Synthesis and in vivo evaluation of a novel 5-HT1A receptor agonist radioligand [O-methyl- 11C]2-(4-(4-(2-methoxyphenyl)piperazin-1-yl)butyl)-4-methyl-1,2,4-triazine-3,5(2H,4H)dione in nonhuman primates

Purpose Serotonin_1A (5-HT_1A) receptors exist in high- and low-affinity states, and agonist ligands bind preferentially to the high-affinity state of the receptor and provide a measure of functional 5-HT_1A receptors. Although the antagonist tracers are established PET ligands in clinical studies, a successful 5-HT_1A receptor agonist radiotracer in living brain has not been reported. [¹¹C]MPT, our first-generation agonist radiotracer, shows in vivo specificity in baboons; however, its utility is limited owing to slow washout and immeasurable plasma free fraction. Hence we performed structure-activity relationship studies of MPT to optimize a radiotracer that will permit valid quantification of 5-HT_1A receptor binding. We now report the synthesis and evaluation of [¹¹C]MMP as an agonist PET tracer for 5-HT_1A receptors in baboons. Methods In vitro binding assays were performed in bovine hippocampal membranes and membranes of CHO cells expressing 5-HT_1A receptors. [¹¹C] labeling of MMP was performed by reacting desmethyl-MMP with [¹¹C]CH₃OTf. In vivo studies were performed in baboons, and blocking studies were conducted by pretreatment with 5-HT_1A receptor ligands WAY-100635 and (±)-8-OH-DPAT. Results MMP is a selective 5-HT_1A receptor agonist (K _i 0.15 nM). Radiosynthesis of [¹¹C]MMP was achieved in 30 ± 5% (n = 15) yield at EOS with a specific activity of 2,600 ± 500 Ci/mmol (n = 12). PET studies in baboons demonstrated specific binding of [¹¹C]MMP to 5-HT_1A receptor-enriched brain regions, as confirmed by blockade with WAY-100635 and (±)-8-OH-DPAT. Conclusion We identified [¹¹C]MMP as an optimal agonist PET tracer that shows quantifiable, specific binding in vivo to 5-HT_1A receptors in baboons.     

Peripheral metabolism of (R)-[11C]verapamil in epilepsy patients

Purpose (R)-[¹¹C]verapamil is a new PET tracer for P-glycoprotein-mediated transport at the blood-brain barrier. For kinetic analysis of (R)-[¹¹C]verapamil PET data the measurement of a metabolite-corrected arterial input function is required. The aim of this study was to assess peripheral (R)-[¹¹C]verapamil metabolism in patients with temporal lobe epilepsy and compare these data with previously reported data from healthy volunteers. Methods Arterial blood samples were collected from eight patients undergoing (R)-[¹¹C]verapamil PET and selected samples were analysed for radiolabelled metabolites of (R)-[¹¹C]verapamil by using an assay that measures polar N-demethylation metabolites by solid-phase extraction and lipophilic N-dealkylation metabolites by HPLC. Results Peripheral metabolism of (R)-[¹¹C]verapamil was significantly faster in patients compared to healthy volunteers (AUC of (R)-[¹¹C]verapamil fraction in plasma: 29.4 ± 3.9 min for patients versus 40.8 ± 5.0 min for healthy volunteers; p < 0.0005, Student’s t-test), which resulted in lower (R)-[¹¹C]verapamil plasma concentrations (AUC of (R)-[¹¹C]verapamil concentration, normalised to injected dose per body weight: 25.5 ± 2.1 min for patients and 30.5 ± 5.9 min for healthy volunteers; p = 0.038). Faster metabolism appeared to be mainly due to increased N-demethylation as the polar [¹¹C]metabolite fraction was up to two-fold greater in patients. Conclusions Faster metabolism of (R)-[¹¹C]verapamil in epilepsy patients may be caused by hepatic cytochrome P450 enzyme induction by antiepileptic drugs. Based on these data caution is warranted when using an averaged arterial input function derived from healthy volunteers for the analysis of patient data. Moreover, our data illustrate how antiepileptic drugs may decrease serum levels of concomitant medication, which may eventually lead to a loss of therapeutic efficacy.     

Human biodistribution and radiation dosimetry of 11C-(R)-PK11195, the prototypic PET ligand to image inflammation

Purpose  

The positron emission tomography (PET) radiotracer ¹¹C-(R)-PK11195 allows the in vivo imaging in humans of the translocator protein 18 kDa (TSPO), previously called peripheral benzodiazepine receptor (PBR), a marker of inflammation. Despite its widespread use, the radiation burden associated with ¹¹C-(R)-PK11195 in humans is not known. To examine this, we performed dynamic whole-body imaging with PET and ¹¹C-(R)-PK11195 in healthy humans.     

