[en] Complete text of publication follows: Introduction There is evidence that clearance of beta-amyloid from brain into blood is mediated by P-glycoprotein (ABCB1) at the blood brain barrier (BBB). Pharmacological induction of ABCB1 is a currently investigated approach for the treatment of Alzheimer's disease. For the development of ABCB1-inducing therapeutics, the availability of a PET tracer to measure ABCB1 function at the BBB would be very helpful. Currently, available avid ABCB1 substrates for PET (e.g., (R)-[¹¹C]verapamil and [¹¹C]N-desmethyl-loperamide) are not suitable to measure ABCB1 induction at the BBB due to their very low brain uptake and presence of brain-penetrant radiolabeled metabolites. We evaluated the ability of the recently introduced weak ABCB1 substrate [¹¹C]metoclopramide ¹¹C]MCP) [1 (to measure ABCB1 induction at the mouse BBB. Methods [¹¹C]MCP was synthesized in a Tracerlab FX C Pro synthesis module by O-methylation of O-desmethyl-metoclopramide with [¹¹C]methyl triflate. Groups of female C57BL/6J mice aged approximately 170 days (n = 4-6 per group) underwent a baseline [¹¹C]MCP PET scan followed by treatment with two different validated ABCB1 induction protocols (PCN: 25 mg/kg i.p. over 7 days or rifampicin: 10 mg/kg i.p. over 5 days) or vehicle solution (safflower oil) and a second [¹¹C]MCP PET scan at the end of treatment. At the end of each PET scan, a small blood sample was collected from each animal and counted for radioactivity in a gamma counter. In separate groups of animals, radiolabelled metabolites of [¹¹C]MCP were analysed by radio-TLC at 15 min after injection (n = 2-5 per group). As an outcome parameter of ABCB1 function, the elimination slope for radioactivity washout from the brain was determined from the log-transformed brain time-activity curves (kE,brain, h^-1). All values are reported as mean ± SD. Results [¹¹C]MCP was synthesized in a decay-corrected radiochemical yield of 8.1 ± 1.6% (n = 15, based on [¹¹C]methane) in a total synthesis time of 31 min with a radiochemical purity >99% and a molar activity at end of synthesis of 96.5 ± 45.3 GBq/μmol. To the radiotracer solution carrier was added (2 mg/kg) to reduce peripheral metabolism of [¹¹C]MCP [1]. KE,brain was not significantly different between baseline, rifampicin-and vehicle-treated groups (0.687 ± 0.056 vs. 0.701 ± 0.075 and 0.775 ± 0.071 h^-1, p ≤ 0.05). Significantly higher kE,brain was observed in the PCN-treated group (0.883 ± 0.195 h^-1, p ≤ 0.001, 1-way ANOVA with Tukey's test) compared to the baseline group. No significant differences between the four groups were observed in blood radioactivity concentrations measured at the end of the PET scan. In plasma and brain, the percentage of unchanged [¹¹C (MCP at 15 min after injection was comparable for all groups (plasma: 33.9 ± 6.2%, brain: 90.9 ± 2.8%). Conclusion We established the synthesis of [¹¹C]MCP and evaluated two validated ABCB1 induction protocols. [¹¹C]MCP was found to lack brain-penetrant radiolabelled metabolites. Treatment with PCN significantly enhanced washout of radioactivity from the brain, which indicated that [¹¹C]MCP is a suitable PET tracer to measure ABCB1 induction at the BBB

[en] Introduction: Transport of 2-["1"8F]fluoro-2-deoxy-D-glucose (["1"8F]FDG) by the multidrug efflux transporters P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2) at the blood–brain barrier (BBB) may confound the interpretation of ["1"8F]FDG brain PET data. Aim of this study was to assess the influence of ABCB1 and ABCG2 at the BBB on brain distribution of ["1"8F]FDG in vivo by performing ["1"8F]FDG PET scans in wild-type and transporter knockout mice and by evaluating changes in ["1"8F]FDG brain distribution after transporter inhibition. Methods: Dynamic small-animal PET experiments (60 min) were performed with ["1"8F]FDG in groups of wild-type and transporter knockout mice (Abcb1a/b"("−"/"−"), Abcg2"("−"/"−") and Abcb1a/b"("−"/"−")Abcg2"("−"/"−")) and in wild-type rats without and with i.v. pretreatment with the known ABCB1 inhibitor tariquidar (15 mg/kg, given at 2 h before PET). Blood was sampled from animals from the orbital sinus vein at the end of the PET scans and measured in a gamma counter. Brain uptake of ["1"8F]FDG was expressed as the brain-to-blood radioactivity concentration ratio in the last PET time frame (K_b_,_b_r_a_i_n). Results: K_b_,_b_r_a_i_n values of ["1"8F]FDG were not significantly different between different mouse types both without and with tariquidar pretreatment. The blood-to-brain transfer rate constant of ["1"8F]FDG was significantly lower in tariquidar-treated as compared with vehicle-treated rats (0.350 ± 0.025 mL/min/g versus 0.416 ± 0.024 mL/min/g, p = 0.026, paired t-test) but K_b_,_b_r_a_i_n values were not significantly different between both rat groups. Conclusion: Our results show that ["1"8F]FDG is not transported by Abcb1 at the mouse and rat BBB in vivo. In addition we found no evidence for Abcg2 transport of ["1"8F]FDG at the mouse BBB. Advances in knowledge and implications for patient care: Our findings imply that functional activity of ABCB1 and ABCG2 at the BBB does not need to be taken into account when interpreting brain ["1"8F]FDG PET data

