Abstracts of the 24th international isotope society (UK group) symposium: synthesis and applications of labelled compounds 2015.

The 24th annual symposium of the International Isotope Society's United Kingdom Group took place at the Møller Centre, Churchill College, Cambridge, UK on Friday 6th November 2015. The meeting was attended by 77 delegates from academia and industry, the life sciences, chemical, radiochemical and scientific instrument suppliers. Delegates were welcomed by Dr Ken Lawrie (GlaxoSmithKline, UK, chair of the IIS UK group). The subsequent scientific programme consisted of oral presentations, short 'flash' presentations in association with particular posters and poster presentations. The scientific areas covered included isotopic synthesis, regulatory issues, applications of labelled compounds in imaging, isotopic separation and novel chemistry with potential implications for isotopic synthesis. Both short-lived and long-lived isotopes were represented, as were stable isotopes. The symposium was divided into a morning session chaired by Dr Rebekka Hueting (University of Oxford, UK) and afternoon sessions chaired by Dr Sofia Pascu (University of Bath, UK) and by Dr Alan Dowling (Syngenta, UK). The UK meeting concluded with remarks from Dr Ken Lawrie (GlaxoSmithKline, UK).

Orbitofrontal dopamine depletion upregulates caudate dopamine and alters behavior via changes in reinforcement sensitivity.

Schizophrenia is associated with upregulation of dopamine (DA) release in the caudate nucleus. The caudate has dense connections with the orbitofrontal cortex (OFC) via the frontostriatal loops, and both areas exhibit pathophysiological change in schizophrenia. Despite evidence that abnormalities in dopaminergic neurotransmission and prefrontal cortex function co-occur in schizophrenia, the influence of OFC DA on caudate DA and reinforcement processing is poorly understood. To test the hypothesis that OFC dopaminergic dysfunction disrupts caudate dopamine function, we selectively depleted dopamine from the OFC of marmoset monkeys and measured striatal extracellular dopamine levels (using microdialysis) and dopamine D2/D3 receptor binding (using positron emission tomography), while modeling reinforcement-related behavior in a discrimination learning paradigm. OFC dopamine depletion caused an increase in tonic dopamine levels in the caudate nucleus and a corresponding reduction in D2/D3 receptor binding. Computational modeling of behavior showed that the lesion increased response exploration, reducing the tendency to persist with a recently chosen response side. This effect is akin to increased response switching previously seen in schizophrenia and was correlated with striatal but not OFC D2/D3 receptor binding. These results demonstrate that OFC dopamine depletion is sufficient to induce striatal hyperdopaminergia and changes in reinforcement learning relevant to schizophrenia.

Radiosynthesis of 11-[(18) F]fluoroundecyltriphenylphosphonium (MitoF) as a potential mitochondria-specific positron emission tomography radiotracer.

Changes in the magnitude of the mitochondrial membrane potential occur in a range of important pathologies. To assess changes in membrane potential in patients, we set out to develop an improved mitochondria-targeted positron emission tomography probe comprising a lipophilic triphenylphosphonium cation attached to a fluorine-18 radionuclide via an 11-carbon alkyl chain, which is well-established to effectively transport to and localise within mitochondria. Here, we describe the radiosynthesis of this probe, 11-[(18) F]fluoroundecyl-triphenylphosphonium (MitoF), from no-carrier-added [(18) F]fluoride and a fully automated synthetic protocol to prepare it in good radiochemical yields (2-3 GBq at end-of-synthesis) and radiochemical purity (97-99%).

A microPET study of the regional distribution of [11C]-PK11195 binding following temporary focal cerebral ischemia in the rat. Correlation with post mortem mapping of microglia activation.