Peripheral benzodiazepine receptors in the brain of cirrhosis patients with manifest hepatic encephalopathy

Purpose It has been suggested that ammonia-induced enhancement of peripheral benzodiazepine receptors (PBRs) in the brain is involved in the development of hepatic encephalopathy (HE). This hypothesis is based on animal experiments and studies of post-mortem human brains using radiolabelled PK11195, a specific ligand for PBR, but to our knowledge has not been tested in living patients. The aim of the present study was to test this hypothesis by measuring the number of cerebral PBRs in specific brain regions in cirrhotic patients with an acute episode of clinically manifest HE and healthy subjects using dynamic ¹¹C-PK11195 brain PET. Methods Eight cirrhotic patients with an acute episode of clinically manifest HE (mean arterial ammonia 81 μmol/l) and five healthy subjects (22 μmol/l) underwent dynamic ¹¹C-PK11195 and ¹⁵O-H₂O PET, co-registered with MR images. Brain regions (putamen, cerebellum, cortex and thalamus) were delineated on co-registered ¹⁵O-H₂ ¹⁵O and MR images and copied to the dynamic ¹⁵O-H₂O and ¹¹C-PK11195 images. Regional cerebral blood flow (CBF) (¹⁵O-H₂O scan) and the volume of distribution of PK11195 (¹¹C-PK11195 scan) were calculated by kinetic analysis. Results There were regional differences in the CBF, with lowest values in the cortex and highest values in the putamen in both groups of subjects (p<0.05), but no significant differences between the groups. There were no significant differences in the volume of distribution of PK11195 (V _d) between regions or between the two groups of subjects. Mean values of V _d ranged from 1.0 to 1.1 in both groups of subjects. Conclusion The results do not confirm the hypothesis of an increased number of PBRs in patients with HE.     

<Superscript>18</Superscript>F-FDG PET analysis of schwannoma: increase of SUVmax in the delayed scan is correlated with elevated VEGF/VPF expression in the tumors

Objective  In order to clarify the increased 2-deoxy-2-fluoro-¹⁸F-d-glucopyranose (¹⁸F-FDG) accumulation in schwannoma by positron emission tomography (PET) analysis, immunohistochemical analysis for the factors involved in glucose transportation and vascular formation was performed. Materials and methods  Twenty-six patients with schwannoma (13 men and 13 women) with ages ranging from 27 to 75 years, who received whole body ¹⁸F-FDG PET scan, were enrolled for the present study. The retention index (RI) was calculated by dividing the increase in the standardized uptake value (SUVmax) at the delayed scan by the SUVmax in the early scan. SUVmax and RI were compared with the histologic variables, including the expression of glucose transporters 1 and 3, hexokinase II, vascular endothelial growth factor/vascular permeability factor (VEGF/VPF), and microvascular density shown by CD31 immunohistochemistry. Results  Mean SUVmax values in the early and delayed scans were 2.64 ± 1.47 and 2.71 ± 1.57 (mean ± SD), respectively. RI was −2.5 ± 21 (percentage). SUVmax showed a positive correlation with the tumor size (tumor size <5 cm, 2.06 ± 0.72; >5 cm, 3.95 ± 1.89; p < 0.05) and the microvascular density (negative density, 2.16 ± 1.12; positive density, 3.56 ± 1.67; p < 0.05). RI correlated with VEGF/VPF expression in the tumors (negative expression, −11 ± 6.1; positive expression, 13 ± 8.1; p < 0.05). Other factors showed no correlation with SUVmax or RI. Conclusions  Microvascular density and vascular permeability of the tumor are suggested to affect the enhanced ¹⁸F-FDG accumulation in schwannoma.     

Uptake of inflammatory cell marker [<Superscript>11</Superscript>C]PK11195 into mouse atherosclerotic plaques

