We present the first preparation of novel 6-O-(fluoroalkyl)-6-O-desmethyl-diprenorphine analogs and 6-O-(tosyloxyalkyl)-6-O-desmethyl-3-O-trityl-diprenorphine-type precursors for the radiosynthesis of 6-O-([18F]fluoroalkyl)-6-O-desmethyl-diprenorphine radiotracers for molecular imaging by positron emission tomography (PET). The synthesis sequence to the new opioid receptor ligands consists of eleven steps starting from the poppy alkaloid thebaine. The precursor molecules were prepared in a three-step synthesis process from the «Luthra precursor» (TDDPN). We report the complete 1H- and 13C-NMR assignment of the new 6-O-(substituted)-6-O-desmethyl-diprenorphine derivatives, as well as the results of docking studies in silico for diverse novel opioid receptor ligands, including a new series of 6-O-(fluoroalkyl)- and 6-O-(hydroxyalkyl)-6-O-desmethyl-diprenorphine derivatives.

The aim of this guideline is to provide standards for the recommendation, performance, interpretation, and reporting of [18F]Fluciclovine PET/CT for prostate cancer imaging. These recommendations will help to improve accuracy, precision, and repeatability of [18F]Fluciclovine PET/CT for prostate cancer essentially needed for implementation of this modality in science and routine clinical practice.

Previous unimodal PET and fMRI studies in humans revealed a reproducible vestibular brain activation pattern, but with variations in its weighting and expansiveness. Hybrid studies minimizing methodological variations at baseline conditions are rare and still lacking for task-based designs. Thus, we applied for the first time hybrid 3T PET-MRI scanning (Siemens mMR) in healthy volunteers using galvanic vestibular stimulation (GVS) in healthy volunteers in order to directly compare H215O-PET and BOLD MRI responses. List mode PET acquisition started with the injection of 750 MBq H215O simultaneously to MRI EPI sequences. Group-level statistical parametric maps were generated for GVS vs. rest contrasts of PET, MR-onset (event-related), and MR-block. All contrasts showed a similar bilateral vestibular activation pattern with remarkable proximity of activation foci. Both BOLD contrasts gave more bilateral wide-spread activation clusters than PET; no area showed contradictory signal responses. PET still confirmed the right-hemispheric lateralization of the vestibular system, whereas BOLD-onset revealed only a tendency. The reciprocal inhibitory visual-vestibular interaction concept was confirmed by PET signal decreases in primary and secondary visual cortices, and BOLD-block decreases in secondary visual areas. In conclusion, MRI activation maps contained a mixture of CBF measured using H215O-PET and additional non-CBF effects, and the activation-deactivation pattern of the BOLD-block appears to be more similar to the H215O-PET than the BOLD-onset.

FACBC PET/CT detected fewer histological verified radio-recurrences within the prostate than mpMRI. In accordance with previous studies, we found that the limitations of FACBC PET were small tumor amounts and uptake in hyperplastic benign tissue.

OBJECTIVE:To investigate the diagnostic potential of simultaneous 18F-fluciclovine PET/MRI for pelvic lymph node (LN) staging in patients with high-risk prostate cancer.METHODS:High-risk prostate cancer patients (n=28) underwent simultaneous 18F-fluciclovine PET/MRI prior to surgery. LNs were removed according to a predefined template of eight regions. PET and MR images were evaluated for presence of LN metastases according to these regions. Sensitivity/specificity for detection of LN metastases were calculated on patient and region basis. Sizes of LN metastases in regions with positive and negative imaging findings were compared with linear mixed models. Clinical parameters of PET-positive and -negative stage N1 patients were compared with the Mann-Whitney U test.RESULTS:Patient- and region-based sensitivity/specificity for detection of pelvic LN metastases was 40 %/87.5 % and 35 %/95.7 %, respectively, for MRI and 40 %/100 % and 30 %/100 %, respectively, for PET. LN metastases in true-positive regions were significantly larger than metastases in false-negative regions. PET-positive stage N1 patients had higher metastatic burden than PET-negative N1 patients.CONCLUSION:Simultaneous 18F-fluciclovine PET/MRI provides high specificity but low sensitivity for detection of LN metastases in high-risk prostate cancer patients. 18F-Fluciclovine PET/MRI scan positive for LN metastases indicates higher metastatic burden than negative scan.KEY POINTS:• 18F-Fluciclovine PET/MRI has high specificity for detection of lymph node metastasis. • 18F-Fluciclovine PET/MRI lacks sensitivity to replace ePLND. • 18F-Fluciclovine PET/MRI may be used to aid surgery and select adjuvant therapy. • 18F-Fluciclovine PET-positive patients have more extensive disease than PET-negative patients. • Size of metastatic lymph nodes is an important factor for detection.

