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1.  Combined SPECT and multidetector CT for prostate cancer evaluations 
111In-capromab pendetide is an imaging probe for noninvasive detection of prostate cancer dissemination, and can be difficult to interpret because of low photon statistics resulting in noisy images with limited anatomical precision. We examined if a 16-slice multidetector computed tomography (MDCT) combined with single photon emission computed tomography (SPECT) could increase the impact on the clinical management and improve confidence in SPECT image interpretations in comparison to a relatively low-mA (limited resolution) CT. 17 scans were reviewed from a SPECT combined with low-mA CT scanner; 21 scans were reviewed from a SPECT combined with 16-slice MDCT scanner. Reports of the clinical interpretations from the imaging studies, additional examinations performed by referring physicians as a follow-up to the imaging results, and long-term clinical and laboratory follow-ups were used to define confidence of the SPECT/CT readings and impact of the readings on the patient management. The impact was defined as: the occurrence of the 111In-capromab pendetide interpretation resulted in additional imaging studies or biopsies. MDCT improved the quality and confidence in the characterization of small lymph nodes with or without uptake of 111In-capromab pendetide. The increased confidence with MDCT in SPECT/CT readings was evident in all cases reviewed in this study, and the impact on the clinical management was higher (8 out of 21) using SPECT/MDCT than the impact using SPECT combined with low-mA CT (2 out of 17). The dual-modality SPECT/CT provides a quantifiable benefit when MDCT is used instead of low-mA CT, particularly for prostate cancer evaluations using 111In-capromab pendetide.
PMCID: PMC3260786  PMID: 22267999
Prostate cancer; capromab pendetide; SPECT/CT; MDCT; prostate specific membrane antigen (PSMA)
2.  Positron emission tomography imaging of CD105 expression in a rat myocardial infarction model with 64Cu-NOTA-TRC105 
Biological changes following myocardial infarction (MI) lead to increased secretion of angiogenic factors that subsequently stimulate the formation of new blood vessels as a compensatory mechanism to reverse ischemia. The goal of this study was to assess the role of CD105 expression during MI-induced angiogenesis by positron emission tomography (PET) imaging using 64Cu-labeled TRC105, an anti-CD105 monoclonal antibody. MI was induced by ligation of the left anterior descending (LAD) artery in female rats. Echocardiography and 18F-fluoro-2-deoxy-D-glucose (18F-FDG) PET scans were performed on post-operative day 3 to confirm the presence of MI in the infarct group and intact heart in the sham group, respectively. Ischemia-induced angiogenesis was non-invasively monitored with 64Cu-NOTA-TRC105 (an extensively validated PET tracer in our previous studies) PET on post-operative days 3, 10, and 17. Tracer uptake in the infarct zone was highest on day 3 following MI, which was significantly higher than that in the sham group (1.41 ± 0.45 %ID/g vs 0.57 ± 0.07 %ID/g; n=3, p<0.05). Subsequently, tracer uptake in the infarct zone decreased over time to the background level on day 17, whereas tracer uptake in the heart of sham rats remained low at all time points examined. Histopathology documented increased CD105 expression following MI, which corroborated in vivo findings. This study indicated that PET imaging of CD105 can be a useful tool for MI-related research, which can potentially improve MI patient management in the future upon clinical translation of the optimized PET tracers.
PMCID: PMC3867724  PMID: 24380040
Angiogenesis; myocardial infarction (MI); positron emission tomography (PET); CD105 (endoglin); molecular imaging; 64Cu
3.  Comparative evaluation of the diagnostic accuracy of 99mTc-sestamibi gated SPECT using five different sets of image acquisitions at stress and rest phases for the diagnosis of coronary artery disease 
On the basis of some new evidences in favor of delayed 99mTc methoxy-isobutyl-isonitrile (99mTc-MIBI) redistribution, doubts about the appropriate time of acquisition following radiotracer injection may be raised. The goal of this study was to find the best acquisition time at stress and rest phases to achieve the highest sensitivity and normalcy rate for 99mTc-MIBI SPECT. Ninety four patients with moderate pretest probability of coronary artery disease (CAD) according to “Framingham Risk Score” enrolled in the study. Myocardial perfusion imaging (MPI) with SPECT was performed on the basis of two-day protocol with stress- and rest-phase images obtained at 15, 60, 120 and 180 minutes after injection of 666-814 MBq 99mTc-MIBI. According to the time of image acquisition at stress/rest phases, five protocols were defined: A, 15/180 min, B, 15/15 min, C, 180/180 min, D, 180/15 min and E, 120/120 min for stress and rest images, respectively. The sensitivity of MPI for the diagnosis of angiographically proven CAD were 77.3%, 50%, 63.6%, 45.5%, 68.2% and normalcy rate were 72.1%, 72.1%, 75.5%, 70.6%, 92.6% in protocol A, B, C, D and E, respectively. A significant association between SSS and Gensini score was detected only with protocol A (p=0.038). The most sensitive and specific two-day protocols for MPI with 99mTc-MIBI were protocol A and E, respectively. In addition, the best relationship between scintigraphic score of ischemia and angiographic score of CAD was achieved using protocol A (i.e. early acquisition at stress phase and late acquisition at rest phase).