Purpose  The ligand [¹¹C]PK11195 binds with high affinity and selectivity to peripheral benzodiazepine receptor, expressed in high amounts in macrophages. In humans, [¹¹C]PK11195 has been used successfully for the in vivo imaging of inflammatory processes of brain tissue. The purpose of this study was to explore the feasibility of [¹¹C]PK11195 in imaging inflammation in the atherosclerotic plaques. Methods  The presence of PK11195 binding sites in the atherosclerotic plaques was verified by examining the in vitro binding of [³H]PK11195 onto mouse aortic sections. Uptake of intravenously administered [¹¹C]PK11195 was studied ex vivo in excised tissue samples and aortic sections of a LDLR/ApoB48 atherosclerotic mice. Accumulation of the tracer was compared between the atherosclerotic plaques and non-atherosclerotic arterial sites by autoradiography and histological analyses. Results  The [³H]PK11195 was found to bind to both the atherosclerotic plaques and the healthy wall. The autoradiography analysis revealed that the uptake of [¹¹C]PK11195 to inflamed regions in plaques was more prominent (p = 0.011) than to non-inflamed plaque regions, but overall it was not higher than the uptake to the healthy vessel wall. Also, the accumulation of ¹¹C radioactivity into the aorta of the atherosclerotic mice was not increased compared to the healthy control mice. Conclusions  Our results indicate that the uptake of [¹¹C]PK11195 is higher in inflamed atherosclerotic plaques containing a large number of inflammatory cells than in the non-inflamed plaques. However, the tracer uptake to other structures of the artery wall was also prominent and may limit the use of [¹¹C]PK11195 in clinical imaging of atherosclerotic plaques.     

Detection of gastric cancer using <Superscript>18</Superscript>F-FLT PET: comparison with <Superscript>18</Superscript>F-FDG PET

Purpose  We prospectively investigated the feasibility of 3′-deoxy-3′-¹⁸F-fluorothymidine (FLT) positron emission tomography (PET) for the detection of gastric cancer, in comparison with 2-deoxy-2-¹⁸F-fluoro-d-glucose (FDG) PET, and determined the degree of correlation between the two radiotracers and proliferative activity as indicated by Ki-67 index. Methods  A total of 21 patients with newly diagnosed advanced gastric cancer were examined with FLT PET and FDG PET. Tumour lesions were identified as areas of focally increased uptake, exceeding that of surrounding normal tissue. For semiquantitative analysis, the maximal standardized uptake value (SUV) was calculated. Results  For detection of advanced gastric cancer, the sensitivities of FLT PET and FDG PET were 95.2% and 95.0%, respectively. The mean (±SD) SUV for FLT (7.0 ± 3.3) was significantly lower than that for FDG (9.4 ± 6.3 p < 0.05). The mean FLT SUV and FDG SUV in nonintestinal tumours were higher than in intestinal tumours, although the difference was not statistically significant. The mean (±SD) FLT SUV in poorly differentiated tumours (8.5 ± 3.5) was significantly higher than that in well and moderately differentiated tumours (5.3 ± 2.1; p < 0.04). The mean FDG SUV in poorly differentiated tumours was higher than in well and moderately differentiated tumours, although the difference was not statistically significant. There was no significant correlation between Ki-67 index and either FLT SUV or FDG SUV. Conclusion  FLT PET showed as high a sensitivity as FDG PET for the detection of gastric cancer, although uptake of FLT in gastric cancer was significantly lower than that of FDG.     

[<Superscript>11</Superscript>C]choline PET/CT imaging in occult local relapse of prostate cancer after radical prostatectomy

Purpose The aim of this study was to assess the accuracy and clinical impact of [¹¹C]choline PET/CT for localizing occult relapse of prostate adenocarcinoma after radical prostatectomy. Methods Fourty-nine patients with prostate adenocarcinoma, radical prostatectomy, no evidence of metastatic disease, and occult relapse underwent [¹¹C]choline PET/CT. Thirty-six of the patients had biochemical evidence and histological evaluation of local recurrence. Thirteen patients had PSA < 0.3 ng/ml and no evidence of active disease after 1 year follow-up. Focal nodular [¹¹C]choline uptake in the prostatic fossa was visually assessed and graded on a five point scale. Maximum standardized radioactivity uptake value (SUV_max) and the lesion size were measured. A receiver operating characteristic (ROC) analysis was performed and the clinical impact of the PET/CT study was determined. Results [¹¹C]choline PET/CT was true positive in 23/33 patients and true negative in 12/13 controls. SUV_max of local recurrence was 3.0 (median, range 0.6–7.4) and 1.1 (0.4–1.6) in controls (p = 0.0002). Lesion size was 1.7 cm (range 0.9–3.7). Area under the ROC curve for detecting relapse was 0.90 ± 0.05 and 0.83 ± 0.06 for visual evaluation and SUV_max, respectively. Sensitivity and specificity of [¹¹C]choline PET/CT were 0.73 and 0.88, respectively. [¹¹C]choline PET/CT identified 12/17 (71%) patients with a favourable biochemical response to local radiotherapy at 2 year (median, 0.8–3.2 range) follow-up. Conclusions Focally increased [¹¹C]choline uptake in the prostatic bed reliably predicted local low volume occult relapsing prostate adenocarcinoma after radical prostatectomy and identified 71% of patients with a favourable biochemical response to local radiotherapy.     