Modifying behavior to maximize reward is integral to adaptive decision-making. In rodents, the μ-opioid receptor (MOR) system encodes motivation and preference for high-value rewards. Yet it remains unclear whether and how human MORs contribute to value-based decision-making. We reasoned that if the human MOR system modulates value-based choice, this would be reflected by opposite effects of agonist and antagonist drugs. In a double-blind pharmacological cross-over study, 30 healthy men received morphine (10 mg), placebo, and the opioid antagonist naltrexone (50 mg). They completed a two-alternative decision-making task known to induce a considerable bias towards the most frequently rewarded response option. To quantify MOR involvement in this bias, we fitted accuracy and reaction time data with the drift–diffusion model (DDM) of decision-making. The DDM analysis revealed the expected bidirectional drug effects for two decision subprocesses. MOR stimulation with morphine increased the preference for the stimulus with high-reward probability (shift in starting point). Compared to placebo, morphine also increased, and naltrexone reduced, the efficiency of evidence accumulation. Since neither drug affected motor-coordination, speed-accuracy trade-off, or subjective state (indeed participants were still blinded after the third session), we interpret the MOR effects on evidence accumulation efficiency as a consequence of changes in effort exerted in the task. Together, these findings support a role for the human MOR system in value-based choice by tuning decision-making towards high-value rewards across stimulus domains.

Paying attention to others' faces and eyes is a cornerstone of human social behavior. The µ-opioid receptor (MOR) system, central to social reward-processing in rodents and primates, has been proposed to mediate the capacity for affiliative reward in humans. We assessed the role of the human MOR system in visual exploration of faces and eyes of conspecifics. Thirty healthy males received a novel, bidirectional battery of psychopharmacological treatment (an MOR agonist, a non-selective opioid antagonist, or placebo, on three separate days). Eye-movements were recorded while participants viewed facial photographs. We predicted that the MOR system would promote visual exploration of faces, and hypothesized that MOR agonism would increase, whereas antagonism decrease overt attention to the information-rich eye region. The expected linear effect of MOR manipulation on visual attention to the stimuli was observed, such that MOR agonism increased while antagonism decreased visual exploration of faces and overt attention to the eyes. The observed effects suggest that the human MOR system promotes overt visual attention to socially significant cues, in line with theories linking reward value to gaze control and target selection. Enhanced attention to others' faces and eyes represents a putative behavioral mechanism through which the human MOR system promotes social interest.

520 Objectives The performance of the investigational amino acid PET tracer fluciclovine F18 (aka FACBC) compared to histopathology was retrospectively evaluated in patients with high risk primary prostate carcinoma to investigate whether fluciclovine F18 PET-CT has utility for disease staging, prior to selection of definitive primary treatment. Methods 86 patients with histologically confirmed primary prostate carcinoma underwent fluciclovine F18 PET-CT scanning, as part of their pre-treatment work up for disease staging at two sites in Norway. Scan data were compared to histopathological standard of truth, which was available for 61/86 subjects. Effectiveness endpoints included detection rate, sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV). Analyses were conducted at Subject and Region level. Results Data were collected under a retrospective protocol, BED-001, in accordance with ICH GCP and the Declaration of Helsinki. Patient risk factors included: Gleason score was 蠅7 for 88% of patients (n=40/45), 64.7% were considered high risk by D’Amico criteria (n=55/85), median PSA at baseline was ~10 ng/mL (n=78). Prostate biopsy data was available for 61 patients and pelvic lymph node histology for 55. In the Prostate region the PPV of fluciclovine F18 was 100% compared to histopathology, with 91.8% sensitivity and detection rate. No data are presented for NPV and specificity since subjects were de facto confirmed prostate cancer patients, or the number of patients with negative standard of truth per region was insufficient to support these analyses. In the extra-prostatic region fluciclovine F18 detected disease in 37.3% of patients, mostly as a consequence of extension to include the pelvic lymph nodes. PPV, NPV, sensitivity and specificity were 59.1%, 70.3%, 54.2% and 74.3%, respectively. At Subject level, the PPV of fluciclovine F18 was 100%, with sensitivity and detection rate of 93.4%. Conclusions Fluciclovine F18 PET-CT scanning is predictive for the detection of regional lymph node metastases. The detection of metastases is a critical factor affecting the choice of initial treatment for patients with prostate cancer, and our data support the utility of fluciclovine F18 PET-CT scanning as an aid to the detection of metastases in patients with high-risk prostate cancer.