PMCID: PMC3867725  PMID: 24380041
SPECT myocardial perfusion scintigraphy; 99mTc-MIBI; redistribution
4.  Design, synthesis, and evaluation of hydroxamic acid-based molecular probes for in vivo imaging of histone deacetylase (HDAC) in brain 
Hydroxamic acid-based histone deacetylase inhibitors (HDACis) are a class of molecules with therapeutic potential currently reflected in the use of suberoylanilide hydroxamic acid (SAHA; Vorinostat) to treat cutaneous T-cell lymphomas (CTCL). HDACis may have utility beyond cancer therapy, as preclinical studies have ascribed HDAC inhibition as beneficial in areas such as heart disease, diabetes, depression, neurodegeneration, and other disorders of the central nervous system (CNS). However, little is known about the pharmacokinetics (PK) of hydroxamates, particularly with respect to CNS-penetration, distribution, and retention. To explore the rodent and non-human primate (NHP) brain permeability of hydroxamic acid-based HDAC inhibitors using positron emission tomography (PET), we modified the structures of belinostat (PXD101) and panobinostat (LBH-589) to incorporate carbon-11. We also labeled PCI 34051 through carbon isotope substitution. After characterizing the in vitro affinity and efficacy of these compounds across nine recombinant HDAC isoforms spanning Class I and Class II family members, we determined the brain uptake of each inhibitor. Each labeled compound has low uptake in brain tissue when administered intravenously to rodents and NHPs. In rodent studies, we observed that brain accumulation of the radiotracers were unaffected by the pre-administration of unlabeled inhibitors. Knowing that CNS-penetration may be desirable for both imaging applications and therapy, we explored whether a liquid chromatography, tandem mass spectrometry (LC-MS-MS) method to predict brain penetrance would be an appropriate method to pre-screen compounds (hydroxamic acid-based HDACi) prior to PET radiolabeling. LC-MS-MS data were indeed useful in identifying additional lead molecules to explore as PET imaging agents to visualize HDAC enzymes in vivo. However, HDACi brain penetrance predicted by LC-MS-MS did not strongly correlate with PET imaging results. This underscores the importance of in vivo PET imaging tools in characterizing putative CNS drug lead compounds and the continued need to discover effect PET tracers for neuroepigenetic imaging.
PMCID: PMC3867727  PMID: 24380043
Hydroxamic acid; HDAC inhibitors; epigenetic; PET; brain; imaging
5.  Peptide receptor radionuclide therapy of treatment-refractory metastatic thyroid cancer using 90Yttrium and 177Lutetium labeled somatostatin analogs: toxicity, response and survival analysis 
The overall survival rate of non-radioiodine avid differentiated (follicular, papillary, medullary) thyroid carcinoma is significantly lower than for patients with iodine-avid lesions. The purpose of this study was to evaluate toxicity and efficacy (response and survival) of peptide receptor radionuclide therapy (PRRT) in non-radioiodine-avid or radioiodine therapy refractory thyroid cancer patients. Sixteen non-radioiodine-avid and/or radioiodine therapy refractory thyroid cancer patients, including follicular thyroid carcinoma (n = 4), medullary thyroid carcinoma (n = 8), Hürthle cell thyroid carcinoma (n = 3), and mixed carcinoma (n = 1) were treated with PRRT by using 90Yttrium and/or 177Lutetium labeled somatostatin analogs. 68Ga somatostatin receptor PET/CT was used to determine the somatostatin receptor density in the residual tumor/metastatic lesions and to assess the treatment response. Hematological profiles and renal function were periodically examined after treatment. By using fractionated regimen, only mild, reversible hematological toxicity (grade 1) or nephrotoxicity (grade 1) were seen. Response assessment (using EORTC criteria) was performed in 11 patients treated with 2 or more (maximum 5) cycles of PRRT and showed disease stabilization in 4 (36.4%) patients. Two patients (18.2%) showed partial remission, in the remaining 5 patients (45.5%) disease remained progressive. Kaplan-Meier analysis resulted in a mean survival after the first PRRT of 4.2 years (95% CI, range 2.9-5.5) and median progression free survival of 25 months (inter-quartiles: 12-43). In non-radioiodine-avid/radioiodine therapy refractory thyroid cancer patients, PRRT is a promising therapeutic option with minimal toxicity, good response rate and excellent survival benefits.
PMCID: PMC3867728  PMID: 24380044
Peptide radionuclide receptor therapy; non-radioiodine-avid; thyroid cancer; somatostatin receptors; survival analysis; 68Ga-DOTA-TOC; 68Ga-DOTA-TATE; positron emission tomography (PET)
6.  Myocardial blood flow measurement with a conventional dual-head SPECT/CT with spatiotemporal iterative reconstructions - a clinical feasibility study 
Cardiac single photon emission computed tomography (SPECT) cameras typically rotate too slowly around a patient to capture changes in the blood pool activity distribution and provide accurate kinetic parameters. A spatiotemporal iterative reconstruction method to overcome these limitations was investigated. Dynamic rest/stress 99mTc-methoxyisobutylisonitrile (99mTc-MIBI) SPECT/CT was performed along with reference standard rest/stress dynamic positron emission tomography (PET/CT) 13N-NH3 in five patients. The SPECT data were reconstructed using conventional and spatiotemporal iterative reconstruction methods. The spatiotemporal reconstruction yielded improved image quality, defined here as a statistically significant (p<0.01) 50% contrast enhancement. We did not observe a statistically significant difference between the correlations of the conventional and spatiotemporal SPECT myocardial uptake K 1 values with PET K 1 values (r=0.25, 0.88, respectively) (p<0.17). These results indicate the clinical feasibility of quantitative, dynamic SPECT/CT using 99mTc-MIBI and warrant further investigation. Spatiotemporal reconstruction clearly provides an advantage over a conventional reconstruction in computing K 1.
