM PET scans were performed before and after administration of 3 mg/kg tariquidar.Results
Inhibitor administration resulted in an up to 11-fold increase in VPM brain distribution volumes (DV) with half-maximum effective dose (ED50) values of 3.0?±?0.2 and 1.2?±?0.1 mg/kg for tariquidar and elacridar, respectively. In paired PET scans, 3 mg/kg tariquidar resulted in regionally different enhancement of brain activity distribution, with lowest DV in cerebellum and highest DV in thalamus.Conclusion
Our data show that tariquidar and elacridar are able to increase VPM brain distribution in rat brain up to 11-fold over baseline at maximum effective doses, with elacridar being about three times more potent than tariquidar. Regional differences in tariquidar-induced modulation of VPM brain uptake point to regional differences in cerebral P-gp function and expression in rat brain. 相似文献3.
Verbeek J Syvänen S Schuit RC Eriksson J de Lange EC Windhorst AD Luurtsema G Lammertsma AA 《Nuclear medicine and biology》2012,39(4):530-539
Objectives(R)-[11C]verapamil is widely used as a positron emission tomography (PET) tracer to evaluate P-glycoprotein (P-gp) functionality at the blood–brain barrier in man. A disadvantage of (R)-[11C]verapamil is the fact that its main metabolite, [11C]D617, also enters the brain. For quantitative analysis of (R)-[11C]verapamil data, it has been assumed that the cerebral kinetics of (R)-[11C]verapamil and [11C]D617 are the same. The aim of the present study was to investigate whether the cerebral kinetics of (R)-[11C]verapamil and [11C]D617 are indeed similar and, if so, whether [11C]D617 itself could serve as an alternative PET tracer for P-gp.Methods[11C]D617 was synthesized and its ex vivo biodistribution was investigated in male rats at four time points following intravenous administration of [11C]D617 (50 MBq) without (n=4) or with (n=4) pretreatment with the P-gp inhibitor tariquidar (15 mg·kg?1, intraperitoneally). Brain distribution was further assessed using consecutive PET scans (n=8) before and after pretreatment with tariquidar (15 mg·kg?1, intravenously), as well as metabolite analysis (n=4).ResultsThe precursor for the radiosynthesis of [11C]D617, 5-amino-2-(3,4-dimethoxy-phenyl)-2-isopropyl-pentanitrile (desmethyl D617), was synthesized in 41% overall yield. [11C]D617 was synthesized in 58%–77% decay-corrected yield with a radiochemical purity of ≥99%. The homogeneously distributed cerebral volume of distribution (VT) of [11C]D617 was 1.1, and this increased 2.4-fold after tariquidar pretreatment.ConclusionVT of [11C]D617 was comparable to that of (R)-[11C]verapamil, but its increase after tariquidar pretreatment was substantially lower. Hence, (R)-[11C]verapamil and [11C]D617 do not show similar brain kinetics after inhibition of P-gp with tariquidar. 相似文献
4.
Severin Mairinger Thomas Wanek Claudia Kuntner Yaprak Doenmez Sabine Strommer Johann Stanek Elena Capparelli Peter Chiba Markus Müller Nicola A. Colabufo Oliver Langer 《Nuclear medicine and biology》2012,39(8):1219-1225
ObjectivesWith the aim to develop a PET tracer to visualize P-glycoprotein (Pgp) expression levels in different organs, the Pgp inhibitor MC113 was labeled with 11C and evaluated using small-animal PET.Methods[11C]MC113 was synthesized by reaction of O-desmethyl MC113 with [11C]methyl triflate. Small-animal PET was performed with [11C]MC113 in FVB wild-type and Mdr1a/b(-/-) mice (n = 3 per group) and in a mouse model of high (EMT6Ar1.0) and low (EMT6) Pgp expressing tumor grafts (n = 5). In the tumor model, PET scans were performed before and after administration of the reference Pgp inhibitor tariquidar (15 mg/kg).ResultsBrain uptake of [11C]MC113, expressed as area under the time-activity curve from time 0 to 60 min (AUC0-60), was moderately but not significantly increased in Mdr1a/b(-/-) compared with wild-type mice (mean ± SD AUC0-60, Mdr1a/b(-/-): 88 ± 7 min, wild-type: 62 ± 6 min, P = 0.100, Mann Whitney test). In the tumor model, AUC0-60 values were not significantly different between EMT6Ar1.0 and EMT6 tumors. Neither in brain nor in tumors was activity concentration significantly changed in response to tariquidar administration. Half-maximum effect concentrations (IC50) for inhibition of Pgp-mediated rhodamine 123 efflux from CCRFvcr1000 cells were 375 ± 60 nM for MC113 versus 8.5 ± 2.5 nM for tariquidar.Conclusion[11C]MC113 showed higher brain uptake in mice than previously described Pgp PET tracers, suggesting that [11C]MC113 was only to a low extent effluxed by Pgp. However, [11C]MC113 was found unsuitable to visualize Pgp expression levels presumably due to insufficiently high Pgp binding affinity of MC113 in relation to Pgp densities in brain and tumors. 相似文献
5.