11C-DPA-713: a novel peripheral benzodiazepine receptor PET ligand for in vivo imaging of neuroinflammation.

The induction of neuroinflammatory processes, characterized by upregulation of the peripheral benzodiazepine receptor (PBR) expressed by microglial cells, is well correlated with neurodegenerative diseases and with acute neuronal loss. The continually increasing incidence of neurodegenerative diseases in developed countries has become a major health problem, for which the development of diagnostic and follow-up tools is required. Here we investigated a new PBR ligand suitable for PET to monitor neuroinflammatory processes as an indirect hallmark of neurodegeneration. METHODS: We compared PK11195, the reference compound for PBR binding sites, with the new ligand DPA-713 (N,N-diethyl-2-[2-(4-methoxyphenyl)-5,7-dimethylpyrazolo[1,5-a]pyrimidin-3-yl]acetamide), using a small-animal dedicated PET camera in a model of neuroinflammation in rats. Seven days after intrastriatal injection of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA), a PET scan was performed using (11)C-PK11195 or (11)C-DPA-713. Immunohistochemistry for neuronal (NeuN), astrocyte (glial fibrillary acidic protein), and microglial (CD11) specific markers as well as (3)H-PK11195 autoradiographic studies were then correlated with the imaging data. RESULTS: Seven days after a unilateral injection of AMPA in the striatum, (11)C-DPA-713 exhibits a better contrast between healthy and damaged brain parenchyma than (11)C-PK11195 (2.5-fold +/- 0.14 increase vs. 1.6-fold +/- 0.05 increase, respectively). (11)C-DPA-713 and (11)C-PK11195 exhibit similar brain uptake in the ipsilateral side, whereas, in the contralateral side, (11)C-DPA-713 uptake was significantly lower than (11)C-PK11195. Modeling of the data using the simplified reference tissue model shows that the binding potential was significantly higher for (11)C-DPA-713 than for (11)C-PK11195. CONCLUSION: (11)C-DPA-713 displays a higher signal-to-noise ratio than (11)C-PK11195 because of a lower level of unspecific binding that is likely related to the lower lipophilicity of (11)C-DPA-713. Although further studies in humans are required, (11)C-DPA-713 represents a suitable alternative to (11)C-PK11195 for PET of PBR as a tracer of neuroinflammatory processes induced by neuronal stress.     

Usefulness of <Superscript>18</Superscript>F-fluorodeoxyglucose positron emission tomography for diagnosing disease activity and monitoring therapeutic response in patients with pulmonary mycobacteriosis

Purpose  To evaluate the usefulness of ¹⁸F-FDG PET in the imaging of pulmonary lesions related to disease activity and in monitoring responses to treatment in patients with pulmonary mycobacteriosis (PM). Materials and methods  We used high-resolution computed tomography (HRCT) and ¹⁸F-FDG PET to evaluate 47 consecutive untreated patients with PM, 25 with tuberculosis (TB) and 22 with Mycobacterium avium-intracellulare complex (MAC), who presented with small peripheral pulmonary nodules ≤3 cm, and compared the findings. The diagnosis of mycobacteriosis was confirmed by bacteriological examinations of bronchoscopic or surgically resected specimens. PET scans were visually and quantitatively analysed using SUVmax. In addition, 14 patients with PM underwent repeat PET scanning during antimycobacterial therapy, and changes in ¹⁸F-FDG uptake were clinically evaluated (6 during treatment and 12 after treatment). Results  Of all the lesions, 87.2% had SUVmax levels ranging from 3 to 7 (5.05 ± 1.56, range 2.5–7.6, n = 47). Further, SUV levels in patients with PM reflected disease activity as estimated by HRCT, but did not differ significantly between those with TB (4.96 ± 1.61, n = 25) and MAC (5.15 ± 1.53, n = 22). ¹⁸F-FDG uptake was significantly decreased in all 14 patients who received chemotherapy, indicating a positive response to treatment. Conclusion   ¹⁸F-FDG PET is considered to be useful for the diagnosis and evaluation of disease activity along with HRCT findings, and in monitoring response to chemotherapy in patients with PM.     