PMCID: PMC3867729  PMID: 24380045
Dynamic SPECT; myocardial perfusion imaging; 99mTc-MIBI; SPECT/CT; spatiotemporal reconstruction; uptake rate constant
7.  68Ga-labeled superparamagnetic iron oxide nanoparticles (SPIONs) for multi-modality PET/MR/Cherenkov luminescence imaging of sentinel lymph nodes 
The aim of this study was to develop 68Ga-SPIONs for use as a single contrast agent for dynamic, quantitative and high resolution PET/MR imaging of Sentinel Lymph Node (SLN). In addition 68Ga enables Cherenkov light emission which can be used for optical guidance during resection of SLN. SPIONs were labeled with 68Ga in ammonium acetate buffer, pH 5.5. The labeling yield and stability in human serum were determined using instant thin layer chromatography. An amount of 0.07-0.1 mL (~5-10 MBq, 0.13 mg Fe) of 68Ga-SPIONs was subcutaneously injected in the hind paw of rats. The animals were imaged at 0-3 h and 25 h post injection with PET/CT, 9.4 T MR and CCDbased Cherenkov optical systems. A biodistribution study was performed by dissecting and measuring the radioactivity in lymph nodes, kidneys, spleen, liver and the injection site. The labeling yield was 97.3 ± 0.05% after 15 min and the 68Ga-SPIONs were stable in human serum. PET, MR and Cherenkov luminescence imaging clearly visualized the SLN. Biodistribution confirmed a high uptake of the 68Ga-SPIONs within the SLN. We conclude that generator produced 68Ga can be labeled to SPIONs. Subcutaneously injected 68Ga-SPIONs can enhance the identification of the SLNs by combining sensitive PET and high resolution MR imaging. Clinically, hybrid PET/MR cameras are already in use and 68Ga-SPIONs have a great potential as a single-dose, tri-modality agent for diagnostic imaging and potential Cherenkov luminescent guided resection of SLN.
PMCID: PMC3867730  PMID: 24380046
68Ga; superparamagnetic iron oxide nanoparticle (SPION); sentinel lymph node (SLN); PET/MR imaging; Cherenkov imaging; lymphatics
8.  Molecular imaging for early prediction of response to Sorafenib treatment in sarcoma 
The role of [18F]fluorodeoxyglucose ([18F]FDG) PET in staging of sarcoma is well established. The aim of this preclinical study was to compare [18F]fluorothymidine ([18F]FLT) PET to [18F]FDG PET regarding early metabolic changes of sarcoma in the course of targeted cancer therapy. SCID mice bearing sarcoma A673 xenotransplants were used for investigation of tumor response after treatment with the multikinase inhibitor Sorafenib. [18F]FLT and/or [18F]FDG-PET were performed prior to and early after initiation of treatment. Tumoral uptake (% Injected Dose per gram (%ID/g) of [18F]FLT-PET was compared to [18F]FDG-PET. Results were correlated with histopathology and in vitro data including cellular uptake, cell cycle-related protein expression, cell cycle distribution and apoptosis. In vitro experiments showed that A673 cells were sensitive to Sorafenib. In vivo, tumor growth was inhibited in comparison to a 4-fold increase of the tumor volume in control mice. Using [18F]FDG as tracer, a moderate reduction in tracer uptake (n=15, mean relative %ID/g 74%, range 35%-121%, p=0.03) was observed. The decrease in %ID/g using [18F]FLT-PET was significantly higher (p=0.003). The mean relative %ID/g in [18F]FLT uptake on day + 5 was significantly reduced to 54% compared to baseline (n=15, range 24%-125%, SD=29%). The PET analysis 24 hr after therapy showed a significant reduction of the mean [18F]FLT-%ID/g (p=0.04). The reduction of %ID/g on day + 1 in [18F]FDG-PET was not statistically significant (p=0.99). In conclusion, both [18F]FDG- and [18F]FLT-PET were able to predict response to Sorafenib treatment. In contrast to [18F]FDG-PET, [18F]FLT-PET was more predictive for very early response to treatment.
PMCID: PMC3867731  PMID: 24380047
Molecular imaging; sarcoma; PET; proliferation; [18F]FLT; [18F]FDG
9.  May bone-targeted radionuclide therapy overcome PRRT-refractory osseous disease in NET? A pilot report on 188Re-HEDP treatment in progressive bone metastases after 177Lu-octreotate 
Bone metastases (BM) of gastroenteropancreatic neuroendocrine tumours (GEP-NET) can be effectively controlled by peptide receptor radionuclide therapy (PRRT). Eventually, however, BM may become refractory and determine survival. We aimed to assess the clinical benefit of bone-targeted radionuclide therapy (BTRT) in this subgroup of patients failing PRRT. A small cohort of n=6 patients with progressive BM failing PRRT with 177Lu-octreotate (mean cumulative activity, 46.7 GBq) were treated with a total of 11 cycles BTRT using 2.6-3.3 GBq 188Re-HEDP per cycle and a median cumulative activity of 5.9 GBq. Pain palliation was quantified applying the visual analogue scale (VAS). The mean VAS decreased from 6.6 (range 5-8) to 3.7 (range 2-7). Five patients experienced partial resolution of bone pain (≥ 2 steps reduction on the VAS for at least 2 weeks) and one patient had no significant improvement. Flare phenomena occurred in 2 patients and lasted for 2-3 days. Tumor response consisted of stable disease in 2 and progressive disease in 4 patients. No regression of bone metastases has been observed. The median overall survival was 5 months (range 2-9). Relevant myelosuppression (grade 3-4; self-limited with no interventions or hospitalization), occurred 4-6 weeks post-treatment, and after 2 (18.1%) administrations or in 1 (16.7%) patient. No other relevant toxicities or treatment-related death was observed. 188Re-HEDP may be safely applied in patients with bone metastatic GEP-NET previously treated with 177Lu-octreotate. While acceptable pain relief may be expected, no tumor-regression or long-term disease stabilization with apparent survival benefit has been observed. This disputes the use of BTRT as salvage anti-tumor therapy in PRRT-refractory neuroendocrine bone metastases.
