Evaluation of [11C]Me-NB1 as a potential PET radioligand for measuring GluN2B-containing NMDA receptors, drug occupancy and receptor crosstalk

Clinical and preclinical research with modulators binding to the NMDA receptor GluN2B N-terminal domain (NTD) aim for the treatment of various neurological diseases. However, the interpretation of the results is hampered by the lack of a suitable NMDA PET tracer for assessing the receptor occupancy of candidate drugs. We have developed [¹¹C]Me-NB1 as a PET tracer for imaging GluN1/GluN2B-containing NMDA receptors and used it to investigate in rats the dose-dependent receptor occupancy of eliprodil, a GluN2B NTD modulator. Methods: [¹¹C]Me-NB1 was synthesized and characterized by in vitro displacement binding experiments with rat brain membranes, in vitro autoradiography, blocking and displacement experiments by PET and PET kinetic modeling with an arterial input function. Receptor occupancy by eliprodil was studied in vivo by PET with [¹¹C]Me-NB1. Results: [¹¹C]Me-NB1 was synthesized at 290±90 GBq/µmol specific activity, 7.4±1.9 GBq total activity at the end of synthesis and >99% radiochemical purity. [¹¹C]Me-NB1 binding in rat brain was blocked in vitro and in vivo by the NTD modulators Ro-25-6981 and eliprodil. In vivo, half maximal receptor occupancy by eliprodil occurred at 1.5 μg/kg. At 1 mg/kg eliprodil, a dose with reported neuroprotective effects, >99.5% binding sites were occupied. In vitro, [¹¹C]Me-NB1 binding was independent of sigma 1 receptor (Sigma1R) and the Sigma1R agonist (+)-pentazocine did not compete for high affinity binding. In vivo, 2.5 mg/kg (+)-pentazocine abolished [¹¹C]Me-NB1 specific binding, indicating an indirect effect of Sigma1R on [¹¹C]Me-NB1 binding. Conclusion: [¹¹C]Me-NB1 is suitable for the in vivo imaging of NMDA GluN1/GluN2B receptors and the assessment of the receptor occupancy by NTD modulators. GluN1/GluN2B NMDA receptors are fully occupied at neuroprotective doses of eliprodil. Furthermore, [¹¹C]Me-NB1 enables imaging of GluN1/GluN2B NMDA receptor crosstalk.

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PSMA-11 Derived Dual-labeled PSMA-Inhibitors for Preoperative PET Imaging and Precise Fluorescence-Guided Surgery of Prostate Cancer

Resection of tumor lesions using targeted dual-modality probes combining preoperative imaging with intraoperative guidance is of high clinical relevance and might considerably impact the outcome of prostate cancer therapy. This work aims at the development of dual-labeled prostate specific membrane antigen (PSMA)-inhibitors derived from the established positron emission tomography (PET)- and N,N'-bis[2-hydroxy-5-(carboxyethyl)benzyl]ethylenediamine-N,N'-diacetic acid (HBED-CC) based tracer ⁶⁸Ga-Glu-urea-Lys(Ahx)-HBED-CC (⁶⁸Ga-PSMA-11) to allow accurate intraoperative detection of PSMA-positive tumor lesions. Methods: A series of novel PSMA-targeting fluorescent dye conjugates of Glu-urea-Lys-HBED-CC were synthesized and their biological properties determined in cell based assays and confocal microscopy. As a preclinical proof-of-concept, specific tumor uptake, pharmacokinetics and feasibility for intraoperative fluorescence-guidance were investigated in tumor-bearing mice and healthy pigs. Results: The designed dual-labeled PSMA-inhibitors exhibit high binding affinity and PSMA-specific effective internalization. Conjugation of Fluoresceinisothiocyanate (FITC) (10.86±0.94 %ID/g), IRDye800CW (13.66±3.73 %ID/g) and DyLight800 (15.62±5.52 %ID/g) resulted in a significantly increased specific tumor uptake, while ⁶⁸Ga-Glu-urea-Lys-HBED-CC-AlexaFluor488 (9.12±5.47 %ID/g) revealed a similar tumor uptake as compared to ⁶⁸Ga-PSMA-11 (4.89±1.34 %ID/g). First proof-of-concept studies with the clinically relevant candidate ⁶⁸Ga-Glu-urea-Lys-HBED-CC-IRDye800CW reinforce a fast specific enrichment in PSMA-positive tumors with rapid background clearance. With regard to intraoperative navigation a specific fluorescence signal was detected in PSMA-expressing tissue. Conclusion: This study demonstrates that PSMA-11 derived dual-labeled dye-conjugates are feasible to provide PSMA-specific pre-, intra- and postoperative detection of prostate cancer lesions and have high potential for future clinical translation.