BACKGROUND: Post-stroke microglial activation (MA) may have both neurotoxic and pro-repair effects, particularly in the salvaged penumbra. Mapping MA in vivo is therefore an important goal. 11C-PK11195, a ligand for the 18 kDa translocator protein, is the reference radioligand for MA imaging, but a correlation between the regional distributions of in vivo tracer binding and post mortem MA after stroke, as assessed with PET and immunohistochemistry, respectively, has not been demonstrated so far. Here we performed 11C-PK11195 microPET in a rat model previously shown to induce extensive cortical MA, and determined the correlation between 11C-PK11195 and immunostaining with the CD11 antibody OX42, so as to verify the presence of activated microglia, in a template of PET-resolution size regions-of-interest (ROIs) spanning the whole affected hemisphere. METHODS: Adult spontaneously hypertensive rats underwent 45 min distal middle cerebral artery occlusion and 11C-PK11195 PET at Days 2 and 14 after stroke according to a longitudinal design. Following perfusion-fixation at Day 14, brains were removed and coronally cut for OX42 staining. 11C-PK11195 binding potential (BPND) parametric maps were generated, and in each rat both BP(ND) and OX42 (intensity×extent score) were obtained in the same set of 44 ROIs extracted from a cytoarchitectonic atlas to cover the whole hemisphere. Correlations were computed across the 44 ROIs both within and across subjects. RESULTS: Significant BPND increases were observed in both the infarct and surrounding areas in all rats at day 14; less strong but still significant increases were present at day 2. There were highly significant (all p<0.001) positive correlations, both within- and across-subjects, between day 14 BPND values and OX42 scores. CONCLUSIONS: The correlation between Day 14 11C-PK11195 and OX42 across the affected hemisphere from the same brain regions and animals further supports the validity of 11C-PK11195 as an in vivo imaging marker of MA following stroke. The finding of statistically significant increases in 11C-PK11195 as early as 48 h after stroke is novel. These results have implications for mapping MA after stroke, with potential therapeutic applications.

T2*-weighted MRI versus oxygen extraction fraction PET in acute stroke.

BACKGROUND: Mapping high oxygen extraction fraction (OEF) in acute stroke is of considerable interest to depict the at-risk tissue. Being sensitive to deoxyhemoglobin, T2*-weighted MRI has been suggested as a potential marker of high OEF. METHODS: We compared T2*-weighted images from pre-contrast arrival perfusion scans against quantitative positron emission tomography in 5 patients studied 7-21 h after onset of carotid territory stroke. OEF and T2* signal were obtained in the voxels with significantly high OEF. RESULTS: All patients showed increased OEF. No significant relationship between OEF and T2*-weighted signal was found either within or between subjects. CONCLUSION: We found no indication that T2*-weighted MRI in the way implemented in this investigation was sensitive to high OEF in acute stroke.

Imaging regional variation of cellular proliferation in gliomas using 3'-deoxy-3'-[18F]fluorothymidine positron-emission tomography: an image-guided biopsy study.

AIM: To compare regional variations in uptake of 3'-deoxy-3'- [(18)F]-fluorothymidine (FLT) images using positron-emission tomography (PET) with measures of cellular proliferation from biopsy specimens obtained by image-guided brain biopsies. MATERIALS AND METHODS: Fourteen patients with a supratentorial glioma that required an image-guided brain biopsy were imaged preoperatively with dynamic PET after the administration of FLT. Maps of FLT irreversible uptake rate (K(i)) and standardized uptake value (SUV) were calculated. These maps were co-registered to a gadolinium-enhanced T1-weighted spoiled gradient echo (SPGR) sequence that was used for biopsy guidance, and the mean and maximum K(i) and SUV determined for each biopsy site. These values were correlated with the MIB-1 labelling index (a tissue marker of proliferation) from these biopsy sites. RESULTS: A total of 57 biopsy sites were studied. Although all measures correlated with MIB-1 labelling index, K(i)(max) provided the best correlation (Pearson coefficient, r=0.68; p<0.001). In low-grade gliomas the K(i)(mean) (+/-SD) was significantly higher than in normal tissue (3.3+/-1.7x10(-3)ml(plasma)/min/ml(tissue) versus 1.2+/-0.7x10(-3)ml(plasma)/min/ml(tissue); p=0.001). High-grade gliomas showed heterogeneous uptake with a mean K(i) of 7.7+/-4x10(-3)ml(plasma)/min/ml(tissue). A threshold K(i)(mean) of 1.8x10(-3) differentiates between normal tissue and tumour (sensitivity 84%, specificity 88%); however, the latter threshold underestimated the extent of tumour in half the cases. SUV closely agreed with K(i) measurements. CONCLUSION: FLT PET is a useful marker of cellular proliferation that correlates with regional variation in cellular proliferation; however, it is unable to identify the margin of gliomas.

