| 1. |
- Lubberink, Mark, et al.
(författare)
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Validity of Simplified 3′-Deoxy-3′-[18F]Fluorothymidine Uptake Measures for Monitoring Response to Chemotherapy in Locally Advanced Breast Cancer
- 2012
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Ingår i: Molecular Imaging and Biology. - : Springer Science and Business Media LLC. - 1536-1632 .- 1860-2002. ; 14:6, s. 777-782
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Tidskriftsartikel (refereegranskat)abstract
- Purpose:Positron emission tomography using 3′-deoxy-3′-[18F]fluorothymidine ([18F]FLT) has been suggested as a means for monitoring response to chemotherapy. The aim of this study was to evaluate the validity of simplified uptake measures for assessing response to chemotherapy using [18F]FLT in locally advanced breast cancer (LABC).Procedures:Fifteen LABC patients underwent dynamic [18F]FLT scans both prior to and after the first cycle of chemotherapy with fluorouracil, epirubicin or doxorubicin, and cyclophosphamide. The net uptake rate constant of [18F]FLT, K i , determined by non-linear regression (NLR) of an irreversible two-tissue compartment model was used as the gold standard. In addition to Patlak graphical analysis, standardised uptake values (SUV) and tumour-to-whole blood ratio (TBR) were used for analysing [18F]FLT data. Correlations and relationships between simplified uptake measures and NLR before and after chemotherapy were assessed using regression analysis.Results: No significant differences in both pre- and post-chemotherapy relationships between any of the simplified uptake measures and NLR were found. However, changes in SUV between baseline and post-therapy scans showed a significant negative bias and slope less than one, while TBR did not.Conclusions:In LABC, TBR instead of SUV may be preferred for monitoring response to chemotherapy with [18F]FLT.
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| 2. |
- Syvänen, Stina, et al.
(författare)
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(R)-[11C]verapamil PET studies to assess changes in P-glycoprotein expression and functionality in rat blood-brain barrier after exposure to kainate-induced status epilepticus.
- 2011
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Ingår i: BMC medical imaging. - : Springer Science and Business Media LLC. - 1471-2342. ; 11, s. 1-
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Increased functionality of efflux transporters at the blood-brain barrier may contribute to decreased drug concentrations at the target site in CNS diseases like epilepsy. In the rat, pharmacoresistant epilepsy can be mimicked by inducing status epilepticus by intraperitoneal injection of kainate, which leads to development of spontaneous seizures after 3 weeks to 3 months. The aim of this study was to investigate potential changes in P-glycoprotein (P-gp) expression and functionality at an early stage after induction of status epilepticus by kainate.METHODS: (R)-[11C]verapamil, which is currently the most frequently used positron emission tomography (PET) ligand for determining P-gp functionality at the blood-brain barrier, was used in kainate and saline (control) treated rats, at 7 days after treatment. To investigate the effect of P-gp on (R)-[11C]verapamil brain distribution, both groups were studied without or with co-administration of the P-gp inhibitor tariquidar. P-gp expression was determined using immunohistochemistry in post mortem brains. (R)-[11C]verapamil kinetics were analyzed with approaches common in PET research (Logan analysis, and compartmental modelling of individual profiles) as well as by population mixed effects modelling (NONMEM).RESULTS: All data analysis approaches indicated only modest differences in brain distribution of (R)-[11C]verapamil between saline and kainate treated rats, while tariquidar treatment in both groups resulted in a more than 10-fold increase. NONMEM provided most precise parameter estimates. P-gp expression was found to be similar for kainate and saline treated rats.CONCLUSIONS: P-gp expression and functionality does not seem to change at early stage after induction of anticipated pharmacoresistant epilepsy by kainate.
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| 3. |
- Syvänen, Stina, et al.
(författare)
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Simultaneous in vivo measurements of receptor density and affinity using [11C]flumazenil and positron emission tomography : comparison of full saturation and steady state methods.