PMCID: PMC3867732  PMID: 24380048
Bone metastases; neuroendocrine tumors; peptide receptor radionuclide therapy; targeted radionuclide therapy; 188Re-HEDP
10.  18F-FDG imaging of human atherosclerotic carotid plaques reflects gene expression of the key hypoxia marker HIF-1α 
To investigate the association between gene expression of key molecular markers of hypoxia and inflammation in atherosclerotic carotid lesions with 2-deoxy-2-[18F]fluoro-D-glucose (18F-FDG) uptake as determined clinically by positron emission tomography (PET). Studies using PET have demonstrated 18F-FDG-uptake in patients with confirmed plaques of the carotid artery. Inflammatory active or “vulnerable” plaques progressively increase in bulk, develop necrotic cores, poor vessel-wall vascularization and become prone to hypoxia. We used quantitative polymerase-chain reaction (qPCR) to determine gene expression of hypoxia-inducible factor 1α (HIF-1α) and cluster of differentiation 68 (CD68) on plaques recovered by carotid endarterectomy (CEA) in 18 patients. Gene expression was compared with 18F-FDG-uptake quantified as the maximum standardized uptake value (SUVmax) on co-registered PET/computed tomography (CT) scans performed the day before CEA. Immunohistochemistry was used to validate target-gene protein expression. In univariate linear regression analysis HIF-1α was significantly correlated with 18F-FDG-uptake (SUVmax) as was CD68. A two-tailed Pearson regression model demonstrated that HIF-1α and CD68 gene expression co-variated and accordingly when entering the variables into multivariate linear regression models with SUV-values as dependent variables, HIF-1α was eliminated in the final models. 18F-FDG-uptake (SUVmax) is correlated with HIF-1α gene expression indicating an association between hypoxia and glucose metabolism in vivo. The marker of inflammation CD68 is also associated with 18F-FDG-uptake (SUVmax). As CD68 and HIF-1α gene expression co-variate their information is overlapping.
PMCID: PMC3784801  PMID: 24116346
Hypoxia; 18F-FDG PET/CT imaging; carotid atherosclerosis; gene expression; HIF-1α
11.  A comparison of PET imaging agents for the assessment of therapy efficacy in a rodent model of glioma 
The aim of the current study was to assess the ability of PET imaging agents to detect early response to therapy in an orthotopic experimental rodent model of glioma. Clinically, MRI and [18F]FDG PET are routinely used but their ability to assess early therapeutic response can be limited. In this study, nude rats were implanted with U87-MG tumors orthotopically and imaged with either [18F]FDG or [18F]FLT to determine which tracer acts as the most sensitive biomarker for evaluation of treatment response in animals undergoing anti-angiogenic therapy with sunitinib, a receptor tyrosine kinase (RTK) inhibitor. Of the radiopharmaceuticals tested, [18F]FLT proved to be the most sensitive biomarker in the proliferating glioma, based on tumour-to-normal tissue radiotracer uptake (TNR ~17) in comparison to [18F]FDG (TNR ~1.7). Furthermore, [18F]FLT displayed earlier assessment of therapy efficacy, than either tumour volume measured by MRI or [18F]FDG PET imaging. Overall, longitudinal molecular imaging with [18F]FLT provides earlier detection of therapy response than either of the commonly used clinical imaging modalities potentially improving patient management.
PMCID: PMC3784803  PMID: 24116348
PET; glioma; sunitinib; [18F]FLT; [18F]FDG; angiogenesis; orthotopic
12.  PET/CT vs. non-contrast CT alone for surveillance 1-year post lobectomy for stage I non-small-cell lung cancer 
18F-FDG PET/CT was compared with non-contrast chest CT in monitoring for recurrence 1-year after lobectomy of stage 1 non-small-cell lung cancer (NSCLC). For surveillance after treatment with curative intent, current (April 2012) National Comprehensive Cancer network guidelines recommend chest CT with or without contrast every 6-12 months for 2 years, then non-contrast chest CT annually. PET/CT is not currently indicated for routine follow-up. One hundred patients receiving surveillance PET/CT 1-year after lobectomy for the treatment of stage 1a or 1b NSCLC were included in the study. Exclusion criteria included the presence or interval diagnosis of a second malignancy, or surgical treatment more radical than single lobectomy. The non-contrast CT obtained from the 1-year PET/CT was interpreted by an experienced chest radiologist blinded to the PET/CT for evidence of recurrence using the following findings: pulmonary nodule, pleural effusion, pleural mass, adenopathy, and extrathoracic mass. The ecision about recurrence was made solely from the non-contrast CT without PET/CT findings. This was compared with the determination made with PET/CT. The reference standard for determination of recurrence was the multi-disciplinary tumor board who had access to all imaging and clinical data. Recurrence at 1 year was documented in 16 of 90 patients. All 16 recurrences were documented with PET/CT and 9 were found with non-contrast CT. Five of the 7 recurrences missed with non-contrast CT were extrathoracic metastases. Sensitivity of CT and PET/CT for recurrence was 56.3% and 100%, respectively (p = 0.015). Specificity of CT and PET/CT for recurrence was 95.9% and 93.2%, respectively (p = 0.62).