Timo Suotunen Jussi Hirvonen Pirjo Immonen-Räihä Sargo Aalto Irina Lisinen Eveliina Arponen Mika Teräs Kari Koski Raimo Sulkava Marko Seppänen Juha O. Rinne 《European journal of nuclear medicine and molecular imaging》2010,37(6):1141-1147
Purpose
The aim of this study was to evaluate the visual assessment of positron emission tomography images of N-[methyl-11C]2-(4′-methylaminophenyl)-6-hydroxybenzothiazole ([11C]PIB) in a patient population with mild to moderate memory impairment or dementia.Methods
We compared the visual ratings of two readers using kappa statistics and correlated the results of visual and quantitative region of interest (ROI) analyses. The one reader had good experience in evaluating PIB images and the other had little previous experience. The sensitivity and specificity of the visual assessment was determined using quantitative data from 18 healthy controls previously examined: [11C]PIB uptake was considered as abnormal if it was more than 2 SD above the mean of the healthy subjects.Results
The evaluation of visual classification as “normal” or “abnormal” showed good interobserver agreement (κ?=?0.90). There was a clear correlation between visual and quantitative analysis (r?=?0.47–0.79, p?<?0.001). The most difficult visually assessed brain area was the putamen (κ?=?0.11; correlation with quantitative analysis: reader A r?=?0.22; reader B r?=?0.60).Conclusion
Our study shows that visual evaluation of [11C]PIB images conforms with quantitative analyses also in a clinical patient population supporting the feasibility of visual evaluation in clinical settings. 相似文献6.
Michael D. Farwell Derek J. Chong Yasuhiko Iida Sung A. Bae Balu Easwaramoorthy Masanori Ichise 《Annals of nuclear medicine》2013,27(7):618-624
Objective
One mechanism that may be responsible for drug resistance in epilepsy is the upregulation of P-glycoprotein (P-gp), a drug efflux pump, at the epileptogenic focus. In this study, we sought to evaluate the potential of a recently developed P-gp PET radiotracer, [11C]N-desmethyl-loperamide ([11C]dLop), for measuring P-gp function in the rat brain.Methods
The precursor to [11C]dLop was synthesized in two steps from commercially available starting materials and subsequently radiolabeled in one step using [11C]methyl iodide. [11C]dLop was then administered to two groups of rats, controls (n = 4) and those treated with a P-gp inhibitor (n = 8). Cyclosporin A (CsA, 50 mg/kg, n = 3) and tariquidar (TQ, 20 mg/kg, n = 5) were both used as P-gp inhibitors. MicroPET brain scans were performed for 120 min with arterial blood sampling. A one-tissue compartment model was used to estimate the distribution volume of radiotracer as the outcome measure of P-gp function.Results
Plasma levels of parent [11C]dLop decreased rapidly to <0.1 mean standardized uptake value (SUV) at 60 min. In controls, brain uptake of [11C]dLop was very low (<0.1 mean SUV). In contrast, the mean SUVs were significantly higher in rats treated with CsA (0.51) or TQ (0.22). Estimation of distribution volumes was stable by 70 min. Estimated distribution volumes were significantly larger after P-gp inhibition (CsA = 7.3, TQ = 4.7) compared to controls (no inhibitor = 2.1).Conclusions
The rat brain demonstrates significantly increased uptake of [11C]dLop after P-gp inhibition. [11C]dLop is a substrate of P-gp, and will serve as a promising radiotracer for studying P-gp function in the future. 相似文献7.