Staging the extent and location of prostate cancer in biochemical relapse (BR) is critical to informing further management of both post-surgical and post-radiation patients with focal or systemic therapies. This retrospective, observational study hypothesized that the investigational amino acid PET tracer fluciclovine F18 could effectively detect disease recurrence in this patient group and would be well tolerated. Diagnostic performance of fluciclovine F18, as compared to histopathology and clinical follow-up, was determined in a patient cohort with sufficient data for truth determination. The safety profile and imaging positivity rate relative to PSA level were evaluated in the larger cohort. Overall, 714 cancer patients underwent fluciclovine F18 PET-CT scanning at 4 sites in Norway, Italy and USA, including 596 patients who presented with BR of prostate cancer. Imaging positivity or detection rate (DR) was determined according to PSA quartile. To determine diagnostic performance in prostate cancer BR, fluciclovine F18 PET-CT results were compared to available histopathological findings (n = 143) and to histopathology plus clinical follow-up (n = 125). Determination of DR, sensitivity and specificity, positive and negative predictive value (PPV, NPV) were made, as applicable, at lesion, regional and subject level (prostate/prostate bed (P/B) or extra-prostatic (E/P)). Fluciclovine F18 was very well tolerated: adverse events possibly related to fluciclovine were reported by 0.6% of patients; no significant treatment-related effects on laboratory values or ECG variables were noted. Risk factors for the prostate cancer BR cohort included: Gleason score ≥7 (80%); intermediate/high risk by D’Amico criteria at initial treatment (65%); median PSA before imaging: 2.03 ng/mL. For diagnostic performance vs. histopathology (n = 143) the sensitivity for detection of P/B disease was 88.1%, with specificity of 32.6% and PPV of 71.8%. The PPV for E/P disease was higher at 92.3%. For diagnostic performance vs pathology plus clinical follow up (n = 125), sensitivity, specificity, PPV, and NPV for the regions P/B and E/P were: P/B: 95.1%, 48.8%, 78%, and 84%, and E/P: 84.2%, 89.7%, 78.0%, and 92.9%. Analysis of patient level DR (%) by PSA quartile (ng/mL) in the full BR cohort (n = 596) was: ≤0.79: 41%; >0.79 to ≤2.03: 59%; >2.03 to ≤ 6.0: 75%; >6.0: 86%. Fluciclovine (18F) PET-CT scanning is well tolerated and able to sensitively detect recurrent prostate cancer, even at PSA levels below 1ng/mL, potentially facilitating the optimization of subsequent patient management, including the scope and dose of radiotherapy.

BACKGROUND:Rodent models highlight the key role of μ-opioid receptor (MOR) signaling in palatable food consumption. In humans, however, the effects of MOR stimulation on eating and food liking remain unclear.OBJECTIVES:Here, we tested sweet pleasantness experience in humans following MOR drug manipulations. We hypothesized that behaviors regulated by the endogenous MOR system would be enhanced by MOR agonism and decreased by antagonism. In line with rodent findings, we expected the strongest drug effects for the sweetest (high-calorie) sucrose stimuli. As very sweet stimuli are considered aversive by many people (called sweet dislikers), we also assessed whether MOR manipulations affect pleasantness ratings of sucrose-water stimuli differently depending on subjective and objective value.METHODS:In a bidirectional psychopharmacological cross-over study, 49 healthy men underwent a sweet taste paradigm following double-blind administration of the MOR agonist morphine, placebo, and the opioid antagonist naltrexone.RESULTS:As hypothesized, MOR stimulation with morphine increased pleasantness of the sweetest of five sucrose solutions, without enhancing pleasantness of the lower-sucrose solutions. For opioid antagonism, an opposite pattern was observed for the sweetest drink only. The observed drug effects on pleasantness of the sweetest drink did not differ between sweet likers and dislikers.CONCLUSIONS:The bidirectional effect of agonist and antagonist treatment aligns with rodent findings showing that MOR manipulations most strongly affect the highest-calorie foods. We speculate that the MOR system promotes survival in part by increasing concordance between the objective (caloric) and subjective (hedonic) value of food stimuli, so that feeding behavior becomes more focused on the richest food available.

