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Excitation functions of the 86Sr(d,n)87m,87gY, 86Sr(d,2n)86m,86gY and 86Sr(d,3n)85m,85gY reactions on enriched 86Sr target were measured by the activation technique up to deuteron energies of 49 MeV. The isomeric cross-section ratios as a function of projectile energy were deduced from the measured data for 87mY, 87gY(cum), 86mY, 86gY(cum), 85mY and 85gY pairs for the same energy range. All measurements are reported for the first time. The experimental data were compared with the data from the TENDL library which is based on TALYS calculation with default parameters. No satisfactory agreement was observed. Nuclear model calculations were then performed using the codes TALYS and EMPIRE with some parameter adjustments, and compared with the experimental data. The quality of the agreement between experimental data and model calculations was numerically quantified. In general, the data as well as the isomeric cross-section ratios are partially reproduced by the model calculations, provided the input model parameters are properly chosen and the level structure of the product nucleus is thoughtfully considered.

Cross sections of the 86Sr(p,3n)84mY, 86Sr(p,αn)82mRb, and 86Sr(p,x)85gSr reactions were measured from their respective thresholds up to 16.2 MeV and from 23.0 to 44.1 MeV at FZJ, and from 14.3 to 24.5 MeV at LBNL, using 96.4% enriched 86SrCO3 as target material. Thin targets prepared by sedimentation were irradiated with protons in a stacked-form, and the induced radioactivity was measured by high-resolution γ-ray spectrometry. Nuclear model calculations based on the code TALYS reproduced our experimental cross section data well. From the excitation functions, the integral yields of the above three radionuclides were calculated. The yield of 85gSr via the natSr(n,γ) process was also measured using the TRIGA Mark-II reactor at AERE, Savar. A comparison of the reactor and cyclotron production of carrier-added 85gSr is given. The production possibilities of the three investigated radionuclides in no-carrier-added forms at a 30 MeV cyclotron via new routes are discussed.

The β+-emitting radionuclide 86gY (t1/2 = 14.7 h) forms a matched-pair with the β--emitting therapeutic radionuclide 90Y (t1/2 = 2.7 d) for theranostic application in medicine. This approach demands a precise knowledge of the positron emission probability of the PET nuclide which was until recently rather uncertain for 86gY. In this work, an 86gY source of high radionuclidic purity was prepared and a direct measurement of the positron emission intensity per 100 decay of the parent (hereafter "positron emission intensity") was performed using high-resolution HPGe detector γ-ray spectroscopy. The electron capture intensity was also determined as an additional check by measuring the Kα and Kβ X-rays of energies 14.1 and 15.8 keV, respectively, using a low energy HPGe detector. From those measurements, normalized values of 27.2 ± 2.0% for β+-emission and 72.8 ± 2.0% for EC were obtained. These results are in excellent agreement with values recently reported in the literature based on a detailed decay scheme study.

In view of several significant discrepancies in the excitation function of the 86Sr(p,n)86g+xmY reaction which is the method of choice for the production of the non-standard positron emitter 86Y for theranostic application, we carried out a careful measurement of the cross sections of this reaction from its threshold up to 16.2 MeV at Forschungszentrum Jülich (FZJ) and from 14.3 to 24.5 MeV at LBNL. Thin samples of 96.4% enriched 86SrCO3 were prepared by sedimentation and, after irradiation with protons in a stacked-form, the induced radioactivity was measured by high-resolution γ-ray spectrometry. The projectile flux was determined by using the monitor reactions natCu(p,xn)62,63,65Zn and natTi(p,x)48V, and the calculated proton energy for each sample was verified by considering the ratios of two reaction products of different thresholds. The experimental cross section data obtained agreed well with the results of a nuclear model calculation based on the code TALYS. From the cross section data, the integral yield of 86Y was calculated. Over the optimum production energy range Ep = 14 → 7 MeV the yield of 86Y amounts to 291 MBq/μA for 1 h irradiation time. This value is appreciably lower than the previous literature values calculated from measured and evaluated excitation functions. It is, however, more compatible with the experimental yields of 86Y obtained in clinical scale production runs. The levels of the isotopic impurities 87mY, 87gY, and 88Y were also estimated and found to be

Degeneration of dopaminergic neurons in the substantia nigra and their striatal axon terminals causes cardinal motor symptoms of Parkinson's disease. In idiopathic cases, high levels of mitochondrial DNA alterations, leading to mitochondrial dysfunction, are a central feature of these vulnerable neurons. Here we present a mouse model expressing the K320E variant of the mitochondrial helicase Twinkle in dopaminergic neurons, leading to accelerated mitochondrial DNA mutations. These K320E-TwinkleDaN mice showed normal motor function at 20 months of age, although ∼70% of nigral dopaminergic neurons had perished. Remaining neurons still preserved ∼75% of axon terminals in the dorsal striatum and enabled normal dopamine release. Transcriptome analysis and viral tracing confirmed compensatory axonal sprouting of the surviving neurons. We conclude that a small population of substantia nigra dopaminergic neurons is able to adapt to the accumulation of mitochondrial DNA mutations and maintain motor control. [ABSTRACT FROM AUTHOR]