PMCID: PMC3784804  PMID: 24116349
Lung cancer; PET/CT; non-small cell; CT; lobectomy; stage 1; lung cancer surveillance
13.  Dynamic PET with 18F-Deoxyglucose (FDG) and quantitative assessment with a two-tissue compartment model reflect the activity of glucose transporters and hexokinases in patients with colorectal tumors 
Dynamic PET (dPET) with 18F-Deoxyglucose (FDG) provides quantitative information about distribution of the tracer in a predefined volume over time. A two-tissue compartment model can be used to obtain quantitative data regarding transport of FDG into and out of the cells, phosphorylation and dephosphorylation rate of intracellular FDG, and fractional blood volume in the target volume, also named vessel density. Aim of the study was the correlation of glucose transporters expression and hexokinases with the corresponding compartment parameters.Patients with colorectal tumors were examined with dynamic PET prior to surgery. Afterwards, tumor samples were obtained during surgery and gene expression was assessed using gene arrays. The dynamic PET data were evaluated to quantify the parameters of a two tissue compartment model for colorectal tumors using a Volume-of-Interest (VOI) technique. A multiple correlation/regression analysis was performed using glucose transporters as independent variables and k1 as the dependent variable. A correlation of r=0.7503 (p=0.03) was obtained for the transporters SLC2A1, SLC2A2, SLC2A4, SLC2A8, SLC2A9, SLC2A10 and k1. The correlation of r=0.7503 refers to an explained variance of data of 56.30 %, therefore more than 50 % of data changes are associated with the gene expression. An analysis of the hexokinases HK1-HK3 and k3 revealed a correlation coefficient of r=0.6093 (p=0.04), which is associated with an explained variance of 37.12 %. Therefore, parameters k1 and k3 reflect gene activity. The results demonstrate that k1 and k3 of the two-tissue compartment model are correlated with glucose transporters and hexokinases.
PMCID: PMC3784805  PMID: 24116350
Dynamic PET; compartment model; glucose transporter; hexokinase
14.  Synthesis and in vivo evaluation of an 18F-labeled glycoconjugate of PD156707 for imaging ETA receptor expression in thyroid carcinoma by positron emission tomography 
Disturbances of the endothelin axis have been described in tumor angiogenesis and in highly vascularized tumors, such as thyroid carcinoma. Consequently, the endothelin (ET) receptor offers a molecular target for the visualization of the endothelin system in vivo by positron emission tomography (PET). We therefore endeavoured to develop a subtype-selective ETA receptor (ETAR) radioligand by introduction of a glycosyl moiety as a hydrophilic building block into the lead compound PD156707. Employing click chemistry we synthesized the triazolyl conjugated fluoroglucosyl derivative 1 that had high selectivity for ETAR (4.5 nM) over ETBR (1.2 μM). The radiosynthesis of the glycoconjugate [18F]1 was achieved by concomitant 18F-labeling and glycosylation, providing [18F]1 in high radiochemical yields (20-25%, not corrected for decay, 70 min) and a specific activity of 41-138 GBq/μmol. Binding properties of [18F]1 were evaluated in vitro, and its biodistribution was measured in K1 thyroid carcinoma xenograft nude mice ex vivo and by molecular imaging. Although the very substantial excretion via hepatobiliary clearance was not decisively influenced by glycosylation, the 18F-glycoconjugate was more stable in blood during PET recordings than was the previously described 18F-fluoroethoxy analog. Small-animal PET imaging showed displacable binding of [18F]1 at ETAR in K1 tumors. The simple and efficient 18F-radiosynthesis together with the excellent stability make the 18F-labeled glycoconjugate [18F]1 a promising molecular tool for preclinical PET imaging studies of ETAR expression in thyroid carcinoma and other conditions with marked angiogenesis.
PMCID: PMC3784806  PMID: 24116351
Endothelin receptor; angiogenesis; positron emission tomography (PET); 18F; glycosylation; thyroid carcinoma
15.  Bone metastases in GEP-NET: response and long-term outcome after PRRT from a follow-up analysis 
Bone metastases of gastroenteropancreatic neuroendocrine tumors (GEP NET) can be associated with pain and a poor prognosis. Peptide receptor radionuclide therapy (PRRT) has been shown to be effective against this tumor manifestation. This study represents an update of the therapeutic assessment of PRRT with 177Lu-octreotate in GEP NET patients with bone metastases focusing on potential predictors for impaired outcome and overall survival.We retrospectively analyzed a consecutive subgroup of n=68 patients with bone metastases (BM) of GEP NET treated with 177Lu-octreotate (4 intended cycles at 3 monthly intervals; mean activity per cycle, 8.1 GBq). Baseline characteristics, including age, performance status, tumor origin, tumor load, plasma chromogranin A (CgA), and neuron-specific enolase (NSE) were analyzed regarding the impact on tumor regression (modified M.D. Anderson criteria) and survival of the patients. Survival analyses were performed using Kaplan–Meier curves, log-rank test at a significance level of p <0.05, and Cox proportional hazards model for uni- and multivariate analyses. Median follow-up was 48 months. The observed response of BMs consisted of complete remission in 2 (2.9%), partial remission in 23 (33.8%), minor response in 8 (11.8%), stable disease in 26 (38.2%), and progressive disease in 8 (13.2%) patients. Median time-to-progression (TTP) of BMs and overall survival (OS) were 35 mo (95% CI: 25-45) and 51 mo (95% CI: 38-64), respectively. Patients with responding BMs survived significantly longer than other patients (median 56 mo vs. 39 mo, p=0.034). NSE >15 ng/ml (p=0.002) and Ki67 index >10% (p=0.008) were associated with shorter overall survival. BM of GEP NET are effectively controlled by PRRT with a long median progression-free survival of approx. 3 years. Non-regression of BM, high proliferation rate and increased plasma NSE at baseline are predictive of shorter survival. However, this study confirms that poor patient condition (Karnofsky-Index ≤70%) and multifocality of BM (>10 lesions) do not affect outcome efficacy, further encouraging the use of PRRT in advanced bone metastatic disease.