Selective neuronal loss in rescued penumbra relates to initial hypoperfusion.

Selective neuronal loss (SNL) in the rescued penumbra could account for suboptimal clinical recovery despite effective early reperfusion. Previous studies of SNL used single-photon emission tomography (SPECT), did not account for potential volume loss secondary to collapse of the infarct cavity, and failed to show a relationship with initial hypoperfusion. Here, we obtained acute-stage computerized tomography (CT) perfusion and follow-up quantitative (11)C-flumazenil (FMZ)-PET to map SNL in the non-infarcted tissue and assess its relationship with acute-stage hypoperfusion. We prospectively recruited seven patients with evidence of (i) acute (<6 h) extensive middle cerebral artery territory ischaemia based on clinical deficit (National Institutes of Health stroke scale, NIHSS score range: 8-23) and CT Perfusion (CTp) findings and (ii) early recanalization (spontaneous or following thrombolysis) based on spectacular clinical recovery (DeltaNIHSS > or =6 at 24 h), good clinical outcome (NIHSS < or =5) and small final infarct (6/7 subcortical) on late-stage MRI. Ten age-matched controls were also studied. FMZ image analysis took into account potential post-stroke volume loss. Across patients, clusters of significantly reduced FMZ binding were more prevalent and extensive in the non-infarcted middle cerebral artery cortical areas than in the non-affected hemisphere (P = 0.028, Wilcoxon sign rank test). Voxel-based between-group comparisons revealed several large clusters of significantly reduced FMZ binding in the affected peri-insular, superior temporal and prefrontal cortices (FDR P < 0.05), as compared with no cluster on the unaffected side. Finally, comparing CTp and PET data revealed a significant negative correlation between FMZ binding and initial hypoperfusion. Applying correction for volume loss did not substantially alter the significance of these results. Although based on a small patient sample sometimes studied late after the index stroke, and as such preliminary, our results establish the presence and distribution of FMZ binding loss in ultimately non-infarcted brain areas after stroke. In addition, the data suggest that this binding loss is proportional to initial hypoperfusion, in keeping with the hypothesis that the rescued penumbra is affected by SNL. Although its clinical counterparts remain uncertain, it is tempting to speculate that peri-infarct SNL could represent a new therapeutic target.

How affected is oxygen metabolism in DWI lesions?: A combined acute stroke PET-MR study.

OBJECTIVE: To use back-to-back diffusion-weighted imaging (DWI) and PET to obtain quantitative measures of the cerebral metabolic rate of oxygen (CMRO(2)) within DWI lesions, and to assess the perfusion-metabolism coupling status by measuring the cerebral blood flow and the oxygen extraction fraction within DWI lesions. METHODS: Six prospectively recruited acute carotid-territory stroke patients completed the imaging protocol, which was commenced 7 to 21 hours from onset and combined DWI derived from state-of-the-art diffusion tensor imaging sequencing using a 3-T magnet and fully quantitative (15)O-PET. The PET variables were obtained in individual DWI lesions in each patient. RESULTS: Across patients, the CMRO(2) was reduced in the DWI lesion relative to mirror (mean reduction 39.5%; p = 0.028). Examining individual DWI lesions, however, revealed considerable variability in the extent of this CMRO(2) reduction. The flow-metabolism coupling pattern underlying the DWI lesion was also variable, including ongoing ischemia, mild oligemia, and partial or complete reperfusion. DISCUSSION: Diffusion-weighted imaging (DWI) lesions generally reflect substantial disruption of energy metabolism. However, the degree of metabolic disruption is variable, indicating DWI lesions may not always represent irreversibly damaged tissue. Finally, because DWI lesions can persist despite reperfusion, assessment of perfusion is necessary for interpretation of DWI changes in acute stroke.