Fumitoshi Kodaka Hiroshi Ito Yasuyuki Kimura Saori Fujie Harumasa Takano Hironobu Fujiwara Takeshi Sasaki Kazuhiko Nakayama Christer Halldin Lars Farde Tetsuya Suhara 《European journal of nuclear medicine and molecular imaging》2013,40(4):574-579
Purpose
Dopamine D2/3 receptors (D2/3Rs) have two affinity states for endogenous dopamine, referred to as high-affinity state (D2/3 HIGH), which has a high affinity for endogenous dopamine, and low-affinity state (D2/3 LOW). The density of D2/3 HIGH can be measured with (R)-2-11CH3O-N-n-propylnorapomorphine ([11C]MNPA), while total density of D2/3 HIGH and D2/3 LOW (D2/3Rs) can be measured with [11C]raclopride using positron emission tomography (PET). Thus, the ratio of the binding potential (BP) of [11C]MNPA to that of [11C]raclopride ([11C]MNPA/[11C]raclopride) may reflect the proportion of the density of D2/3 HIGH to that of D2/3Rs. In the caudate and putamen, [11C]MNPA/[11C]raclopride reflects the proportion of the density of D2 HIGH to that of D2Rs. To evaluate the reliability of the PET paradigm with [11C]MNPA and [11C]raclopride, we investigated the test-retest reproducibility of non-displaceable BP (BP ND) measured with [11C]MNPA and of [11C]MNPA/[11C]raclopride in healthy humans.Methods
Eleven healthy male volunteers underwent two sets of PET studies on separate days that each included [11C]MNPA and [11C]raclopride scans. BP ND values in the caudate and putamen were calculated. Test-retest reproducibility of BP ND of [11C]MNPA and [11C]MNPA/[11C]raclopride was assessed by intra-subject variability (absolute variability) and test-retest reliability (intraclass correlation coefficient: ICC).Results
The absolute variability of [11C]MNPA BP ND was 5.30?±?3.96 % and 12.3?±?7.95 % and the ICC values of [11C]MNPA BP ND were 0.72 and 0.82 in the caudate and putamen, respectively. The absolute variability of [11C]MNPA/[11C]raclopride was 6.11?±?3.68 % and 11.60?±?5.70 % and the ICC values of [11C]MNPA/[11C]raclopride were 0.79 and 0.80 in the caudate and putamen, respectively.Conclusion
In the present preliminary study, the test-retest reproducibility of BP ND of [11C]MNPA and of [11C]MNPA/[11C]raclopride was reliable in the caudate and putamen. 相似文献8.
Bent W. Schoultz Trine Hjornevik Frode Willoch János Marton Akihiro Noda Yoshihiro Murakami Sosuke Miyoshi Shintaro Nishimura Erik Årstad Alexander Drzezga Ichiro Matsunari Gjermund Henriksen 《European journal of nuclear medicine and molecular imaging》2010,37(6):1174-1180
Purpose
The recent development in radiosynthesis of the 11C-carbamate function increases the potential of [11C]GR103545, which for the last decade has been regarded as promising for imaging the kappa-opioid receptor (κ-OR) with PET. In the present study, [11C]GR103545 was evaluated in awake rhesus macaques. Separate investigations were performed to clarify the OR subtype selectivity of this compound.Methods
Regional brain uptake kinetics of [11C]GR103545 was studied 0–120 min after injection. The binding affinity and opioid subtype selectivity of [11C]GR103545 was determined in cells transfected with cloned human opioid receptors.Results
In vitro binding assays demonstrated a high affinity of GR103545 for κ-OR (Ki?=?0.02?±?0.01 nM) with excellent selectivity over μ-OR (6?×?102-fold) and) δ-OR (2?×?104-fold). PET imaging revealed a volume of distribution (VT) pattern consistent with the known distribution of κ-OR, with striatum = temporal cortex > cingulate cortex > frontal cortex > parietal cortex > thalamus > cerebellum.Conclusion
[11C]GR103545 is selective for κ-OR and holds promise for use to selectively depict and quantify this receptor in humans by means of PET. 相似文献9.
