EJNMMI Research - Latest Articles

11C-LY2428703, a positron emission tomographic radioligand for the metabotropic glutamate receptor 1, is unsuitable for imaging in monkey and human brains

Paolo Zanotti-Fregonara — 2013-06-10T00:00:00Z

Background: A recent study from our laboratory demonstrated that 11C-LY2428703, a new positron emission tomographic radioligand for metabotropic glutamate receptor 1 (mGluR1), has promising in vitro properties and excellent in vivo performance for imaging rat brain. The present study evaluated 11C-LY2428703 for imaging mGluR1 in monkey and human brains. Methods: Rhesus monkeys were imaged at baseline and after administration of an mGluR1 blocking agent to calculate nonspecific binding, as well as after the administration of permeability glycoprotein (P-gp) and breast cancer resistance protein (BCRP) blockers to assess whether 11C-LY2428703 is a substrate for efflux transporters at the blood–brain barrier. Human imaging was performed at baseline in three healthy volunteers, and arterial input function was measured. Results: Overall brain uptake was low in monkeys, though slightly higher in the cerebellum, where mGluR1s are concentrated. However, the uptake was not clearly displaceable in the scans after mGluR1 blockade. Brain penetration of the ligand did not increase after P-gp and BCRP blockade. Brain uptake was similarly low in all human subjects (mean V T with a two-tissue compartment model, 0.093 ± 0.012 mL/cm3) and for all regions, including the cerebellum. Conclusions: Despite promising in vitro and in vivo results in rodents, 11C-LY2428703 was unsuitable for imaging mGluR1s in monkey or human brain because of low brain uptake, which was likely caused by high binding to plasma proteins.

High correlation between in vivo [123I]beta-CIT SPECT/CT imaging and post-mortem immunohistochemical findings in the evaluation of lesions induced by 6-OHDA in rats

Susanne Bäck — 2013-06-10T00:00:00Z

Background: 6-Hydroxydopamine (6-OHDA) is widely used in pre-clinical animal studies to induce degeneration of midbrain dopamine neurons to create animal models of Parkinson's disease. The aim of our study was to evaluate the potential of combined single-photon emission computed tomography/computed tomography (SPECT/CT) for the detection of differences in 6-OHDA-induced partial lesions in a dose- and time-dependent manner using the dopamine transporter (DAT) ligand 2beta-carbomethoxy-3beta-(4-[123I]iodophenyl)tropane ([123I]beta-CIT). Methods: Rats were unilaterally lesioned with intrastriatal injections of 8 or 2 x 10 mug 6-OHDA. At 2 or 4 weeks post-lesion, 40 to 50 MBq [123I]beta-CIT was administered intravenously and rats were imaged with small-animal SPECT/CT under isoflurane anesthesia. The striatum was delineated and mean striatal activity in the lesioned side was compared to the intact side. After the [123I]beta-CIT SPECT/CT scan, the rats were tested for amphetamine-induced rotation asymmetry, and their brains were immunohistochemically stained for DAT and tyrosine hydroxylase (TH). The fiber density of DAT- and TH-stained striata was estimated, and TH-immunoreactive cells in the rat substantia nigra pars compacta (SNpc) were stereologically counted. Results: The striatal uptake of [123I]beta-CIT differed significantly between the lesion groups and the results were highly correlated to both striatal DAT- and TH-immunoreactive fiber densities and to TH-immunoreactive cell numbers in the rat SNpc. No clear progression of the lesion could be seen. Conclusions: [123I]beta-CIT SPECT/CT is a valuable tool in predicting the condition of the rat midbrain dopaminergic pathway in the unilateral partial 6-OHDA lesion model of Parkinson's disease and it offers many advantages, allowing repeated non-invasive analysis of living animals.