Physiological thresholds for irreversible tissue damage in contusional regions following traumatic brain injury.

Cerebral ischaemia appears to be an important mechanism of secondary neuronal injury in traumatic brain injury (TBI) and is an important predictor of outcome. To date, the thresholds of cerebral blood flow (CBF) and cerebral oxygen utilization (CMRO(2)) for irreversible tissue damage used in TBI studies have been adopted from experimental and clinical ischaemic stroke studies. Identification of irreversibly damaged tissue in the acute phase following TBI could have considerable therapeutic and prognostic implications. However, it is questionable whether stroke thresholds are applicable to TBI. Therefore, the aim of this study was to determine physiological thresholds for the development of irreversible tissue damage in contusional and pericontusional regions in TBI, and to determine the ability of such thresholds to accurately differentiate irreversibly damaged tissue. This study involved 14 patients with structural abnormalities on late-stage MRI, all of whom had been studied with (15)O PET within 72 h of TBI. Lesion regions of interest (ROI) and non-lesion ROIs were constructed on late-stage MRIs and applied to co-registered PET maps of CBF, CMRO(2) and oxygen extraction fraction (OEF). From the entire population of voxels in non-lesion ROIs, we determined thresholds for the development of irreversible tissue damage as the lower limit of the 95% confidence interval for CBF, CMRO(2) and OEF. To test the ability of a physiological variable to differentiate lesion and non-lesion tissue, we constructed probability curves, demonstrating the ability of a physiological variable to predict lesion and non-lesion outcomes. The lower limits of the 95% confidence interval for CBF, CMRO(2) and OEF in non-lesion tissue were 15.0 ml/100 ml/min, 36.7 mumol/100 ml/min and 25.9% respectively. Voxels below these values were significantly more frequent in lesion tissue (all P < 0.005, Mann-Whitney U-test). However, a significant proportion of lesion voxels had values above these thresholds, so that definition of the full extent of irreversible tissue damage would not be possible based upon single physiological thresholds. We conclude that, in TBI, the threshold of CBF below which irreversible tissue damage consistently occurs differs from the classical CBF threshold for stroke (where similar methodology is used to define such thresholds). The CMRO(2) threshold is comparable to that reported in the stroke literature. At a voxel-based level, however (and in common with ischaemic stroke), the extent of irreversible tissue damage cannot be accurately predicted by early abnormalities of any single physiological variable.

Cerebrovascular pressure reactivity is related to global cerebral oxygen metabolism after head injury.

BACKGROUND: After head injury, impaired cerebrovascular autoregulation has been associated with abnormally high or low cerebral blood flow. The physiological relevance of cerebral blood flow levels is difficult to assess in these patients, whose cerebral metabolic rate for oxygen (CMRO(2)) is known to be abnormal. Investigation of these relations requires quantitative measures of cerebral blood flow and CMRO(2), to allow assessment of oxygen supply and demand relations. OBJECTIVES: To investigate the relation between dysautoregulation and global cerebral oxygen metabolism following head injury. METHODS: Using positron emission tomography, global cerebral blood flow, CMRO(2), and oxygen extraction fraction were determined in 22 patients who were investigated in 26 examinations on days 1 to 11 (mean (SD), 3.5 (2.3)) after head injury. Cerebrovascular pressure reactivity was assessed using a pressure reactivity index, calculated as the moving linear correlation coefficient between mean arterial blood pressure and intracranial pressure. Outcome was assessed six months after injury using the Glasgow outcome scale. RESULTS: Low CMRO(2) was associated with disturbed pressure reactivity (inverse function, R(2) = 0.21, p = 0.018) and there was a correlation between disturbed pressure reactivity and oxygen extraction fraction (quadratic function, R(2) = 0.55, p = 0.0001). There was no significant relation between pressure reactivity and cerebral blood flow. An unfavourable outcome was associated with disturbed pressure reactivity. There was no significant relation between outcome and CMRO(2) or oxygen extraction fraction. CONCLUSIONS: There is a close relation between dysautoregulation and abnormal cerebral metabolism but not blood flow. Further studies are needed to determine whether metabolic dysfunction is a result of or a cause of disturbed pressure reactivity, and to establish if there is a relation between cerebral oxygen metabolism and outcome.