Comparison of integrated whole-body [11C]choline PET/MR with PET/CT in patients with prostate cancer
Michael Souvatzoglou Matthias Eiber Toshiki Takei Sebastian Fürst Tobias Maurer Florian Gaertner Hans Geinitz Alexander Drzezga Sibylle Ziegler Stephan G. Nekolla Ernst J. Rummeny Markus Schwaiger Ambros J. Beer 《European journal of nuclear medicine and molecular imaging》2013,40(10):1486-1499
Purpose
To evaluate the performance of conventional [11C]choline PET/CT in comparison to that of simultaneous whole-body PET/MR.Methods
The study population comprised 32 patients with prostate cancer who underwent a single-injection dual-imaging protocol with PET/CT and subsequent PET/MR. PET/CT scans were performed applying standard clinical protocols (5 min after injection of 793?±?69 MBq [11C]choline, 3 min per bed position, intravenous contrast agent). Subsequently (52?±?15 min after injection) PET/MR was performed (4 min per bed position). PET images were reconstructed iteratively (OSEM 3D), scatter and attenuation correction of emission data and regional allocation of [11C]choline foci were performed using CT data for PET/CT and segmented Dixon MR, T1 and T2 sequences for PET/MR. Image quality of the respective PET scans and PET alignment with the respective morphological imaging modality were compared using a four point scale (0–3). Furthermore, number, location and conspicuity of the detected lesions were evaluated. SUVs for suspicious lesions, lung, liver, spleen, vertebral bone and muscle were compared.Results
Overall 80 lesions were scored visually in 29 of the 32 patients. There was no significant difference between the two PET scans concerning number or conspicuity of the detected lesions (p not significant). PET/MR with T1 and T2 sequences performed better than PET/CT in anatomical allocation of lesions (2.87?±?0.3 vs. 2.72?±?0.5; p?=?0.005). The quality of PET/CT images (2.97?±?0.2) was better than that of the respective PET scan of the PET/MR (2.69?±?0.5; p?=?0.007). Overall the maximum and mean lesional SUVs exhibited high correlations between PET/CT and PET/MR (ρ?=?0.87 and ρ?=?0.86, respectively; both p?<?0.001).Conclusion
Despite a substantially later imaging time-point, the performance of simultaneous PET/MR was comparable to that of PET/CT in detecting lesions with increased [11C]choline uptake in patients with prostate cancer. Anatomical allocation of lesions was better with simultaneous PET/MR than with PET/CT, especially in the bone and pelvis. These promising findings suggest that [11C]choline PET/MR might have a diagnostic benefit compared to PET/CT in patients with prostate cancer, and now needs to be further evaluated in prospective trials. 相似文献10.
Zhangjie Su Karl Herholz Alexander Gerhard Federico Roncaroli Daniel Du Plessis Alan Jackson Federico Turkheimer Rainer Hinz 《European journal of nuclear medicine and molecular imaging》2013,40(9):1406-1419
Purpose
Translocator protein (TSPO) is a biomarker of neuroinflammation that can be imaged by PET using [11C]-(R)PK11195. We sought to characterize the [11C]-(R)PK11195 kinetics in gliomas of different histotypes and grades, and to compare two reference tissue input functions (supervised cluster analysis versus cerebellar grey matter) for the estimation of [11C]-(R)PK11195 binding in gliomas and surrounding brain structures.Methods
Twenty-three glioma patients and ten age-matched controls underwent structural MRI and dynamic [11C]-(R)PK11195 PET scans. Tissue time–activity curves (TACs) were extracted from tumour regions as well as grey matter (GM) and white matter (WM) of the brains. Parametric maps of binding potential (BPND) were generated with the simplified reference tissue model using the two input functions, and were compared with each other. TSPO expression was assessed in tumour tissue sections by immunohistochemistry.Results
Three types of regional kinetics were observed in individual tumour TACs: GM-like kinetics (n?=?6, clearance of the tracer similar to that in cerebellar GM), WM-like kinetics (n?=?8, clearance of the tracer similar to that in cerebral WM) and a form of mixed kinetics (n?=?9, intermediate rate of clearance). Such kinetic patterns differed between low-grade astrocytomas (WM-like kinetics) and oligodendrogliomas (GM-like and mixed kinetics), but were independent of tumour grade. There was good agreement between parametric maps of BPND derived from the two input functions in all controls and 10 of 23 glioma patients. In 13 of the 23 patients, BPND values derived from the supervised cluster input were systematically smaller than those using the cerebellar input. Immunohistochemistry confirmed that TSPO expression increased with tumour grade.Conclusion
The three types of [11C]-(R)PK11195 kinetics in gliomas are determined in part by tracer delivery, and indicated that kinetic analysis is a valuable tool in the study of gliomas with the potential for in vivo discrimination between low-grade astrocytomas and oligodendrogliomas. Supervised cluster and cerebellar input functions produced consistent BPND estimates in approximately half of the gliomas investigated, but had a systematic difference in the remainder. The cerebellar input is preferred based on theoretical and practical considerations. 相似文献11.