Quantification of 99mTc-DPD concentration in the lumbar spine with SPECT/CT

Michal Cachovan — 2013-06-05T00:00:00Z

Background: Routine single-photon emission computed tomography (SPECT) currently lacks quantitative information on regional activity concentration (ACC) of the injected tracer (e.g. kBq/ml). Furthermore, little is known on the skeletal absolute concentration of 99mTc-DPD after intravenous injection in bone scintigraphy. The aim of this study is to determine ACC in the healthy lumbar vertebrae of patients using a recently published quantitative SPECT/computed tomography (CT) protocol. Methods: Lumbar vertebrae ACC estimates were performed in 50 female patients (mean age 69.88 ± 13.73 years) who had been administered 562.84 ± 102.33 MBq of 99mTc-DPD and had undergone SPECT acquisition 4 h after the injection. The SPECT/CT system was calibrated against a well counter. Images were reconstructed with Flash3D. ACC and CT tissue density were measured in volumes of interest drawn over the spongious bone tissue of the three lower lumbar vertebral bodies when these exhibited no focal CT or SPECT pathology. Results: Average ACC measured in the normal spongious bone tissue was 48.15 ± 13.66 kBq/ml (95% confidence interval (CI) 45.81 to 50.50 kBq/ml). This corresponds to a mean standardised uptake value (SUV) of (5.91 ± 1.54) (95% CI (5.64 to 6.17) SUV). SUV correlated significantly with Hounsfield units (HU) (r = 0.678, p < 0.0001). Significant negative correlations were observed between age and HU (r = −0.650, p < 0.0001) and between age and SUV (r = −0.385, p < 0.0001). Conclusions: The SUVs determined for 99mTc-DPD uptake 4 h post injection are in the same range as those reported for [18F]fluoride in positron emission tomography. The strong correlation of SUV with bone CT density underlines the physiological significance of this variable. Our data suggest further investigation of the potential value of ACC measurement in the diagnosis of pathological conditions such as osteoporosis or in following up osseous metastases under therapy.

SERT-to-DAT ratios in early Parkinson¿s disease do not correlate with the development of dyskinesias

Sven Suwijn — 2013-06-05T00:00:00Z

Background: Although the treatment of Parkinson’s disease (PD) is very effective, in the course of the disease, 40% to 60% of patients develop dyskinesias. The pathophysiology of dyskinesias is still unclear. Results of preclinical research suggest that uptake and uncontrolled release of dopamine by serotonergic neurons is an important factor. Based on this model, we hypothesized that dyskinesias will develop predominantly in PD patients with a relatively preserved serotonergic system. Methods: Between 1995 and 1998, 50 patients with early-stage untreated PD, diagnosed according to clinical criteria, and reduced striatal [123I]β-carboxymethyoxy-3-beta-(4-iodophenyl) tropane (CIT) single-photon emission computed tomography (SPECT) binding were recruited. To test our hypothesis, we retrospectively assessed baseline [123I]β-CIT SPECT scans for striatal dopamine transporter (DAT) and midbrain serotonin transporter (SERT) availability as well as the SERT-to-DAT ratios. We compared these data between patients that developed dyskinesias and patients that did not develop dyskinesias during a mean follow-up of 14.2 years. Results: Approximately half of the PD patients developed dyskinesias. No differences in baseline [123I]β-CIT DAT availability, SERT availability, or SERT-to-DAT ratios were found between the dyskinetic and non-dyskinetic group. The development of dyskinesias was most strongly associated with the age of onset (P = 0.002). Conclusions: SERT-to-DAT ratios in early-stage untreated PD do not correlate with the future development of dyskinesias. However, our study does not exclude the possibility that SERT-to-DAT ratios increase with disease progression in patients that develop dyskinesias because of a slower rate of degeneration of the serotonergic system.

Cortical florbetapir-PET amyloid load in prodromal Alzheimer's disease patients

Laure Saint-Aubert — 2013-06-03T00:00:00Z

Background: Florbetapir (AV-45) has been shown to be a reliable tool to assess amyloid load in patients with Alzheimer's disease (AD) at demential stages. Longitudinal studies also suggest that AV-45 has the ability to bind amyloid in the early stages of AD. In this study, we investigated AV-45 binding and its relation with cognitive performance in a group of patients at the prodromal stage of Alzheimer's disease, recruited according to strict inclusion criteria. Methods: We recruited patients at the prodromal stage of AD and matched control subjects. AV-45 binding was assessed using an innovative extraction method allowing quantifying uptake in the cortex only. AV-45 uptake was compared between groups in the precuneus, posterior cingulate, anterior cingulate, and orbito-frontal regions. Correlations between AV-45 uptake and cognitive performance were assessed. Results: Twenty-two patients and 17 matched control subjects were included in the study. We report a significant increase of cortical AV-45 uptake in the patients compared to the control subjects in all regions of interest. Specific correlations were found within the patient group between mean global amyloid cortical load and cognitive performance in three different memory tests. Conclusions: These findings suggest that at the prodromal stage of AD, memory decline is linked to an increase of cortical beta-amyloid load.