<Superscript>18</Superscript>F-FDG PET/CT findings of sinonasal inverted papilloma with or without coexistent malignancy: comparison with MR imaging findings in eight patients

Introduction  Sinonasal inverted papilloma (IP) is known for high rate of associated malignancy. The purpose of this study was to identify ¹⁸F-FDG PET/CT findings of sinonasal IPs. We also tried to compare the PET/CT findings with the MR imaging findings. Methods  We retrospectively reviewed PET/CT and MR images of eight patients with sinonasal IP with (n = 6) or without (n = 2) coexistent squamous cell carcinoma (SCC). Particular attention was paid to correlate the PET/CT findings with the MR imaging findings in terms of area distribution of standard uptake values (SUVs) and a convoluted cerebriform pattern (CCP). Results  In two benign IPs, the maximum SUVs measured 8.2 and 7.8, respectively (mean, 8.0). In both tumors, MR images demonstrated a diffuse CCP. In six IPs with coexistent SCC, the maximum SUVs ranged from 13.3 to 31.9 (mean ± SD, 20.2 ± 6.6). In these tumors, MR images demonstrated a diffuse CCP in two, a partial CCP in three, and no CCP in one. A wide discrepancy was noted between MR imaging and PET/CT in terms of area distribution of a CCP and SUVs. Conclusion  In sinonasal lesions with MR imaging features of IP, ¹⁸F-FDG PET/CT demonstrating avid FDG uptake does not necessarily imply the presence of coexistent malignancy. In our small series, although IPs containing foci of SCC had consistently higher SUVs than IPs without SCC, the limited literature on this subject suggests that PET cannot be used reliably to make the distinction.     

Quantification of (<Emphasis Type="Italic">R</Emphasis>)-[<Superscript>11</Superscript>C]PK11195 binding in rheumatoid arthritis

Purpose  Rheumatoid arthritis (RA) involves migration of macrophages into inflamed areas. (R)-[¹¹C]PK11195 binds to peripheral benzodiazepine receptors, expressed on macrophages, and may be used to quantify inflammation using positron emission tomography (PET). This study evaluated methods for the quantification of (R)-[¹¹C]PK11195 binding in the knee joints of RA patients. Methods  Data from six patients with RA were analysed. Dynamic PET scans were acquired in 3-D mode following (R)-[¹¹C]PK11195 injection. During scanning arterial radioactivity concentrations were measured to determine the plasma (R)-[¹¹C]PK11195 concentrations. Data were analysed using irreversible and reversible one-tissue and two-tissue compartment models and input functions with various types of metabolite correction. Model preferences according to the Akaike information criterion (AIC) and correlations between measures were evaluated. Correlations between distribution volume (V_d) and standardized uptake values (SUV) were evaluated. Results  AIC indicated optimal performance for a one-tissue reversible compartment model including blood volume. High correlations were observed between V_d obtained using different input functions (R ²=0.80–1.00) and between V_d obtained with one- and two-tissue reversible compartment models (R ²=0.75–0.94). A high correlation was observed between optimal V_d and SUV after injection (R ²=0.73). Conclusion  (R)-[¹¹C]PK11195 kinetics in the knee were best described by a reversible single-tissue compartment model including blood volume. Applying metabolite corrections did not increase sensitivity. Due to the high correlation with V_d, SUV is a practical alternative for clinical use. Financial support: There were no sources of financial support other than the VU University Medical Centre. The authors had full control of all primary data and agree to allow EJNM to review their data if requested.     

Comparison of MRI (including SS SE-EPI and SPIO-enhanced MRI) and FDG-PET/CT for the detection of colorectal liver metastases

Fluoro-18-deoxyglucose positron emission tomography computed tomography (FDG-PET/CT) and magnetic resonance imaging (MRI), including unenhanced single-shot spin-echo echo planar imaging (SS SE-EPI) and small paramagnetic iron oxide (SPIO) enhancement, were compared prospectively for detecting colorectal liver metastases. Twenty-four consecutive patients suspected for metastases underwent MRI and FDG-PET/CT. Fourteen patients (58%) had previously received chemotherapy, including seven patients whose chemotherapy was still continuing to within 1 month of the PET/CT study. The mean interval between PET/CT and MRI was 10.2 ± 5.2 days. Histopathology (n = 18) or follow-up imaging (n = 6) were used as reference. Seventy-seven metastases were detected. In nine patients, MRI and PET/CT gave concordant results. Sensitivities for unenhanced SS SE-EPI, MRI without SS SE-EPI and FDG-PET/CT were, respectively, 100% (p = 9 × 10⁻¹⁰ vs PET, p = 8 × 10⁻³ vs MRI without SS SE-EPI), 90% (p = 2 × 10⁻⁷ vs PET) and 60%. PET/CT sensitivity dropped significantly with decreasing size, from 100% in lesions larger than 20 mm (identical to MRI), over 54% in lesions between 10 and 20 mm (p = 3 × 10⁵ versus unenhanced SS SE-EPI), to 32% in lesions under 10 mm (p = 6 × 10⁻⁵ versus unenhanced SS SE-EPI). Positive predictive value of PET was 100% (identical to MRI). MRI, particularly unenhanced SS SE-EPI, has good sensitivity and positive predictive value for detecting liver metastases from colorectal carcinoma. Its sensitivity is better than that of FDG-PET/CT, especially for small lesions.     