Synthesis and evaluation of [11C]XR9576 to assess the function of drug efflux transporters using PET
Kazunori Kawamura Fujiko Konno Joji Yui Tomoteru Yamasaki Akiko Hatori Kazuhiko Yanamoto Hidekatsu Wakizaka Makoto Takei Nobuki Nengaki Toshimitsu Fukumura Ming-Rong Zhang 《Annals of nuclear medicine》2010,24(5):403-412
Objective
XR9576 (tariquidar) is an anthranilic acid derivative and potent P-glycoprotein (P-gp) inhibitor. XR9576 has undergone phase I and II studies as combined chemotherapy against cancer. XR9576 has been developed as a useful therapeutic agent but not as a PET probe. We therefore developed [11C]XR9576 as a PET probe and assessed whether PET studies using [11C]XR9576 are a promising approach to assess P-gp function primarily.Methods
We synthesized [11C]XR9576 by methylation of 7-O-desmethyl XR9576 with [11C]methyl iodide. In in vivo tissue distribution, the effects of co-injection with XR9576 on the uptake of [11C]XR9576 in mice were investigated. PET studies using [11C]XR9576 were performed in P-gp and/or Bcrp knockout mice as well as in wild-type mice. Metabolites of [11C]XR9576 were measured in the brain and plasma of mice.Results
[11C]XR9576 was successfully synthesized with suitable radioactivity for injection as well as appropriate radiochemical purity and stability. In in vivo tissue distribution, the brain uptake of [11C]XR9576 significantly increased about tenfold of control on co-injection with >10 mg/kg of XR9576. In PET studies, the AUCbrain [0–60 min] in P-gp and P-gp/Bcrp knockout mice was 2- and 11-fold higher than that in wild-type mice. [11C]XR9576 showed a high metabolic stability (>90% unchanged form) in the brain and plasma of mice 30 min after injection. These results suggest that a tracer amount of [11C]XR9576 behave as the P-gp and Bcrp substrate, and the increased brain uptake or AUCbrain of [11C]XR9576 correlates with P-gp and Bcrp functions.Conclusions
PET studies using [11C]XR9576 may be a promising approach for evaluating deficiency of the function of drug efflux transporters targeting intracranial diseases and tumors. 相似文献12.
Daniele de Paula Faria Sjef Copray Jurgen W. A. Sijbesma Antoon T. M. Willemsen Carlos A. Buchpiguel Rudi A. J. O. Dierckx Erik F. J. de Vries 《European journal of nuclear medicine and molecular imaging》2014,41(5):995-1003
Purpose
In this study, we compared the ability of [11C]CIC, [11C]MeDAS and [11C]PIB to reveal temporal changes in myelin content in focal lesions in the lysolecithin rat model of multiple sclerosis. Pharmacokinetic modelling was performed to determine the best method to quantify tracer uptake.Methods
Sprague-Dawley rats were stereotactically injected with either 1 % lysolecithin or saline into the corpus callosum and striatum of the right brain hemisphere. Dynamic PET imaging with simultaneous arterial blood sampling was performed 7 days after saline injection (control group), 7 days after lysolecithin injection (demyelination group) and 4 weeks after lysolecithin injection (remyelination group).Results
The kinetics of [11C]CIC, [11C]MeDAS and [11C]PIB was best fitted by Logan graphical analysis, suggesting that tracer binding is reversible. Compartment modelling revealed that all tracers were fitted best with the reversible two-tissue compartment model. Tracer uptake and distribution volume in lesions were in agreement with myelin status. However, the slow kinetics and homogeneous brain uptake of [11C]CIC make this tracer less suitable for in vivo PET imaging. [11C]PIB showed good uptake in the white matter in the cerebrum, but [11C]PIB uptake in the cerebellum was low, despite high myelin density in this region. [11C]MeDAS distribution correlated well with myelin density in different brain regions.Conclusion
This study showed that PET imaging of demyelination and remyelination processes in focal lesions is feasible. Our comparison of three myelin tracers showed that [11C]MeDAS has more favourable properties for quantitative PET imaging of demyelinated and remyelinated lesions throughout the CNS than [11C]CIC and [11C]PIB. 相似文献13.
Fabrice G. Siméon Jeih-San Liow Yi Zhang Jinsoo Hong Robert L. Gladding Sami S. Zoghbi Robert B. Innis Victor W. Pike 《European journal of nuclear medicine and molecular imaging》2012,39(12):1949-1958
Purpose
[18F]SP203 (3-fluoro-5-(2-(2-([18F]fluoromethyl)-thiazol-4-yl)ethynyl)benzonitrile) is an effective high-affinity and selective radioligand for imaging metabotropic 5 receptors (mGluR5) in human brain with PET. To provide a radioligand that may be used for more than one scanning session in the same subject in a single day, we set out to label SP203 with shorter-lived 11C (t 1/2?=?20.4?min) and to characterize its behavior as a radioligand with PET in the monkey.Methods
Iodo and bromo precursors were obtained by cross-coupling 2-fluoromethyl-4-((trimethylsilyl)ethynyl)-1,3-thiazole with 3,5-diiodofluorobenzene and 3,5-dibromofluorobenzene, respectively. Treatment of either precursor with [11C]cyanide ion rapidly gave [11C]SP203, which was purified with high-performance liquid chromatography. PET was used to measure the uptake of radioactivity in brain regions after injecting [11C]SP203 intravenously into rhesus monkeys at baseline and under conditions in which mGluR5 were blocked with 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine (MTEP). The emergence of radiometabolites in monkey blood in vitro and in vivo was assessed with radio-HPLC. The stability of [11C]SP203 in human blood in vitro was also measured.Results
The iodo precursor gave [11C]SP203 in higher radiochemical yield (>98?%) than the bromo precursor (20–52?%). After intravenous administration of [11C]SP203 into three rhesus monkeys, radioactivity peaked early in brain (average 12.5?min) with a regional distribution in rank order of expected mGluR5 density. Peak uptake was followed by a steady decline. No radioactivity accumulated in the skull. In monkeys pretreated with MTEP before [11C]SP203 administration, radioactivity uptake in brain was again high but then declined more rapidly than in the baseline scan to a common low level. [11C]SP203 was unstable in monkey blood in vitro and in vivo, and gave predominantly less lipophilic radiometabolites. By contrast, [11C]SP203 was stable in human blood in vitro.Conclusion
[11C]SP203 emulates [18F]SP203 with regard to providing a sizeable mGluR5-specific signal in monkey brain, and advantageously avoids troublesome accumulation of radioactivity in bone. Although [11C]SP203 is unsuitable for mGluR5 quantification in monkey brain, its evaluation as a PET radioligand for studying human brain mGluR5 is nevertheless warranted. 相似文献14.
