Optimization of Q.Clear reconstruction for dynamic 18F PET imaging

Abstract Background Q.Clear, a Bayesian penalized likelihood reconstruction algorithm, has shown high potential in improving quantitation accuracy in PET systems. The Q.Clear algorithm controls noise during the iterative reconstruction through a β penalization factor. This study aimed to determine the optimal β-factor for accurate quantitation of dynamic PET scans. Methods A Flangeless Esser PET Phantom with eight hollow spheres (4–25 mm) was scanned on a GE Discovery MI PET/CT system. Data were reconstructed into five sets of variable acquisition times using Q.Clear with 18 different β-factors ranging from 100 to 3500. The recovery coefficient (RC), coefficient of variation (CVRC) and root-mean-square error (RMSERC) were evaluated for the phantom data. Two male patients with recurrent glioblastoma were scanned on the same scanner using 18F-PSMA-1007. Using an irreversible two-tissue compartment model, the area under curve (AUC) and the net influx rate Ki were calculated to assess the impact of different β-factors on the pharmacokinetic analysis of clinical PET brain data. Results In general, RC and CVRC decreased with increasing β-factor in the phantom data. For small spheres (< 10 mm), and in particular for short acquisition times, low β-factors resulted in high variability and an overestimation of measured activity. Increasing the β-factor improves the variability, however at a cost of underestimating the measured activity. For the clinical data, AUC decreased and Ki increased with increased β-factor; a change in β-factor from 300 to 1000 resulted in a 25.5% increase in the Ki. Conclusion In a complex dynamic dataset with variable acquisition times, the optimal β-factor provides a balance between accuracy and precision. Based on our results, we suggest a β-factor of 300–500 for quantitation of small structures with dynamic PET imaging, while large structures may benefit from higher β-factors. Trial registration Clinicaltrials.gov, NCT03951142. Registered 5 October 2019, https://clinicaltrials.gov/ct2/show/NCT03951142 . EudraCT no 2018-003229-27. Registered 26 February 2019, https://www.clinicaltrialsregister.eu/ctr-search/trial/2018-003229-27/NO

Morphine reduced perceived anger from neutral and implicit emotional expressions

The μ-opioid system modulates responses to pain and psychosocial stress and mediates non-social and social reward. In humans, the μ-opioid agonist morphine can increase overt attention to the eye-region and visual exploration of faces with neutral expressions. However, little is known about how the human μ-opioid system influences sensitivity to and appraisal of subtle and explicit cues of social threats and reward. Here, we examined the effects of selective μ-opioid stimulation on perception of anger and happiness in faces with explicit, neutral or implicit emotion expressions. Sixty-three healthy adults (32 females) attended two sessions where they received either placebo or 10 mg per oral morphine in randomised order under double-blind conditions. Based on the known μ-opioid reduction of pain and discomfort, as well as reports suggesting that the non-specific partial agonist buprenorphine or the non-specific antagonist naltrexone affect appraisal of social emotional stimuli, we hypothesised that morphine would reduce threat sensitivity and enhance perception of happy facial expressions. While overall perception of others’ happiness was unaffected by morphine treatment, morphine reduced perception of anger in stimuli with neutral and implicit expressions without affecting perception of explicit anger. This effect was statistically unrelated to gender, subjective drug effects, mood and autism trait measures. The finding that a low dose of μ-agonist reduced the propensity to perceive anger in photos with subtle facial expressions is consistent with the notion that μ-opioids mediate social confidence and reduce sensitivity to threat cues

Brain penetrant small 18F-GnRH receptor (GnRH-R) antagonists: Synthesis and preliminary positron emission tomography imaging in rats