Purpose: Sensitive detection of cancer foci in men experiencing biochemical recurrence following initial treatment of prostate cancer is of great clinical significance with a possible impact on subsequent treatment choice. We describe a multisite experience of the efficacy and safety of the positron emission tomography/computerized tomography agent fluciclovine (F-18) after biochemical recurrence.Materials and Methods: A total of 596 patients underwent fluciclovine (F-18) positron emission tomography/computerized tomography at 4 clinical sites. Detection rate determinations were stratified by the baseline prostate specific antigen value. Diagnostic performance was assessed against a histological reference standard in 143 scans.Results: The subject level fluciclovine (18 F) positron emission tomography/computer tomography detection rate was 67.7% (403 of 595 scans). Positive findings were detected in the prostate/bed and pelvic lymph node regions in 38.7% (232 of 599) and 32.6% of scans (194 of 596), respectively. Metastatic involvement outside the pelvis was detected in 26.2% of scans (155 of 591). The subject level detection rate in patients in the lowest quartile for baseline prostate specific antigen (0.79 ng/ml or less) was 41.4% (53 of 128). Of these patients 13 had involvement in the prostate/bed only, 16 had pelvic lymph node involvement without distant disease and 24 had distant metastases. The positive predictive value of fluciclovine (18 F) positron emission tomography/computerized tomography scanning for all sampled lesions was 62.2%, and it was 92.3% and 71.8% for extraprostatic and prostate/bed involvement, respectively. Fluciclovine (F-18) was well tolerated and the safety profile was not altered following repeat administration.Conclusions: Fluciclovine (F-18) is well tolerated and able to detect local and distant prostate cancer recurrence across a wide range of prostate specific antigen values.

We report the synthesis and biological evaluation of a triplet of 6-O-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-O-desmethyl-precursors. The results indicate suitable properties of the three 6-O-18F-fluoroethylated derivatives as functional analogues to the native carbon-11 labeled versions with similar pharmacological properties.

Correction to: Molecular Psychiatry (2014) 19; 746–747; doi:10.1038/mp.2014.1 Following publication of this paper, the authors noticed that the correct version of their Supplementary Information was not published alongside their paper. The correct version of the Supplementary Information can be found linked to this paper.

We report the synthesis and biological evaluation of a triplet of 6-O-(18)F-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. [(18)F]fluoroethyl-diprenorphine, [(18)F]fluoroethyl-buprenorphine, and [(18)F]fluoroethyl-phenethyl-orvinol were prepared in high yields and quality from their 6-O-desmethyl-precursors. The results indicate suitable properties of the three 6-O-(18)F-fluoroethylated derivatives as functional analogues to the native carbon-11 labeled versions with similar pharmacological properties.

Sarco(endo)plasmic reticulum Ca2+ -ATPase (SERCA)2 transports Ca2+ from the cytosol into the sarcoplasmic reticulum of cardiomyocytes and is essential for maintaining myocardial Ca2+ handling and thus the mechanical function of the heart. SERCA2 is a major ATP consumer in excitation-contraction coupling but is regarded to contribute to energetically efficient Ca2+ handling in the cardiomyocyte. Previous studies using cardiomyocyte-specific SERCA2 knockout (KO) mice have demonstrated that decreased SERCA2 activity reduces the Ca2+ transient amplitude and induces compensatory Ca2+ transport mechanisms that may lead to more inefficient Ca2+ transport. In this study, we examined the relationship between left ventricular (LV) function and myocardial O2 consumption (MVo2) in ex vivo hearts from SERCA2 KO mice to directly measure how SERCA2 elimination influences mechanical and energetic features of the heart. Ex vivo hearts from SERCA2 KO hearts developed mechanical dysfunction at 4 wk and demonstrated virtually no working capacity at 7 wk. In accordance with the reported reduction in Ca2+ transient amplitude in cardiomyocytes from SERCA2 KO mice, work-independent MVo2 was decreased due to a reduced energy cost of excitation-contraction coupling. As these hearts also showed a marked impairment in the efficiency of chemomechanical energy transduction (contractile efficiency, i.e, work-dependent MVo2), hearts from SERCA2 KO mice were found to be mechanically inefficient. This ex vivo evaluation of mechanical and energetic function in hearts from SERCA2 KO mice brings together findings from previous experimental and mathematical modeling-based studies and demonstrates that reduced SERCA2 activity not only leads to mechanical dysfunction but also to energetic dysfunction.