Disseminated iodine-avid lung metastases in differentiated thyroid cancer: a challenge to 124I PET

Aim This study assessed the ability of visual and quantitative 124-iodine positron emission tomography (¹²⁴I PET) data to detect disseminated iodine-avid lung metastases (DILM) of differentiated thyroid cancer (DTC). Materials and methods Using “post-therapy” 131-iodine (¹³¹I) whole-body scintigraphy (TxWBS) and thoracic computed tomography (CT), we retrospectively divided 70 consecutive DTC patients undergoing ¹²⁴I PET dosimetry ∼1 week before ¹³¹I therapy into subgroups positive (n = 7) or negative (n = 63) for DILM, defined as lung metastases visible on TxWBS but not thoracic CT. To determine whether ¹²⁴I PET data could distinguish patients with versus without DILM, we compared these data with the TxWBS findings. The ¹²⁴I PET data were acquired via whole-body PET scans ∼24 h after oral administration of ¹²⁴I, 24 ± 2 MBq. Quantitative data comprised absolute lung ¹²⁴I activity concentrations and lung-to-background (L/B) ¹²⁴I uptake ratios. Results Only 1/7 DILM-positive patients had visible disseminated lung uptake. Absolute ¹²⁴I lung uptake activities overlapped considerably between both groups and did not differ significantly (P = 0.150). Mean L/B ratios, however, differed significantly between the DILM-positive and negative groups (P < 0.001). Nevertheless, L/B ratios overlapped between the groups (0.62–1.37 versus 0.13–0.69). Conclusion Quantitative analysis of ¹²⁴I PET data using the L/B ratio is a promising tool to detect patients suspicious for DILM. However, L/B ratios overlapped between the groups to an extent that an unequivocal diagnosis based solely on this criterion was impossible in some patients. In those cases, additional diagnostic tests are necessary for diagnosis.     

Dual-time-point <Superscript>18</Superscript>F-FDG PET imaging for diagnosis of disease type and disease activity in patients with idiopathic interstitial pneumonia

Purpose  Individual clinical courses of idiopathic interstitial pneumonia (IIP) are variable and difficult to predict because the pathology and disease activity are contingent, and chest computed tomography (CT) provides little information about disease activity. In this study, we applied dual-time-point [¹⁸F]-fluoro-2-deoxy-D-glucose (¹⁸F-FDG) positron emission tomography (PET), commonly used for diagnosis of malignant tumours, to the differential diagnosis and prediction of disease progression in IIP patients. Methods  Fifty patients with IIP, including idiopathic pulmonary fibrosis (IPF, n = 21), non-specific interstitial pneumonia (NSIP, n = 18) and cryptogenic organizing pneumonia (COP, n = 11), underwent ¹⁸F-FDG PET examinations at two time points: scan 1 at 60 min (early imaging) and scan 2 at 180 min (delayed imaging) after ¹⁸F-FDG injection. The standardized uptake values (SUV) at the two points and the retention index (RI-SUV) calculated from them were evaluated and compared with chest CT findings, disease progression and disease types. To evaluate short-term disease progression, all patients were examined by pulmonary function test every 3 months for 1 year after ¹⁸F-FDG PET scanning. Results  The early SUV for COP (2.47 ± 0.74) was significantly higher than that for IPF (0.99 ± 0.29, p = 0.0002) or NSIP (1.22 ± 0.44, p= 0.0025). When an early SUV cut-off value of 1.5 and greater was used to distinguish COP from IPF and NSIP, the sensitivity, specificity and accuracy were 90.9, 94.3 and 93.5%, respectively. The RI-SUV for IPF and NSIP lesions was significantly greater in patients with deteriorated pulmonary function after 1 year of follow-up (progressive group, 13.0 ± 8.9%) than in cases without deterioration during the 1-year observation period (stable group, −16.8 ± 5.9%, p < 0.0001). However, the early SUV for all IIP types provided no additional information of disease progression. When an RI-SUV cut-off value of 0% and greater was used to distinguish progressive IIPs from stable IIPs, the sensitivity, specificity and accuracy were 95.5, 100 and 97.8%, respectively. Conclusion  Early SUV and RI-SUV obtained from dual-time-point ¹⁸F-FDG PET are useful parameters for the differential diagnosis and prediction of disease progression in patients with IIP.     