Stina Syvänen Vera Russmann Joost Verbeek Jonas Eriksson Maaike Labots Christina Zellinger Natalie Seeger Robert Schuit Marissa Rongen Rolph van Kooij Albert D. Windhorst Adriaan A. Lammertsma Elizabeth C. de Lange Rob A. Voskuyl Matthias Koepp Heidrun Potschka 《Nuclear medicine and biology》2013,40(6):764-775
IntroductionTo analyse the impact of both epilepsy and pharmacological modulation of P-glycoprotein on brain uptake and kinetics of positron emission tomography (PET) radiotracers [11C]quinidine and [11C]laniquidar.MethodsMetabolism and brain kinetics of both [11C]quinidine and [11C]laniquidar were assessed in naive rats, electrode-implanted control rats, and rats with spontaneous recurrent seizures. The latter group was further classified according to their response to the antiepileptic drug phenobarbital into “responders” and “non-responders”. Additional experiments were performed following pre-treatment with the P-glycoprotein modulator tariquidar.Results[11C]quinidine was metabolized rapidly, whereas [11C]laniquidar was more stable. Brain concentrations of both radiotracers remained at relatively low levels at baseline conditions. Tariquidar pre-treatment resulted in significant increases of [11C]quinidine and [11C]laniquidar brain concentrations. In the epileptic subgroup “non-responders”, brain uptake of [11C]quinidine in selected brain regions reached higher levels than in electrode-implanted control rats. However, the relative response to tariquidar did not differ between groups with full blockade of P-glycoprotein by 15 mg/kg of tariquidar. For [11C]laniquidar differences between epileptic and control animals were only evident at baseline conditions but not after tariquidar pretreatment.ConclusionsWe confirmed that both [11C]quinidine and [11C]laniquidar are P-glycoprotein substrates. At full P-gp blockade, tariquidar pre-treatment only demonstrated slight differences for [11C]quinidine between drug-resistant and drug-sensitive animals. 相似文献
15.
Emanuel?Steiner Lukas?Kazianka Robert?Breuer Marcus?Hacker Wolfgang?Wadsak Markus?Mitterhauser Thomas?Stimpfl Birgit?Reiter Georgios?Karanikas
Purpose
[S-methyl-11C]-L-methionine ([11C]MET) uptake in the pancreas might be a central indicator of beta cell function. Since gastric emptying was recently shown to influence glycemic control in subjects after pancreaticoduodenectomy (PD, the surgical treatment of neoplasms of the pancreas head), we looked for imaginable relationships between gastric emptying, pre- and postprandial insulin concentrations, and [11C]MET uptake.Methods
Nineteen tumor-free survivors after PD (age mean?±?SD: 61?±?8.7 yrs.; 10 male, 9 female) and 10 healthy controls (age: 27?±?8.7 yrs.; 7 male, 3 female) were given a mixed test meal. One gram of paracetamol was ingested with the meal to evaluate the speed of gastric emptying. Insulin, glucose, and paracetamol plasma concentrations were measured before and over 180 minutes after ingestion. Beta cell function was calculated from fasting glucose and insulin plasma concentrations. Simultaneously, 800 MBq of [11C]MET were administered and the activity (maximum tissue standardized uptake values [SUVmax]) over the pancreas was measured at 15, 30, and 60 minutes after injection. Total integrated SUVmax (area under the curve [AUC]) and incremental SUVmax were calculated.Results
The uptake of [11C]MET in the pancreas was significantly higher (p?<?0.0001) in controls compared to the PD group. Gastric emptying was significantly slower in controls compared to pancreatectomy subjects (p?<?0.0001). Paracetamol AUC30 correlated with the SUVmax increment between 15 and 30 minutes (R2?=?0.27,Conclusion
Postprandial [11C]MET uptake may represent basal and postprandial beta cell function. The findings suggest a possible usefulness of this imaging procedure for further studying beta cell function.16.