Pilot study of PET imaging of 124I-iodoazomycin galactopyranoside (IAZGP), a putative hypoxia imaging agent, in patients with colorectal cancer and head and neck cancer

Joseph O¿Donoghue — 2013-06-03T00:00:00Z

Background: Hypoxia within solid tumors confers radiation resistance and a poorer prognosis. 124I-iodoazomycin galactopyranoside (124I-IAZGP) has shown promise as a hypoxia radiotracer in animal models. We performed a clinical study to evaluate the safety, biodistribution, and imaging characteristics of 124I-IAZGP in patients with advanced colorectal cancer and head and neck cancer using serial positron emission tomography (PET) imaging. Methods: Ten patients underwent serial whole-torso (head/neck to pelvis) PET imaging together with multiple whole-body counts and blood sampling. These data were used to generate absorbed dose estimates to normal tissues for 124I-IAZGP. Tumors were scored as either positive or negative for 124I-IAZGP uptake. Results: There were no clinical toxicities or adverse effects associated with 124I-IAZGP administration. Clearance from the whole body and blood was rapid, primarily via the urinary tract, with no focal uptake in any parenchymal organ. The tissues receiving the highest absorbed doses were the mucosal walls of the urinary bladder and the intestinal tract, in particular the lower large intestine. All 124I-IAZGP PET scans were interpreted as negative for tumor uptake. Conclusions: It is safe to administer 124I-IAZGP to human subjects. However, there was insufficient tumor uptake to support a clinical role for 124I-IAZGP PET in colorectal cancer and head and neck cancer patients.Trial registrationClinicalTrials.gov NCT00588276

Imaging of the appearance time of cerebral blood using [15O]H2O PET for the computation of correct CBF

Nobuyuki Kudomi — 2013-05-23T00:00:00Z

Background: Quantification of cerebral blood flow (CBF) is important for the understanding of normal and pathologic brain physiology. Positron emission tomography (PET) with H2 15O (or C15O2) can quantify CBF and apply kinetic analyses, including autoradiography (ARG) and the basis function methods (BFM). These approaches, however, are sensitive to input function errors such as the appearance time of cerebral blood (ATB), known as the delay time. We estimated brain ATB in an image-based fashion to correct CBF by accounting for differences in computed CBF values using three different analyses: ARG and BFM with and without fixing the partition coefficient. Methods: Subject groups included those with no significant disorders, those with elevated cerebral blood volume, and those with reduced CBF. All subjects underwent PET examination, and CBF was estimated using the three analyses. The ATB was then computed from the differences of the obtained CBF values, and ATB-corrected CBF values were computed. ATB was also estimated for regions of interest (ROIs) of multiple cortical regions. The feasibility of the present method was tested in a simulation study. Results: There were no significant differences in the obtained ATB between the image- and ROI-based methods. Significantly later appearance was found in the cerebellum compared to other brain regions for all groups. In cortical regions where CBF was reduced due to occlusive lesions, the ATB was 0.2 ± 1.2 s, which was significantly delayed relative to the contralateral regions. A simulation study showed that the ATB-corrected CBF was less sensitive to errors in input function, and noise on the tissue curve did not enhance the degree of noise on ATB-corrected CBF image. Conclusions: This study demonstrates the potential utility of visualizing the ATB in the brain, enabling the determination of CBF with less sensitivity to error in input function.

99mTc-NTP 15-5 assessment of the early therapeutic response of chondrosarcoma to zoledronic acid in the Swarm rat orthotopic model

Elisabeth Miot-Noirault — 2013-05-20T00:00:00Z

Background: Since proteoglycans (PGs) appear as key partners in chondrosarcoma biology, PG-targeted imaging using the radiotracer 99mTc-N-(triethylammonium)-3-propyl-[15]ane-N5 (99mTc-NTP 15-5) developed by our group was previously demonstrated to be a good single-photon emission computed tomography tracer for cartilage neoplasms. We therefore initiated this new preclinical study to evaluate the relevance of 99mTc-NTP 15-5 imaging for the in vivo monitoring and quantitative assessment of chondrosarcoma response to zoledronic acid (ZOL) in the Swarm rat orthotopic model.FindingsRats bearing chondrosarcoma in the orthotopic paratibial location were treated by ZOL (100 μg/kg, subcutaneously) or phosphate-buffered saline, twice a week, from day 4 to day 48 post-tumor implantation. 99mTc-NTP 15-5 imaging was performed at regular intervals with the target-to-background ratio (TBR) determined. Tumor volume was monitored using a calliper, and histology was performed at the end of the study. From day 11 to day 48, mean TBR values ranged from 1.7 ± 0.6 to 2.3 ± 0.6 in ZOL-treated rats and from 2.1 ± 1.0 to 4.9 ± 0.9 in controls. Tumor growth inhibition was evidenced using a calliper from day 24 and associated to a decrease in PG content in treated tumor tissues (confirmed by histology). Conclusions: This work demonstrated two proofs of concept: (1) biphosphonate therapy could be a promising therapeutic approach for chondrosarcoma; (2) 99mTc-NTP 15-5 is expected to offer a novel imaging modality for the in vivo evaluation of the extracellular matrix features of chondrosarcoma, which could be useful for the follow-up and quantitative assessment of proteoglycan ‘downregulation’ associated to the response to therapeutic attempts.