<h4 id="absSec_2">Introduction</h4>The gonadotropin releasing hormone receptor (GnRH-R) has a well-described neuroendocrine function in the anterior pituitary. However, little is known about its function in the central nervous system (CNS), where it is most abundantly expressed in hippocampus and amygdala. Since peptide ligands based upon the endogenous decapetide GnRH do not pass the blood brain-barrier, we are seeking a high-affinity small molecule GnRH-R ligand suitable for brain imaging by positron emission tomography. We have previously reported the radiosynthesis and <em>in vitro</em> evaluation of two novel [¹⁸F]fluorinated GnRH-R ligands belonging to the furamide class of antagonists, with molecular weight less than 500 Da. We now extend this work using palladium coupling for the synthesis of four novel radioligands, with putatively reduced polar surface area and hydrophilicity relative to the two previously described compounds, and report the uptake of these ¹⁸F-labeled compounds in brain of living rats.</p><h4 id="absSec_2">Methods</h4><p id="sp0085">We synthesized reference standards of the small molecule GnRH-R antagonists as well as mesylate precursors for ¹⁸F-labeling. The antagonists were tested for binding affinity for both human and rat GnRH-R. Serum and blood stability <em>in vitro</em> and <em>in vivo</em> were studied. Biodistribution and PET imaging studies were performed in male rats in order to assess brain penetration <em>in vivo</em>.</p><h4 id="absSec_3">Results</h4><p id="sp0090">A palladium coupling methodology served for the synthesis of four novel fluorinated furamide GnRH receptor antagonists with reduced heteroatomic count. Radioligand binding assays <em>in vitro</em> revealed subnanomolar affinity of the new fluorinated compounds for both human and rat GnRH-R. The ¹⁸F-GnRH antagonists were synthesized from the corresponding mesylate precursors in 5-15% overall radiochemical yield. The radiolabeled compounds demonstrated good <em>in vivo</em> stability. PET imaging with the ¹⁸F-radiotracers in naive rats showed good permeability into brain and rapid washout, but absence of discernible specific binding <em>in vivo</em>.</p><h4 id="absSec_4">Conclusions</h4><p id="sp0095">The novel small molecule ¹⁸F-fluorinated GnRH-R antagonist compounds show high receptor affinity <em>in vitro</em>, and may prove useful for quantitative autoradiographic studies <em>in vitro</em>. The compounds were permeable to the blood-brain barrier, but nonetheless failed to reveal significant specific binding in brain of living rats. Nonetheless, our approach may serve as a foundation for designing PET ligands suitable to image the GnRH-R distribution in brain

Synthesis and Evaluation of Three Structurally Related ¹⁸F‑Labeled Orvinols of Different Intrinsic Activities: 6‑<i>O</i>‑[¹⁸F]Fluoroethyl-diprenorphine ([¹⁸F]FDPN), 6‑<i>O</i>‑[¹⁸F]Fluoroethyl-buprenorphine ([¹⁸F]FBPN), and 6‑<i>O</i>‑[¹⁸F]Fluoroethyl-phenethyl-orvinol ([¹⁸F]FPEO)

We report the synthesis and biological evaluation of a triplet of 6-<i>O</i>-¹⁸F-fluoroethylated derivatives of structurally related orvinols that span across the full range of intrinsic activities, the antagonist diprenorphine, the partial agonist buprenorphine, and the full agonist phenethyl-orvinol. [¹⁸F]­fluoroethyl-diprenorphine, [¹⁸F]­fluoroethyl-buprenorphine, and [¹⁸F]­fluoroethyl-phenethyl-orvinol were prepared in high yields and quality from their 6-<i>O</i>-desmethyl-precursors. The results indicate suitable properties of the three 6-<i>O</i>-¹⁸F-fluoroethylated derivatives as functional analogues to the native carbon-11 labeled versions with similar pharmacological properties

MR elastography identifies regions of extracellular matrix reorganization associated with shorter survival in glioblastoma patients

Abstract Background Biomechanical tissue properties of glioblastoma tumors are heterogeneous, but the molecular mechanisms involved and the biological implications are poorly understood. Here, we combine magnetic resonance elastography (MRE) measurement of tissue stiffness with RNA sequencing of tissue biopsies to explore the molecular characteristics of the stiffness signal. Methods MRE was performed preoperatively in 13 patients with glioblastoma. Navigated biopsies were harvested during surgery and classified as “stiff” or “soft” according to MRE stiffness measurements (|G*|norm). Twenty-two biopsies from eight patients were analyzed by RNA sequencing. Results The mean whole-tumor stiffness was lower than normal-appearing white matter. The surgeon’s stiffness evaluation did not correlate with the MRE measurements, which suggests that these measures assess different physiological properties. Pathway analysis of the differentially expressed genes between “stiff” and “soft” biopsies showed that genes involved in extracellular matrix reorganization and cellular adhesion were overexpressed in “stiff” biopsies. Supervised dimensionality reduction identified a gene expression signal separating “stiff” and “soft” biopsies. Using the NIH Genomic Data Portal, 265 glioblastoma patients were divided into those with (n = 63) and without (n = 202) this gene expression signal. The median survival time of patients with tumors expressing the gene signal associated with “stiff” biopsies was 100 days shorter than that of patients not expressing it (360 versus 460 days, hazard ratio: 1.45, P &lt; .05). Conclusion MRE imaging of glioblastoma can provide noninvasive information on intratumoral heterogeneity. Regions of increased stiffness were associated with extracellular matrix reorganization. An expression signal associated with “stiff” biopsies correlated with shorter survival of glioblastoma patients