Bernd J. Krause Michael Souvatzoglou Ken Herrmann Axel W. Weber Tibor Schuster Andreas K. Buck Roman Nawroth Gregor Weirich Uwe Treiber Hans-Jürgen Wester Sibylle I. Ziegler Reingard Senekowitsch-Schmidtke Markus Schwaiger 《European journal of nuclear medicine and molecular imaging》2010,37(10):1861-1868
Purpose
[11C]Choline has been established as a PET tracer for imaging prostate cancer. The aim of this study was to determine whether [11C]choline can be used for monitoring the effects of therapy in a prostate cancer mouse xenograft model.Methods
The androgen-independent human prostate cancer cell line PC-3 was implanted subcutaneously into the flanks of 13 NMRI (nu/nu) mice. All mice were injected 4–6 weeks after xenograft implantation with 37 MBq [11C]choline via a tail vein. Dynamic imaging was performed for 60 min with a small-animal PET/CT scanner (Siemens Medical Solutions). Six mice were subsequently injected intravenously with docetaxel twice (days 1 and 5) at a dose of 3 mg/kg body weight. Seven mice were treated with PBS as a control. [11C]Choline imaging was performed prior to and 1, 2 and 3 weeks after treatment. To determine choline uptake the images were analysed in terms of tumour-to-muscle (T/M) ratios. Every week the size of the implanted tumour was determined with a sliding calliper.Results
The PC-3 tumours could be visualized by [11C]choline PET. Before treatment the T/Mmean ratio was 1.6±0.5 in the control group and 1.8±0.4 in the docetaxel-treated group (p=0.65). There was a reduction in the mean [11C]choline uptake after docetaxel treatment as early as 1 week after initiation of therapy (T/M ratio 1.8±0.4 before treatment, 0.9±0.3 after 1 week, 1.1±0.3 after 2 weeks and 0.8±0.2 after 3 weeks). There were no decrease in [11C]choline uptake in the control group following treatment (T/M ratio 1.6±0.5 before treatment, 1.7±0.4 after 1 week, 1.8±0.7 after 2 weeks and 1.7±0.4 after 3 weeks). For analysis of the dynamic data, a generalized estimation equation model revealed a significant decrease in the T/Mdyn ratios 1 week after docetaxel treatment, and the ratio remained at that level through week 3 (mean change ?0.93±0.24, p<0.001, after 1 week; ?0.78±0.21, p<0.001, after 2 weeks; ?1.08±0.26, p<0.001, after 3 weeks). In the control group there was no significant decrease in the T/Mdyn ratios (mean change 0.085±0.39, p=0.83, after 1 week; 0.31±0.48, p=0.52, after 2 weeks; 0.11±0.30, p=0.72, after 3 weeks). Metabolic changes occurred 1 week after therapy and preceded morphological changes of tumour size during therapy.Conclusion
Our results demonstrate that [11C]choline has the potential for use in the early monitoring of the therapeutic effect of docetaxel in a prostate cancer xenograft animal model. The results also indicate that PET with radioactively labelled choline derivatives might be a useful tool for monitoring responses to taxane-based chemotherapy in patients with advanced prostate cancer. 相似文献17.
A. Brück J. R. Virta J. Koivunen J. Koikkalainen N. M. Scheinin H. Helenius K. Någren S. Helin R. Parkkola M. Viitanen J. O. Rinne 《European journal of nuclear medicine and molecular imaging》2013,40(10):1567-1572
Purpose
Cortical glucose metabolism, brain amyloid β accumulation and hippocampal atrophy imaging have all been suggested as potential biomarkers in predicting which patients with mild cognitive impairment (MCI) will convert to Alzheimer’s disease (AD). The aim of this study was to compare the prognostic ability of [11C]PIB PET, [18F]FDG PET and quantitative hippocampal volumes measured with MR imaging in predicting conversion to AD in patients with MCI.Methods
The study group comprised 29 patients with MCI who underwent [11C]PIB PET and MR imaging. Of these, 22 also underwent [18F]FDG PET. All subjects were invited back for clinical evaluation after 2 years.Results
During the follow-up time 17 patients had converted to AD while 12 continued to meet the criteria for MCI. The two groups did not differ in age, gender or education level, but the converter group tended to have lower MMSE and Word List learning than the nonconverter group. High [11C]PIB retention in the frontotemporal regions and anterior and posterior cingulate (p?<?0.05) predicted conversion to AD. Also reduced [18F]FDG uptake in the left lateral temporal cortex (LTC) predicted conversion (p?<?0.05), but quantitative hippocampal volumes did not (p?>?0.1). In receiver operating characteristic (ROC) analysis the measurements that best predicted the conversion were [11C]PIB retention in the lateral frontal cortex and [18F]FDG uptake in the left LTC. Both PET methods resulted in good sensitivity and specificity and neither was significantly superior to the other.Conclusion
The findings indicate that [11C]PIB and [18F]FDG are superior to hippocampal volumes in predicting conversion to AD in patients with MCI. 相似文献18.