[en] Introduction: In recent years extra-corporal application of boron neutron capture therapy (BNCT) was evaluated for liver primary tumors or liver metastases. A prerequisite for such a high-risk procedure is proof of preferential delivery and high uptake of a ¹⁰B-pharmaceutical in liver malignancies. In this work we evaluated in a preclinical tumor model if [¹⁸F]FBPA tissue distribution measured with PET is able to predict the tissue distribution of [¹⁰B]L-BPA. Methods: Tumor bearing mice (hepatocellular carcinoma cell line, HuH-7) were either subject of a [¹⁸F]FBPA-PET scan with subsequent measurement of radioactivity content in extracted organs using a gamma counter or injected with [¹⁰B]L-BPA with tissue samples analyzed by prompt gamma activation analysis (PGAA) or quantitative neutron capture radiography (QNCR). The impact of L-tyrosine, L-DOPA and L-BPA preloading on the tissue distribution of [¹⁸F]FBPA and [¹⁰B]L-BPA was evaluated and the pharmacokinetics of [¹⁸F]FBPA investigated by compartment modeling. Results: We found a significant correlation between [¹⁸F]FBPA and [¹⁰B]L-BPA uptake in tumors and various organs as well as high accumulation levels in pancreas and kidneys as reported in previous studies. Tumor-to-liver ratios of [¹⁸F]FBPA ranged from 1.2 to 1.5. Preloading did not increase the uptake of [¹⁸F]FBPA or [¹⁰B]L-BPA in any organ and compartment modeling showed no statistically significant differences in [¹⁸F]FBPA tumor kinetics. Conclusions: [¹⁸F]FBPA-PET predicts [¹⁰B]L-BPA concentration after amino acid preloading in HuH-7 hepatocellular carcinoma models. Preloading had no effect on tumor uptake of [¹⁸F]FBPA. Advances in knowledge: Despite differences in chemical structure and administered dose [¹⁸F]FBPA and [¹⁰B]L-BPA demonstrate an equivalent biodistribution in a preclinical tumor model. Implications for patient care: [¹⁸F]FBPA-PET is suitable for treatment planning and dose calculations in BNCT applications for liver malignancies. However, alternative tracers with more favorable tumor-to-liver ratios should be investigated.

[en] One important mechanism for chemoresistance of tumours is overexpression of the adenosine triphosphate-binding cassette transporter P-glycoprotein (Pgp). Pgp reduces intracellular concentrations of chemotherapeutic drugs. The aim of this study was to compare the suitability of the radiolabelled Pgp inhibitors [¹¹C]tariquidar and [¹¹C]elacridar with the Pgp substrate radiotracer (R)-[¹¹C]verapamil for discriminating tumours expressing low and high levels of Pgp using small-animal PET imaging in a murine breast cancer model. Murine mammary carcinoma cells (EMT6) were continuously exposed to doxorubicin to generate a Pgp-overexpressing, doxorubicin-resistant cell line (EMT6AR1.0 cells). Both cell lines were subcutaneously injected into female athymic nude mice. One week after implantation, animals underwent PET scans with [¹¹C]tariquidar (n = 7), [¹¹C]elacridar (n = 6) and (R)-[¹¹C]verapamil (n = 7), before and after administration of unlabelled tariquidar (15 mg/kg). Pgp expression in tumour grafts was evaluated by Western blotting. [¹¹C]Tariquidar showed significantly higher retention in Pgp-overexpressing EMT6AR1.0 compared with EMT6 tumours: the mean ± SD areas under the time-activity curves in scan 1 from time 0 to 60 min (AUC_0-60) were 38.8 ± 2.2 min and 25.0 ± 5.3 min (p = 0.016, Wilcoxon matched pairs test). [¹¹C]Elacridar and (R)-[¹¹C]verapamil were not able to discriminate Pgp expression in tumour models. Following administration of unlabelled tariquidar, both EMT6Ar1.0 and EMT6 tumours showed increases in uptake of [¹¹C]tariquidar, [¹¹C]elacridar and (R)-[¹¹C]verapamil. Among the tested radiotracers, [¹¹C]tariquidar performed best in discriminating tumours expressing high and low levels of Pgp. Therefore [¹¹C]tariquidar merits further investigation as a PET tracer to assess Pgp expression levels in solid tumours. (orig.)