- 2011
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Ingår i: NeuroImage. - : Elsevier BV. - 1053-8119 .- 1095-9572. ; 57:3, s. 928-37
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Tidskriftsartikel (refereegranskat)abstract
- The binding of PET radiotracer [(11)C]flumazenil to the GABA(A) receptors is described by the receptor density (B(max)) and binding affinity (K(D)). The estimation of B(max) and K(D) is usually based on Scatchard analysis including at least two PET scans at steady state of various specific activities. Recently, a novel full saturation method to estimate both B(max) and K(D) was proposed, in which a saturating dose of flumazenil is given to cover a wide range of different receptor occupancies within a single scan. The aim of the present study was a direct comparison of steady state and full saturation methods for determining B(max) and K(D) of [(11)C]flumazenil in the same group of male Sprague-Dawley rats. Fourteen rats underwent 3 consecutive [(11)C]flumazenil scans of 30 min duration each. A tracer dose was injected at the start of the first scan. Prior to the second scan the tracer was mixed with 5, 20, 100 or 500 μg unlabelled (cold) flumazenil to cover a wide range of receptor occupancies during the scan. The third scan was performed during a constant intravenous infusion of unlabelled flumazenil, resulting in ~50% GABA(A) receptor occupancy. The first and third scans were part of the steady state method, whilst the second scan was performed according to the full saturation method. For both methods, B(max) and K(D) were then derived by compartmental modelling. Both methods yielded similar B(max) and K(D) estimates. The full saturation method yielded B(max) values of 37 ± 5.8 ng · mL(-1) and K(D) values of 7.6 ± 2.0 ng · mL(-1), whilst the steady state method yielded B(max) values of 33 ± 5.4 ng · mL(-1) and K(D) values of 7.1 ± 0.8 ng · mL(-1). The main advantage of the full saturation method is that B(max) and K(D) can be obtained from a single PET scan.
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| 4. |
- Verbeek, Joost, et al.
(författare)
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Synthesis and preliminary preclinical evaluation of fluorine-18 labelled isatin-4-(4-methoxyphenyl)-3-thiosemicarbazone ([18F]4FIMPTC) as a novel PET tracer of P-glycoprotein expression
- 2018
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Ingår i: EJNMMI Radiopharmacy and Chemistry. - : Springer. - 2365-421X. ; 3:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: Several P-glycoprotein (P-gp) substrate tracers are available to assess P-gp function in vivo, but attempts to develop a tracer for measuring expression levels of P-gp have not been successful. Recently, (Z)-2-(5-fluoro-2-oxoindolin-3-ylidene)-N-(4-methoxyphenyl)hydrazine-carbothioamide was described as a potential selective P-gp inhibitor that is not transported by P-gp. Therefore, the purpose of this study was to radiolabel two of its analogues and to assess their potential for imaging P-gp expression using PET.Results: [18F]2-(4-fluoro-2-oxoindolin-3-ylidene)-N-(4-methoxyphenyl)hydrazine-carbothioamide ([18F]5) and [18F]2-(6-fluoro-2-oxoindolin-3-ylidene)-N-(4-methoxyphenyl)hydrazine-carbothioamide ([18F]6) were synthesized and both their biodistribution and metabolism were evaluated in rats. In addition, PET scans were acquired in rats before and after tariquidar (P-gp inhibitor) administration as well as in P-gp knockout (KO) mice.Both [18F]5 and [18F]6 were synthesized in 2-3% overall yield, and showed high brain uptake in ex vivo biodistribution studies. [18F]6 appeared to be metabolically unstable in vivo, while [18F]5 showed moderate stability with limited uptake of radiolabelled metabolites in the brain. PET studies showed that transport of [18F]5 across the blood-brain barrier was not altered by pre-treatment with the P-gp inhibitor tariquidar, and uptake was significantly lower in P-gp KO than in wild-type animals and indeed transported across the BBB or bound to P-gp in endothelial cells.Conclusion: In conclusion, [18F]5 and [18F]6 were successfully and reproducibly synthesized, albeit with low radiochemical yields. [18F]5 appears to be a radiotracer that binds to P-gp, as showed in P-gp knock-out animals, but is not a substrate for P-gp.
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