No difference in striatal dopamine transporter availability between active smokers, ex-smokers and non-smokers using [123I]FP-CIT (DaTSCAN) and SPECT

Gerda Thomsen — 2013-05-20T00:00:00Z

Background: Mesolimbic and nigrostriatal dopaminergic pathways play important roles in both the rewarding and conditioning effects of drugs. The dopamine transporter (DAT) is of central importance in regulating dopaminergic neurotransmission and in particular in activating the striatal D2-like receptors. Molecular imaging studies of the relationship between DAT availability/dopamine synthesis capacity and active cigarette smoking have shown conflicting results. Through the collaboration between 13 SPECT centres located in 10 different European countries, a database of FP-CIT-binding in healthy controls was established. We used the database to test the hypothesis that striatal DAT availability is changed in active smokers compared to non-smokers and ex-smokers. Methods: A total of 129 healthy volunteers were included. Subjects were divided into three categories according to past and present tobacco smoking: (1) non-smokers (n = 64), (2) ex-smokers (n = 39) and (3) active smokers (n = 26). For imaging of the DAT availability, we used [123I]FP-CIT (DaTSCAN) and single photon emission computed tomography (SPECT). Data were collected in collaboration between 13 SPECT centres located in 10 different European countries. The striatal measure of DAT availability was analyzed in a multiple regression model with age, SPECT centre and smoking as predictor. Results: There was no statistically significant difference in DAT availability between the groups of active smokers, ex-smokers and non-smokers (p = 0.34). Further, we could not demonstrate a significant association between striatal DAT and the number of cigarettes per day or total lifetime cigarette packages in smokers and ex-smokers. Conclusion: Our results do not support the hypothesis that large differences in striatal DAT availability are present in smokers compared to ex-smokers and healthy volunteers with no history of smoking.

Comparison of cyclic RGD peptides for ¿vß3 integrin detection in a rat model of myocardial infarction

Iina Laitinen — 2013-05-11T00:00:00Z

Background: Expression of αvβ3 integrin is increased after myocardial infarction as part of the repair process. Increased expression of αvβ3 has been shown by molecular imaging with 18F-galacto-RGD in a rat model. The 68Ga-labelled RGD compounds 68Ga-NODAGA-RGD and 68Ga-TRAP(RGD)3 have high specificity and affinity, and may therefore serve as alternatives of 18F-galacto-RGD for integrin imaging. Methods: Left coronary artery ligation was performed in rats. After 1 week, rats were imaged with [13N]NH3, followed by 18F-galacto-RGD, 68Ga-NODAGA-RGD or 68Ga-TRAP(RGD)3 using a dedicated animal PET/CT device. Rats were killed, and the activity in tissues was measured by gamma counting. The heart was sectioned for autoradiography and histology. Immunohistochemistry was performed on consecutive sections using CD31 for the endothelial cells and CD61 for β3 expression (as part of the αvβ3 receptor). Results: In vivo imaging showed focal RGD uptake in the hypoperfused area of infarcted myocardium as defined with [13N]NH3 scan. In autoradiography images, augmented uptake of all RGD tracers was observed within the infarct area as verified by the HE staining. The tracer uptake ratios (infarct vs. remote) were 4.7 ± 0.8 for 18F-galacto-RGD, 5.2 ± 0.8 for 68Ga-NODAGA-RGD, and 4.1 ± 0.7 for 68Ga-TRAP(RGD)3. The 68Ga-NODAGA-RGD ratio was higher compared to 68Ga-TRAP(RGD)3 (p = 0.04), but neither of the 68Ga tracers differed from 18F-galacto-RGD (p > 0.05). The area of augmented 68Ga-RGD uptake was associated with β3 integrin expression (CD61). Conclusion: 68Ga-NODAGA-RGD and 68Ga-TRAP(RGD)3 uptake was equally increased in the infarct area at 1 week post infarction as 18F-galacto-RGD. These results show the potential of 68Ga-labelled RGD peptides to monitor integrin expression as a part of myocardial repair and angiogenesis after ischaemic injury in vivo.