PMCID: PMC3784807  PMID: 24116352
Bone metastases; gastroenteropancreatic neuroendocrine tumors (GEP NET); peptide receptor radionuclide therapy (PRRT)
16.  Molecular MRI of atherosclerotic plaque progression in an ApoE-/- mouse model with a CLT1 peptide targeted macrocyclic Gd(III) chelate 
Molecular imaging of atherosclerotic biomarkers is critical for non-invasive detection and diagnosis of atherosclerotic plaques and therapeutic management. Fibrin and fibronectin accumulate at elevated levels in atherosclerotic plaques and are associated with atherogenesis and disease progression. Molecular imaging of these biomarkers has the potential to non-invasively characterize plaque burden. In this work, we investigated the effectiveness of a peptide-targeted macrocyclic Gd(III) chelate, CLT1-dL-(DOTA-Gd)4, specific to fibrin-fibronectin complexes for molecular MRI of atherosclerosis. Atherosclerotic plaques were induced in Apolipoprotein E-knockout (ApoE-/-) mice by feeding with high fat and cholesterol-enriched diet (HFD) for up to 30 weeks. MRI of the vessel wall in the arch aorta was performed at 10, 20 and 30 weeks after the onset of HFD. High spatial-resolution MRI was performed prior and up to 35 minutes after i.v. injection of CLT1-dL-(DOTA-Gd)4 or a nonspecific control agent at a dose of 0.1 mmol-Gd/kg. CLT1-dL-(DOTA-Gd)4 produced stronger enhancement in the atherosclerotic lesions of the aortic wall than the control at all time points in the mice. Cross sectional MR images of the aortic arch revealed progressive thickening of the atherosclerotic vessel wall in the mice on HFD for up to 30 weeks. This progression correlated well to histological staining, as well as fibrin and fibronectin immunochemical stained images. Molecular MRI with CLT1-dL-(DOTA-Gd)4 has a potential for detecting atherosclerosis and non-invasive monitoring of the progression of the plaques.
PMCID: PMC3784808  PMID: 24116353
Molecular MRI; atherosclerosis; CLT1 peptide; targeted contrast agent; macrocyclic Gd(III) chelate
17.  Feasibility of simultaneous PET/MR of the carotid artery: first clinical experience and comparison to PET/CT 
The study aimed at comparing PET/MR to PET/CT for imaging the carotid arteries in patients with known increased risk of atherosclerosis. Six HIV-positive men underwent sequential PET/MR and PET/CT of the carotid arteries after injection of 400 MBq of 18F-FDG. PET/MR was performed a median of 131 min after injection. Subsequently,PET/CT was performed. Regions of interest (ROI) were drawn slice by slice to include the carotid arteries and standardized uptake values (SUV) were calculated from both datasets independently. Quantitative comparison of 18F-FDG uptake revealed a high congruence between PET data acquired using the PET/MR system compared to the PET/CT system. The mean difference for SUVmean was -0.18 (p < 0.001) and -0.14 for SUVmax (p < 0.001) indicating a small but significant bias towards lower values using the PET/MR system. The 95% limits of agreement were -0.55 to 0.20 for SUVmean and -0.93 to 0.65 for SUVmax. The image quality of the PET/MR allowed for delineation of the carotid vessel wall. The correlations between 18F-FDG uptake from ROI including both vessel wall and vessel lumen to ROI including only the wall were strong (r = 0.98 for SUVmean and r = 1.00 for SUVmax) indicating that the luminal 18F-FDG content had minimal influence on the values. The study shows for the first time that simultaneous PET/MR of the carotid arteries is feasible in patients with increased risk of atherosclerosis. Quantification of 18F-FDG uptake correlated well between PET/MR and PET/CT despite difference in method of PET attenuation correction, reconstruction algorithm, and detector technology.
PMCID: PMC3715780  PMID: 23900769
Atherosclerosis; positron emission tomography; magnetic resonance imaging; PET/MR; hybrid scanners
18.  Molecular MRI differentiation of VEGF receptor-2 levels in C6 and RG2 glioma models 
Vascular endothelial growth factor receptor 2 (VEGFR2) is an important angiogenic marker over-expressed in gliomas. With the use of molecular magnetic resonance imaging (mMRI) differing levels of VEGFR2 can be characterized in vivo with in rodent gliomas varying in angiogenesis. VEGFR2 levels were assessed by intravenous administration of an anti-VEGFR2 probe (anti-VEGFR2-albumin-Gd (gadolinium)-DTPA (diethylene triamine penta acetic acid)-biotin) into C6 or RG2 glioma-bearing rats, and visualized with mMRI. A non-specific IgG was coupled to the albumin-Gd-DTPA-biotin construct as a contrast agent molecular weight control. VEGFR2 levels are heterogeneous in different regions of C6 gliomas, whereas VEGFR2 was more homogenous or evenly distributed in RG2 gliomas. RG2 gliomas have less VEGFR2 within tumor periphery and peri-necrotic (p<0.05) regions, but more VEGFR2 within tumor interior regions (p<0.01), compared to C6 gliomas. mMRI results were confirmed with fluorescence staining and mean fluorescence intensity (MFI) quantification of the anti-VEGFR2 probe in excised glioma and brain tissues, as well as detection of VEGFR2 in C6 and RG2 gliomas and corresponding contalateral brain tissues. Ex vivo VEGFR2 levels were found to be significantly higher in C6 gliomas compared to RG2 tumors (p<0.001), which corresponded with in vivo detection using the VEGFR2 probe. Immunohistochemistry staining for HIF-1α (hypoxia inducible factor 1α), which is associated with angiogenesis, indicated higher levels in RG2 (p<0.01) compared to C6 gliomas. The data suggests that C6 gliomas have angiogenesis which is associated more with large blood vessels in tumor periphery and peri-necrotic regions, and less microvascular angiogenesis within the tumor interior, compared to RG2 gliomas.