Dual-modality optical and positron emission tomography imaging of vascular endothelial growth factor receptor on tumor vasculature using quantum dots

Purpose  To date, the in vivo imaging of quantum dots (QDs) has been mostly qualitative or semiquantitative. The development of a dual-function positron emission tomography (PET)/near-infrared fluorescence (NIRF) probe might allow the accurate assessment of the tumor-targeting efficacy of QDs. Materials and methods  An amine-functionalized QD was conjugated with VEGF protein and DOTA chelator for VEGFR-targeted PET/NIRF imaging after ⁶⁴Cu-labeling. The targeting efficacy of this dual functional probe was evaluated in vitro and in vivo through cell-binding assay, cell staining, in vivo optical/PET imaging, ex vivo optical/PET imaging, and histology. Results  The DOTA–QD–VEGF exhibited VEGFR-specific binding in both cell-binding assay and cell staining experiment. Both NIR fluorescence imaging and microPET showed VEGFR-specific delivery of conjugated DOTA–QD–VEGF nanoparticle and prominent reticuloendothelial system uptake. The U87MG tumor uptake of ⁶⁴Cu-labeled DOTA–QD was less than one percentage injected dose per gram (%ID/g), significantly lower than that of ⁶⁴Cu-labeled DOTA–QD–VEGF (1.52 ± 0.6%ID/g, 2.81 ± 0.3%ID/g, 3.84 ± 0.4%ID/g, and 4.16 ± 0.5%ID/g at 1, 4, 16, and 24 h post injection, respectively; n = 3). Good correlation was also observed between the results measured by ex vivo PET and NIRF organ imaging. Histologic examination revealed that DOTA–QD–VEGF primarily targets the tumor vasculature through a VEGF–VEGFR interaction. Conclusion  We have successfully developed a QD-based nanoprobe for dual PET and NIRF imaging of tumor VEGFR expression. The success of this bifunctional imaging approach may render higher degree of accuracy for the quantitative targeted NIRF imaging in deep tissue.     

Radiation dosimetry and biodistribution of 11C-ABP688 measured in healthy volunteers

Introduction In this study, we assessed the whole-body biodistribution and radiation dosimetry of the new glutamatergic ligand ¹¹C-ABP688. This ligand binds specifically to the metabotropic glutamatergic receptor of subtype 5 (mGluR5). Materials and methods The study included five healthy male volunteers aged 20–29 years. After intravenous injection of 240–260 MBq, a series of four to ten whole-body positron emission tomography/computed tomography scans were initiated, yielding 60–80 min of data. Residence times were then calculated in the relevant organs, and the software packages Mirdose and Olinda were used to calculate the absorbed radiation dose and the effective dose equivalent. Results Of the excreted ¹¹C activity at 1 hour, approximately 80% were eliminated via the hepato-biliary pathway and 20% through the urinary tract. The absorbed dose (mGy/MBq) was highest in the liver (1.64 E -2 ± 5.08 E -3), gallbladder (8.13 E -3 ± 5.6 E -3), and kidneys (7.27 E -3 ± 2.79 E -3). The effective dose equivalent was 3.68 ± 0.84 microSv/MBq. Brain uptake in the areas with high mGluR5 density was 2–3 (SUV). The agreement between the values obtained from Mirdose and the Olinda was excellent. Conclusion ¹¹C-ABP688 is a very promising ligand for the investigation of mGluR5 receptors in humans. Brain uptake is high and the effective dose equivalent so low that serial examinations in the same subject seem feasible.     

The efficacy of whole-body FDG-PET or PET/CT for autoimmune pancreatitis and associated extrapancreatic autoimmune lesions

Purpose The aim of this study was to evaluate retrospectively the efficacy of whole-body ¹⁸F-fluorodeoxyglucose positron emission tomography (FDG-PET) for autoimmune pancreatitis (AIP) and associated extrapancreatic autoimmune lesions. Methods Whole-body FDG-PET or PET/computed tomography (CT) findings were reviewed in six patients with AIP. The initial PET scans were performed 1 h and 2 h after FDG injection in all six patients. Follow-up PET scans were performed during or following steroid therapy in five patients and in one patient who did not have steroid therapy. Results The initial PET scans revealed intense FDG uptake by AIP in all six patients. The maximum standardized uptake value (SUVmax) increased in four patients and was stable in two patients. The intense uptake in the pancreas disappeared during or following steroid therapy in five patients and in one patient who showed spontaneous remission of AIP. Abnormal FDG uptake by extrapancreatic autoimmune diseases was observed in five of the six patients: sclerosing sialadenitis (n = 5), lymphadenopathy (n = 5), retroperitoneal fibrosis (n = 2), interstitial nephritis (n = 2) and sclerosing cholecystitis (n = 1). Abnormal FDG uptake disappeared in the salivary glands (n = 4), lymph nodes (n = 4), retroperitoneum (n = 2), kidneys (n = 1) and gallbladder (n = 1) during or following steroid therapy and remained in the salivary glands and lymph nodes of a spontaneous remission patient. Conclusion These results suggest that whole-body FDG-PET may be useful for detecting AIP and associated extrapancreatic autoimmune lesions and for monitoring their disease activity but that dual time point imaging may not be useful for differentiating malignancy from AIP.     