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Flortaucipir F 18 Quantitation using a Parametric Estimate of Reference Signal Intensity (PERSI)

Introduction: PET imaging of tau pathology in Alzheimer's disease may benefit from the use of white matter reference regions. These regions have shown reduced variability compared to conventional cerebellar regions in amyloid imaging. However, they are susceptible to contamination from partial-volume blurring of tracer uptake in cortex. We present a new technique (PERSI) for Flortaucipir F 18 count normalization that leverages the advantages of white matter reference regions while mitigating potential partial-volume effects. Methods: Subjects with clinical diagnoses of Alzheimer's Disease (AD), mild cognitive impairment (MCI) or normal cognition (CN) underwent T1 MRI and florbetapir imaging (to determine amyloid (Aβ) status) at screening, and flortaucipir imaging at single or multiple time points. Flortaucipir images acquired as 4x5 minute frames, 80 minutes after a 370 MBq injection, were motion corrected, averaged and transformed to MNI space. The PERSI reference region was calculated for each scan by fitting a bimodal Gaussian distribution to the voxel-intensity histogram within an atlas-based white matter region, and using the center and width of the lower-intensity peak to identify the voxel intensities to be included. Four conventional reference regions were also evaluated: 1) whole cerebellum, 2) cerebellar gray matter, 3) atlas-based white matter, and 4) subject-specific white matter. SUVr was calculated for a statistically-defined neocortical volume-of-interest (MUBADA). Performance was evaluated with respect to test-retest variability in a Phase 2 study of 21 subjects (5-34 days between scans). Baseline variability in controls (SD of SUVr and SUVr values) and effect sizes for group differences (Cohen's d; Aβ+ impaired vs. Aβ- normal) were evaluated in another Phase 2 study with cross-sectional (n = 215) and longitudinal (n = 142/215; 18±2 months between scans) data. Results: PERSI showed superior test-retest reproducibility (1.84%) and group separation ability (cross-sectional Cohen's d=9.45; longitudinal Cohen's d=2.34) compared to other reference regions. Baseline SUVr variability and SUVr were minimal in Aβ- control subjects with no specific flortaucipir uptake (SUVr 1.0±0.04, SUVr 0.0±0.02). Conclusion: PERSI reduced variability while enhancing discrimination between diagnostic cohorts. Such improvements could lead to more accurate disease staging and robust measurements of changes in tau burden over time for the evaluation of putative therapeutic treatments.

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Peripheral neuropathy induced by microtubule-targeted chemotherapies: insights into acute injury and long-term recovery

Chemotherapy-induced peripheral neuropathy (CIPN) is a major cause of disability in cancer survivors. CIPN investigations in preclinical model systems have focused on either behaviors or acute changes in nerve conduction velocity (NCV) and amplitude, but greater understanding of the underlying nature of axonal injury and its long-term processes is needed as cancer patients live longer. In this study, we used multiple independent endpoints to systematically characterize CIPN recovery in mice exposed to the anti-tubulin cancer drugs eribulin (ERIB), ixabepilone (IXA), paclitaxel (PACLI) or vinorelbine (VINO) at maximal tolerated doses. All of the drugs ablated intra-epidermal nerve fibers and produced axonopathy, with a secondary disruption in myelin structure within two weeks of drug administration. Additionally, all of the drugs reduced sensory NCV and amplitude, with greater deficits after PACLI and lesser deficits after IXA. These effects correlated with degeneration in dorsal root ganglia (DRG) and sciatic nerve and abundance of Schwann cells. While most injuries were fully reversible after 3-6 months after administration of ERIB, VINO, and IXA, we observed delayed recovery after PACLI that produced a more severe, pervasive and prolonged neurotoxicity. Compared to other agents, PACLI also displayed a unique prolonged exposure in sciatic nerve and DRG. The most sensitive indicator of toxicity was axonopathy and secondary myelin changes accompanied by a reduction in intra-epidermal nerve fiber density. Taken together, our findings suggest that intra-epidermal nerve fiber density and changes in NCV and amplitude might provide measures of axonal injury to guide clinical practice.

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Using proprioception to get a better grasp on embodiment

Abstract

We interact with, interpret, and understand the world around us through our senses. We see our environment, touch the things in it, feel the ground beneath our feet, and know how we move within our surroundings.

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Mutations in Homologous Recombination Genes and Outcomes in Ovarian Carcinoma Patients in GOG 218: an NRG Oncology/Gynecologic Oncology Group Study

Purpose: We hypothesized that mutations in homologous recombination repair (HRR) genes beyond BRCA1 and BRCA2 improve outcomes for ovarian carcinoma (OC) patients treated with platinum therapy and would impact the relative benefit of adding prolonged bevacizumab.  Experimental Design: We sequenced DNA from blood and/or neoplasm from 1,195 women enrolled in GOG-0218, a randomized phase III trial in advanced OC of bevacizumab added to carboplatin and paclitaxel. Defects in HRR were defined as damaging mutations in 16 genes. Proportional hazards models were used to estimate relative hazards for progression-free survival (PFS) and overall survival (OS). Results: Of 1,195 women with OC, HRR mutations were identified in 307 (25.7%). Adjusted hazards for progression and death compared to those without mutations were lower for women with non-BRCA HRR mutations (HR 0.73, 95% CI 0.57 - 0.94, p=0.01 for PFS; HR 0.67, 95% CI 0.50 - 0.90, p=0.007 for OS) and BRCA1 mutations (hazard ratio (HR) 0.80, 95% CI 0.66 - 0.97, p=0.02 for PFS; HR 0.74, 95% CI 0.59 - 0.94, p=0.01 for OS) and were lowest for BRCA2 mutations (HR 0.52, 95% CI 0.40 - 0.67, p<0.0001 for PFS; HR 0.36, 95% CI 0.25 - 0.53, p<0.0001 for OS). A test of interaction showed no difference in the effect of bevacizumab on PFS between cases with and without mutations.  Conclusions: HRR mutations, including non-BRCA genes, significantly prolong PFS and OS in OC and should be stratified for in clinical trials. The benefit of adding bevacizumab was not significantly modified by mutation status.

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