PMCID: PMC3715774  PMID: 23901356
Molecular magnetic resonance imaging (mMRI); vascular endothelial growth factor receptor 2 (VEGFR2); C6 and RG2 rat gliomas; in vivo; fluorescence imaging
19.  The normal variant 18F FDG uptake in the lower thoracic spinal cord segments in cancer patients without CNS malignancy 
Focal increased lower thoracic spinal cord 18F FDG uptake is not infrequently observed as a normal physiological finding and may be confused for spinal cord metastases. This study was conducted to evaluate a possible correlation between the lower thoracic (T11-T12) spinal uptake and lower limb movements/ambulatory status of the patients as a surrogate. The primary endpoint was to identify the possible cause(s) of the normal variant focal increased thoracic spinal cord (T11-T12) 18F FDG activity and correlate it with the lower limb movements/ambulatory status of the patients. This was a retrospective analysis of PET-CT scans of 200 patients with solid and hematological malignancies. The focal relatively increased 18F FDG activity in the lower thoracic spinal cord correlated strongly with the 18F FDG intensity of the liver, bowel, C3-C5 cervical cord activity, weight of the patient and injected dose of 18F FDG. With regard to the primary endpoint, no significant correlation was found between the ambulatory status of patients in any of the groups and thoracic spine SUVmax. This could be further assessed by performing dual studies in the same patient with and without moderate to excessive leg motion. Identifying this variant focal increased 18F FDG activity can minimize errors of misdiagnosis and unnecessary further investigation.
PMCID: PMC3715776  PMID: 23901357
18F FDG PET-CT; spinal cord; metastases; ambulatory status
20.  Assessment of an elastin binding molecule for PET imaging of atherosclerotic plaques 
Elastin is considered as a key player in human vascular diseases and it might contribute to the development of atherosclerosis. The elastin binding radiotracer, [18F]AlF-NOTA-EBM ([18F]2), was evaluated in a wild type mouse to determine its in vivo distribution and on human carotid atherosclerotic plaque tissues to assess its utility as a PET imaging agent for visualizing human atherosclerotic plaque lesions. The free ligand NOTA-EBM, which served as the precursor, was obtained in 25% chemical yield. The radiosynthesis of [18F]2 was accomplished by coordination of Al18F to NOTA-EBM in 8-13% decay corrected radiochemical yield (n = 7) and specific radioactivity of 59 ± 12 GBq/μmol. A dynamic in vivo PET scan in a healthy wild type mouse (C57BL/6) showed high accumulation of radioactivity in heart and lungs, organs reported to have high elastin content. Excretion of [18F]2 proceeded via the renal pathway and through the hepatobiliary system as indicated by a high uptake of radioactivity in the liver, intestines and gall bladder. In vitro autoradiography on human atherosclerotic plaque sections showed a heterogeneous distribution of [18F]2 with an elevated accumulation in stable and vulnerable atherosclerotic plaques compared to control samples of normal arteries. However, there was no statistical significance between the different plaque phenotypes and control samples. Competition experiments with 10.000-fold excess of free ligand NOTA-EBM resulted in a marked decrease of radioactivity accumulation, consistent with a target-specific ligand.
PMCID: PMC3715777  PMID: 23901358
Elastin; atherosclerotic plaques; PET imaging; autoradiography; Al18F
21.  In vivo validation and 3D visualization of broadband ultrasound molecular imaging 
Ultrasound can selectively and specifically visualize upregulated vascular receptors through the detection of bound microbubbles. However, most current ultrasound molecular imaging methods incur delays that result in longer acquisition times and reduced frame rates. These delays occur for two main reasons: 1) multi-pulse imaging techniques are used to differentiate microbubbles from tissue and 2) acquisition occurs after free bubble clearance (>6 minutes) in order to differentiate bound from freely circulating microbubbles. In this paper, we validate tumor imaging with a broadband single pulse molecular imaging method that is faster than the multi-pulse methods typically implemented on commercial scanners. We also combine the single pulse method with interframe filtering to selectively image targeted microbubbles without waiting for unbound bubble clearance, thereby reducing acquisition time from 10 to 2 minutes. The single pulse imaging method leverages non-linear bubble behavior by transmitting at low and receiving at high frequencies (TLRH). We implemented TLRH imaging and visualized the accumulation of intravenously administrated integrin-targeted microbubbles in a phantom and a Met-1 mouse tumor model. We found that the TLRH contrast imaging has a ~2-fold resolution improvement over standard contrast pulse sequencing (CPS) imaging. By using interframe filtering, the tumor contrast was 24.8±1.6 dB higher after the injection of integrin-targeted microbubbles than non-targeted control MBs, while echoes from regions lacking the target integrin were suppressed by 26.2±2.1 dB as compared with tumor echoes. Since real-time three-dimensional (3D) molecular imaging provides a more comprehensive view of receptor distribution, we generated 3D images of tumors to estimate their volume, and these measurements correlated well with expected tumor sizes. We conclude that TLRH combined with interframe filtering is a feasible method for 3D targeted ultrasound imaging that is faster than current multi-pulse strategies.