Decision-making in mania: a PET study.

Poor decision-making is often observed clinically in the manic syndrome. In normal volunteers, decision-making has been associated with activation in the ventral prefrontal cortex and the anterior cingulate gyrus. The aim of this study was to evaluate task-related activation in bipolar manic patients in these regions of the prefrontal cortex using PET. Six subjects with mania, 10 controls and six subjects with unipolar depression (an affective patient control group) were scanned using the bolus H(2)(15)O method while they were performing a decision-making task. Activations associated with the decision-making task were observed at two levels of difficulty. Task-related activation was increased in the manic patients compared with the control patients in the left dorsal anterior cingulate [Brodmann area (BA) 32] but decreased in the right frontal polar region (BA 10). In addition, controls showed greater task-related activation in the inferior frontal gyrus (BA 47) than manic patients. A positive correlation (r(s) = 0.88) between task-related activation in the anterior cingulate and increasing severity of manic symptoms was found. Depressed patients did not show significant task-related differences in activation compared with control subjects in the regions of interest. In conclusion, these patterns of activation point to abnormal task-related responses in specific frontal regions in manic patients. Moreover, they are consistent with neuropsychological observations in patients with lesions in the ventromedial prefrontal cortex, who show similar difficulties with decision-making and provide early evidence for context-specific neural correlates of mania.

Syntheses of the first endothelin-A- and -B-selective radioligands for positron emission tomography.

We have synthesized two potential positron emission tomography (PET) radioligands for the endothelin (ET) receptor. [11C]-PD156707 was produced by O-methylation of PD169390 using [11C]iodomethane. Radiochemical conversions of the order of 74 +/- 3.2% (n = 8) were obtained. The radiochemical purity of the isolated [11C]-PD156707 was 99% and the specific activity was 538 mCi/micromol. [18F]-BQ3020 was produced from [18F]fluoride in a total radiochemical yield of 2.7 +/- 0.4% (n = 10) in 238 +/- 5 min. The radiochemical purity was 95% and specific activities of the order of 670-930 mCi/micromol were obtained.

Disposition of inhaled 1,1,1,2-tetrafluoroethane (HFA134A) in healthy subjects and in patients with chronic airflow limitation. Measurement by 18F-labeling and whole-body gamma-counting.

HFA134a (1,1,1,2-tetrafluoroethane) is a nonozone-depleting candidate to replace the chlorofluorocarbons used as propellants in metered-dose inhalers (MDIs) for pharmaceuticals that are widely used in the treatment of respiratory tract disease. As a means for ensuring the safety of such a compound for human use, it is necessary to establish that there is no excessive or unexpected accumulation in the body and in selected regions. A sensitive whole-body gamma-counting technique has been used with 18F-labeled HFA134a to measure the whole-body and regional absorption, distribution, and retention of HFA134a after administration in humans by single-breath inhalation. In seven healthy subjects, labeled HFA134a was rapidly eliminated by ventilation during the first few minutes, with an average of 9.6% of the radioactivity retained in the body at 5 min. This radioactivity cleared with an apparent terminal half-life of 1.5-4.2 hr to leave, on average, < 1% of the administered dose (< 750 micrograms, approximately 0.2 microCi) retained in the body at 5.8 hr. Disposition of radioactivity was independent of the position of label. Thus, there was no evidence of any significant degradative metabolism. On average, only 0.0056% of the administered dose appeared in the urine within the first 2 hr. Later samples contained no significant radioactivity. Inhaled HFA134a first distributed to all regions of the body and then cleared without evident accumulation in any specific region.(ABSTRACT TRUNCATED AT 250 WORDS)