Tumour hypoxia imaging with [18F]FAZA PET in head and neck cancer patients: a pilot study

Purpose Hypoxia is an important negative prognostic factor for radiation treatment of head and neck cancer. This study was performed to evaluate the feasibility of use of ¹⁸F-labelled fluoroazomycin arabinoside ([¹⁸F]FAZA) for clinical PET imaging of tumour hypoxia. Methods Eleven patients (age 59.6 ± 9 years) with untreated advanced head and neck cancer were included. After injection of approximately 300 MBq of [¹⁸F]FAZA, a dynamic sequence up to 60 min was acquired on an ECAT HR+ PET scanner. In addition, approximately 2 and 4 h p.i., static whole-body PET (n = 5) or PET/CT (n = 6) imaging was performed. PET data were reconstructed iteratively (OSEM) and fused with CT images (either an external CT or the CT of integrated PET/CT). Standardised uptake values (SUVs) and tumour-to-muscle (T/M) ratios were calculated in tumour and normal tissues. Also, the tumour volume displaying a T/M ratio >1.5 was determined. Results Within the first 60 min of the dynamic sequence, the T/M ratio generally decreased, while generally increasing at later time points. At 2 h p.i., the tumour SUV_max and SUV_mean were found to be 2.3 ± 0.5 (range 1.5–3.4) and 1.4 ± 0.3 (range 1.0–2.1), respectively. The mean T/M ratio at 2 h p.i. was 2.0 ± 0.3 (range 1.6–2.4). The tumour volume displaying a T/M ratio above 1.5 was highly variable. At 2 h p.i., [¹⁸F]FAZA organ distribution was determined as follows: kidney > gallbladder > liver > tumour > muscle > bone > brain > lung. Conclusion [¹⁸F]FAZA PET imaging appears feasible in head and neck cancer patients, and the achieved image quality is adequate for clinical purposes. Based on our initial results, [¹⁸F]FAZA warrants further evaluation as a hypoxia PET tracer for imaging of cancer.     

Coronary and peripheral endothelial function in HIV patients studied with positron emission tomography and flow-mediated dilation: relation to hypercholesterolemia

Background  The mechanisms underlying increased cardiovascular risk in HIV patients in antiretroviral therapy (ART) are not known. Our aim was to study the endothelial function of the coronary arteries by cardiac perfusion positron emission tomography (PET), in HIV patients with normal or high cholesterol levels. Flow mediated dilation (FMD) of the brachial artery and circulating endothelial markers were also assessed. Methods and results  HIV patients in ART with total cholesterol ≤ 5.5 mmol/L (215 mg/dL; n = 13) or total cholesterol ≥ 6.5 mmol/L (254 mg/dL; n = 12) and healthy controls (n = 14) were included. ¹³NH₃ perfusion PET, FMD, and measurement of plasma levels of E-Selectin, ICAM-1, VCAM-1, tPAI-1, and hs-CRP were performed. Baseline myocardial perfusion and the coronary flow reserve measured by PET (3.2 ± 0.3, 3.2 ± 0.3 and 3.0 ± 0.3; ns) was similar in HIV patients with normal or high total cholesterol and controls. FMD did not differ between the groups and was 4.6 ± 1.1%, 5.1 ± 1.2%, and 4.6 ± 0.8%, respectively. Increased levels of plasma E-Selectin, ICAM-1, tPAI-1, and hs-CRP were found in HIV patients when compared to controls (p < 0.05). E-Selectin and ICAM-1 levels were higher in HIV patients receiving protease inhibitors (PI) compared to those not receiving PI (p < 0.05). None of the measured endothelial biomarkers differed between the normal and high cholesterol HIV groups. Conclusions  In ART-treated HIV patients with a low overall cardiovascular risk, no sign of endothelial dysfunction was found not even in hypercholesterolemic patients. Also, the increased level of plasma endothelial markers found in HIV patients was not related to hypercholesterolemia.