PMCID: PMC3715778  PMID: 23901359
Targeted microbubbles; ultrasound molecular imaging; angiogenesis; 3D visualization
22.  The effect of omalizumab on ventilation and perfusion in adults with allergic asthma 
Omalizumab promotes clinical improvement in patients with allergic asthma, but its effect on pulmonary function is unclear. One possibility is that omalizumab improves asthma symptoms through effects on the regional distributions of ventilation, perfusion, and ventilation/perfusion matching, metrics which can be assessed with Nitrogen-13-saline Position Emission Tomography (PET). Four adults with moderate to severe uncontrolled allergic asthma underwent symptom assessment, spirometry and functional pulmonary imaging with Nitrogen-13-saline PET before and after 4-5 months of treatment with omalizumab. PET imaging was used to determine ventilation/perfusion ratios, the heterogeneity (coefficient of variation, COV) of ventilation and perfusion, and lung regions with ventilation defects. There were no significant changes in spirometry values after omalizumab treatment, but there was a trend towards an improvement in symptom scores. There was little change in the matching of ventilation and perfusion. The COV of perfusion was similar before and after omalizumab treatment. The COV of ventilation was also similar before (0.57 (0.28)) and after (0.66 (0.13)) treatment, and it was similar to previously published values for healthy subjects. There was a non-significant trend towards an increase in the extent of ventilation defects after omalizumab treatment, from 5 (15)% to 12.8 (14.7)%. Treatment of moderate to severe uncontrolled allergic asthma with omalizumab did not result in a significant improvement in ventilation and perfusion metrics assessed with functional PET imaging. The normal COV of ventilation which was unaffected by treatment supports the hypothesis that omalizumab exerts its clinical effect on lung function during allergen exposure rather than in between exacerbations.
PMCID: PMC3715779  PMID: 23901360
PET functional imaging; omalizumab; Xolair; asthma; V/Q ratios
23.  Design, synthesis and in vitro characterization of fluorescent and paramagnetic CXCR4-targeted imaging agents 
The G-protein coupled C-X-C chemokine receptor type 4 (CXCR4) is highly overexpressed in a range of cancers and is therefore an excellent biomarker for cancer imaging. To this end targeted iron oxide nanoparticles were developed and utilised for in vitro imaging of MDA-MB-231 breast cancer cells overexpressing the CXCR4 receptor. Nanoparticles comprising an iron oxide core, encapsulated in a stabilising epichlorohydrin crossed-linked dextran polymer, were conjugated to a cyclopentapeptide with affinity to the CXCR4 receptor. The particles were characterized for their size, surface charge and r2 relaxivity at 4.7 T. MR imaging of the CXCR4 receptor with targeted iron oxide nanoparticles revealed an approximately 3-fold increase in T2 signal enhancement of MDA-MB-231 cells compared to non-targeted controls. Prussian blue staining of labeled MDA-MB-231 cells revealed darker and more intense staining of the cellular membrane. This study demonstrates the potential of targeted iron oxide nanoparticles for the imaging of the CXCR4 receptor by magnetic resonance imaging (MRI).
PMCID: PMC3715781  PMID: 23901361
CXCR4; iron oxide nanoparticles; tumor MRI; targeted nanoparticles; T2 imaging; cyclopentapeptide
24.  Limitations of SRTM, Logan graphical method, and equilibrium analysis for measuring transient dopamine release with [11C]raclopride PET 
Conventional PET methods to estimate [11C]raclopride binding potential (BP ND) assume that endogenous dopamine concentration does not change during the scan time. However, this assumption is purposely violated in studies using pharmacological or behavioral stimuli to invoke acute dopamine release. When the assumption of steady-state dopamine is violated, conventional analysis methods may produce biased or even unusable estimates of BP ND. To illustrate this problem, we examined the effect of scan duration on ΔBP ND estimated by three common analysis methods (simplified reference tissue model, Logan graphical reference method, and equilibrium analysis) applied to simulated and experimental single-scan activation studies. The activation – dopamine release – in both the simulated and experimental studies was brief. Simulations showed ΔBP ND to be highly dependent on the window of data used to determine BP ND in the activation state. A similar pattern was seen in the data from human smoking studies. No such pattern of ΔBP ND dependence on the window of data used was apparent in simulations where dopamine was held constant. The dependence of ΔBP ND on the duration of data analyzed illustrates the inability of conventional methods to reliably quantify short-lived increases in endogenous dopamine.
PMCID: PMC3627521  PMID: 23638336
Binding potential (BPND); transient dopamine release; model selection; scan duration; smoking; time-invariant
25.  Re-evaluating the potentials and limitations of 99mTc-aprotinin scintigraphy for amyloid imaging 
The definitive diagnosis of amyloidosis is made histologically with Congo red stain. Noninvasive imaging techniques for amyloidosis are beneficial for early and definite diagnosis of amyloid deposition in the body. 99mTc-aprotinin has the benefit of detecting amyloid deposits mainly in the heart, but it can also detect a wide range of lesions in other locations. The usefulness and limitations of 99mTc-Aprotinin scintigraphy for amyloid imaging were re-evaluated based on results from 25 patients (15 men and 10 women; median age, 62.9 y; range, 34-83 y). In addition, other nuclear tracers for imaging amyloidosis are discussed. Of the 25 patients with suspected amyloidosis, 19 patients were proven to have amyloid deposits by histopathological diagnosis. Major 99mTc-aprotinin positive sites were confirmed in the myocardium, thyroid, large joints, vertebrae, colon, and lungs. If 99mTc-Aprotinin images showed positive findings, the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of existing amyloid deposits were 94.7, 33.3, 81.8, and 66.7%, respectively. For analysis based on biopsy region, the sensitivity, specificity, PPV, and NPV of existing amyloid deposition were 30.6, 82.6, 73.3, and 43.2%, respectively. 99mTc-Aprotinin has a high potential for diagnosis of amyloid deposition in body; however, due to its physiological uptake, its potential is limited for detection of amyloid deposits in the liver, kidney, and spleen.
PMCID: PMC3627522  PMID: 23638337
99mTc-aprotinin; amyloidosis; SPECT/CT; SPECT; scintigraphy

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