In progressive supranuclear palsy (PSP), subcortical tau and cortical perfusion can be assessed using the tracer [18F]PI-2620. We investigated if subcortical tau (globus pallidus internus, dentate nucleus) and frontal/limbic perfusion correlate in a cohort of 32 PSP patients. Tau in subcortical regions showed significant negative correlation with perfusion in limbic cortex. Perfusion in frontal regions was negatively associated with tau in both subcortical regions, but the significance threshold was only passed for the dentate nucleus. A reason could be a diaschisis-like phenomenon; that is, subcortical tau could lead to reduced connectivity to frontal regions and, thereby, to decreased perfusion. Plain Language Summary: In a study of 32 patients with progressive supranuclear palsy (PSP), we used a molecular imaging tracer called [18F]PI-2620 to measure two things: the presence of a protein called tau in deep brain areas (specifically, the globus pallidus internus and dentate nucleus) and the function of the brain's cortex by assessing blood flow (perfusion). We found that higher amounts of tau in these deep brain areas were associated with reduced blood flow in the limbic cortex, which is involved in emotion regulation. Also, the frontal areas of the brain showed reduced blood flow related to tau in these deep brain regions. However, this connection was statistically significant only for the dentate nucleus. This study suggests that the buildup of tau protein in deeper brain areas can disrupt function in parts of the brain's cortex, highlighting the damaging role of tau in PSP. [ABSTRACT FROM AUTHOR]

Mutations of isocitrate dehydrogenase 1 (IDH1) are key biomarkers for glioma classification, but current methods for detection of mutated IDH1 (mIDH1) require invasive tissue sampling and cannot be used for longitudinal studies. Positron emission tomography (PET) imaging with mIDH1-selective radioligands is a promising alternative approach that could enable non-invasive assessment of the IDH status. In the present work, we developed efficient protocols for the preparation of four 18F-labeled derivatives of the mIDH1-selective inhibitor olutasidenib. All four probes were characterized by cellular uptake studies with U87 glioma cells harboring a heterozygous IDH1 mutation (U87-mIDH) and the corresponding wildtype cells (U87-WT). In addition, the most promising probe was evaluated by PET imaging in healthy mice and mice bearing subcutaneous U87-mIDH and U87-WT tumors. Although all four probes inhibited mIDH1 with variable potencies, only one of them ([18F]mIDH-138) showed significantly higher in vitro uptake into U87-mIDH compared to U87-WT cells. In addition, PET imaging with [18F]mIDH-138 in mice demonstrated good in vivo stability and low non-specific uptake of the probe, but also revealed significantly higher uptake into U87-WT compared to U87-mIDH tumors. Finally, application of a two-tissue compartment model (2TCM) to the PET data indicated that preferential tracer uptake into U87-WT tumors results from higher specific binding rather than from differences in tracer perfusion. In conclusion, these results corroborate recent findings that mIDH1-selective inhibition may not directly correlate with mIDH1-selective target engagement and indicate that in vivo engagement of wildtype and mutated IDH1 may be governed by factors that are not faithfully reproduced by in vitro assays, both of which could complicate development of PET probes. [ABSTRACT FROM AUTHOR]

Compensatory changes in brain connectivity keep motor symptoms mild in prodromal Parkinson's disease. Studying compensation in patients is hampered by the steady progression of the disease and a lack of individual baseline controls. Furthermore, combining fMRI with walking is intricate. We therefore used a seed-based metabolic connectivity analysis based on 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) uptake in a unilateral 6-OHDA rat model. At baseline and in the chronic phase 6–7 months after lesion, rats received an intraperitoneal injection of [18F]FDG and spent 50 min walking on a horizontal treadmill, followed by a brain PET-scan under anesthesia. High activity was found in the cerebellar anterior vermis in both conditions. At baseline, the anterior vermis showed hardly any stable connections to the rest of the brain. The (future) ipsilesional cerebellar hemisphere was not particularly active during walking but was extensively connected to many brain areas. After unilateral dopamine depletion, rats still walked normally without obvious impairments. The ipsilesional cerebellar hemisphere increased its activity, but narrowed its connections down to the vestibulocerebellum, probably aiding lateral stability. The anterior vermis established a network involving the motor cortex, hippocampus and thalamus. Adding those regions to the vermis network of (previously) automatic control of locomotion suggests that after unilateral dopamine depletion considerable conscious and cognitive effort has to be provided to achieve stable walking. [ABSTRACT FROM AUTHOR]

Nuclear reaction cross sections for the formation of 72As and 71As in proton-induced reactions on enriched 72Ge targets were measured up to 45 MeV utilizing three different cyclotrons at the Forschungszentrum Jülich. The stacked-thin sample activation technique in combination with high-resolution γ-ray spectrometry was used. The major γ-ray peaks of 72As and 71As formed via the 72Ge(p,n)72As and 72Ge(p,2n)71As reactions, respectively, were analyzed. The incident proton energy and flux on a foil were determined using several monitor reactions. Based on integrated counts, irradiation data and the nuclear decay data, the reaction cross sections were measured. All data describe the first measurements. Theoretical nuclear model calculations were then carried out by using the codes TALYS 1.96, EMPIRE 3.2 and ALICE-IPPE. A very good agreement between the measured data and calculated values was found. The new data enabled us to calculate the thick target yields and estimate the radionuclidic impurities for a given energy range. Over the optimum energy range Ep = 14 → 7 MeV, the calculated thick target yield of 72As amounts to 272 MBq/μAh with no 71As impurity at all. The 72Ge(p,n)72As reaction on the enriched 72Ge is thus very suitable for clinical scale production of 72As at a medical cyclotron. [ABSTRACT FROM AUTHOR]