Abrahim A Luurtsema G Bauer M Karch R Lubberink M Pataraia E Joukhadar C Kletter K Lammertsma AA Baumgartner C Müller M Langer O 《European journal of nuclear medicine and molecular imaging》2008,35(1):116-123
Purpose (R)-[11C]verapamil is a new PET tracer for P-glycoprotein-mediated transport at the blood-brain barrier. For kinetic analysis of
(R)-[11C]verapamil PET data the measurement of a metabolite-corrected arterial input function is required. The aim of this study
was to assess peripheral (R)-[11C]verapamil metabolism in patients with temporal lobe epilepsy and compare these data with previously reported data from healthy
volunteers.
Methods Arterial blood samples were collected from eight patients undergoing (R)-[11C]verapamil PET and selected samples were analysed for radiolabelled metabolites of (R)-[11C]verapamil by using an assay that measures polar N-demethylation metabolites by solid-phase extraction and lipophilic N-dealkylation metabolites by HPLC.
Results Peripheral metabolism of (R)-[11C]verapamil was significantly faster in patients compared to healthy volunteers (AUC of (R)-[11C]verapamil fraction in plasma: 29.4 ± 3.9 min for patients versus 40.8 ± 5.0 min for healthy volunteers; p < 0.0005, Student’s t-test), which resulted in lower (R)-[11C]verapamil plasma concentrations (AUC of (R)-[11C]verapamil concentration, normalised to injected dose per body weight: 25.5 ± 2.1 min for patients and 30.5 ± 5.9 min for
healthy volunteers; p = 0.038). Faster metabolism appeared to be mainly due to increased N-demethylation as the polar [11C]metabolite fraction was up to two-fold greater in patients.
Conclusions Faster metabolism of (R)-[11C]verapamil in epilepsy patients may be caused by hepatic cytochrome P450 enzyme induction by antiepileptic drugs. Based on
these data caution is warranted when using an averaged arterial input function derived from healthy volunteers for the analysis
of patient data. Moreover, our data illustrate how antiepileptic drugs may decrease serum levels of concomitant medication,
which may eventually lead to a loss of therapeutic efficacy. 相似文献
19.
Geeraerts T Coles JP Aigbirhio FI Pickard JD Menon DK Fryer TD Hong YT 《Annals of nuclear medicine》2011,25(6):396-405
Objective
[11C]Flumazenil ([11C]FMZ) positron emission tomography (PET) can be used as a measure of neuronal loss. The purpose of this study was to validate reference tissue kinetic modelling of [11C]FMZ PET within a group of patients with head injury.Methods
Following earlier studies, the pons was used as the reference region. PET scans were performed on 16 controls and 11 patients at least 6 months following injury, each of whom also had arterial blood sampling to provide whole blood and metabolite-corrected plasma input functions. Regional non-displaceable binding potentials (BPND) were calculated from five reference tissue models and compared to BPND from arterial input models. For the patients, the regions included a peri-lesional region of interest (ROI).Results
Total distribution volume of the pons was not significantly different between control and patient groups (P = 0.24). BPND from all the reference tissue approaches correlated well with BPND from the plasma input models for both controls (r 2 = 0.98–1.00; P < 0.001) and patients (r 2 = 0.99–1.00; P < 0.001). For the peri-lesional regions (n = 11 ROI values), the correlation was also high (r 2 = 0.91).Conclusions
These results indicate that reference tissue modelling with the pons as the reference region is valid for [11C]FMZ PET in head-injured patients at 6 months following injury within both normal appearing and peri-lesional brain regions. 相似文献20.
Nadja Van Camp Raphael Boisgard Bertrand Kuhnast Benoit Thézé Thomas Viel Marie-Claude Grégoire Fabien Chauveau Hervé Boutin Andrew Katsifis Frédéric Dollé Bertrand Tavitian 《European journal of nuclear medicine and molecular imaging》2010,37(5):962-972