EJNMMI Research - Most accessed articles

Kinetic analysis and test-retest variability of the radioligand [11C](R)-PK11195 binding to TSPO in the human brain - a PET study in control subjects

Aurelija Jucaite — 2012-04-23T00:00:00Z

Background: Positron-emission tomography and the radioligand [11C](R)-PK11195 have been used for the imaging of the translocator protein (TSPO) and applied to map microglia cells in the brain in neuropsychiatric disorders. [11C](R)-PK11195 binding has been quantified using reference region approaches, with the reference defined anatomically or using unsupervised or supervised clustering algorithms. Kinetic compartment modelling so far has not been presented. In the present test-retest study, we examine the characteristics of [11C](R)-PK11195 binding in detail, using the classical compartment analysis with a metabolite-corrected arterial input function. Methods: [11C](R)-PK11195 binding was examined in six control subjects at two separate occasions, 6 weeks apart. Results of one-tissue and two-tissue compartment models (1TCM, 2TCM) were compared using the Akaike criteria and F-statistics. The reproducibility of binding potential (BPND) estimates was evaluated by difference in measurements (error in percent) and intraclass correlation coefficients (ICCs). Results: [11C](R)-PK11195 binding could be described by 2TCM which was the preferred model. Measurement error (in percent) indicated good reproducibility in large brain regions (mean error: whole brain 4%, grey matter 5%), but not in smaller subcortical regions (putamen 25%, caudate 55%). The ICC values were moderate to low, highest for the white matter (0.73), whole brain and thalamus (0.57), and cortical grey matter (0.47). Sizeable [11C](R)-PK11195 BPND could be identified throughout the human brain (range 1.11 to 2.21). Conclusions: High intra-subject variability of [11C](R)-PK11195 binding limits longitudinal monitoring of TSPO changes. The interpretation of [11C](R)-PK11195 binding by 2TCM suggests that the presence of specific binding to TSPO cannot be excluded at physiological conditions.

18F-fluoride PET: changes in uptake as a method to assess response in bone metastases from castrate-resistant prostate cancer patients treated with 223Ra-chloride (Alpharadin)

Gary Cook — 2011-06-07T00:00:00Z

Background: A qualitative assessment of conventional bone scintigraphy with 99mTc methylene diphosphonate is perceived as an insensitive method for monitoring the treatment response of bone metastases, and we postulated that semi-quantitative 18F-fluoride positron emission tomography (PET) might serve as a suitable alternative biomarker of the treatment response. Methods: Five patients with castrate-resistant prostate cancer and bone metastases with no known soft tissue disease received 100 kBq/kg of radium-223 (223Ra)-chloride (Alpharadin) therapy at 0 and 6 weeks and had whole body 18F-fluoride PET scans at baseline, 6 and 12 weeks with concurrent prostatic-specific antigen (PSA) and alkaline phosphatase (ALP) measurements. A qualitative comparison of the PET scans was performed blinded to the PSA and ALP results. A semi-quantitative comparison was made by measuring the maximum standardised uptake values (SUVmax) in five bone metastases in each patient. The means of the five SUVmax measurements in each subject were used as a quantitative measure of global metastatic activity at each time point. Results: Three patients showed a PSA decline at 12 weeks (-44%, -31%, -27% reduction) whilst two patients showed PSA increases (+10%, +17%). All five patients showed a reduction in ALP of greater than 25%. The qualitative assessment of the 18F-fluoride scans recorded a stable disease in each case. However, the semi-quantitative assessment showed agreement with the PSA decline in three patients (-52%, -75%, -49%) and minimal change (+12%, -16%) in two patients with increased PSA at 12 weeks. Four patients showed similar reductions in mean SUVmax and ALP at 12 weeks. Conclusions: The semi-quantitative 18F-fluoride PET is more accurate than the qualitative comparison of scans in assessing response in bone metastases, correlating with the PSA response and ALP activity and offering a potential imaging biomarker for monitoring treatment response in bone metastases following treatment with 223Ra-chloride.

High resolution tumor targeting in living mice by means of multispectral optoacoustic tomography

Andreas Buehler — 2012-04-01T00:00:00Z

Background: Tumor targeting is of high clinical and biological relevance, and major efforts have been made to develop molecular imaging technologies for visualization of the disease markers in tissue. Of particular interest is apoptosis which has a profound role within tumor development and has significant effect on cancer malignancy. Methods: Herein, we report on targeting of phosphatidylserine-exposing cells within live tumor allograft models using a synthetic near infrared zinc(II)-dipicolylamine probe. Visualization of the probe biodistribution is performed with whole body multispectral optoacoustic tomography (MSOT) system and subsequently compared to results attained by planar and tomographic fluorescence imaging systems. Results: Compared to whole body optical visualization methods, MSOT attains remarkably better imaging capacity by delivering high-resolution scans of both disease morphology and molecular function in real time. Enhanced resolution of MSOT clearly showed that the probe mainly localizes in the vessels surrounding the tumor, suggesting that its tumor selectivity is gained by targeting the phosphatidylserine exposed on the surface of tumor vessels. Conclusions: The current study demonstrates the high potential of MSOT to broadly impact the fields of tumor diagnostics and preclinical drug development.

[11C]Flumazenil brain uptake is influenced by the blood-brain barrier efflux transporter P-glycoprotein

Femke Froklage — 2012-03-28T00:00:00Z

Background: [11C]Flumazenil and positron emission tomography (PET) are used clinically to assess gamma-aminobutyric acid (GABA)-ergic function and to localize epileptic foci prior to resective surgery. Enhanced P-glycoprotein (P-gp) activity has been reported in epilepsy and this may confound interpretation of clinical scans if [11C]flumazenil is a P-gp substrate. The purpose of this study was to investigate whether [11C]flumazenil is a P-gp substrate. Methods: [11C]Flumazenil PET scans were performed in wild type (WT) (n = 9) and Mdr1a/1b, (the genes that encode for P-gp) double knockout (dKO) (n = 10) mice, and in naive rats (n = 10). In parallel to PET scanning, [11C]flumazenil plasma concentrations were measured in rats. For 6 of the WT and 6 of the dKO mice a second, [11C]flumazenil scan was acquired after administration of the P-gp inhibitor tariquidar. Cerebral [11C]flumazenil concentrations in WT and Mdr1a/1b dKO mice were compared (genetic disruption model). Furthermore, pre and post P-gp-blocking cerebral [11C]flumazenil concentrations were compared in all animals (pharmacological inhibition model). Results: Mdr1a/1b dKO mice had approximately 70% higher [11C]flumazenil uptake in the brain than WT mice. After administration of tariquidar, cerebral [11C]flumazenil uptake in WT mice increased by about 80% in WT mice, while it remained the same in Mdr1a/1b dKO mice. In rats, cerebral [11C]flumazenil uptake increased by about 60% after tariquidar administration. Tariquidar had only a small effect on plasma clearance of flumazenil. Conclusions: The present study showed that [11C]flumazenil is a P-gp substrate in rodents. Consequently, altered cerebral [11C]flumazenil uptake, as observed in epilepsy, may not reflect solely GABAA receptor density changes but also changes in P-gp activity.

A method for model-free partial volume correction in oncological PET

Frank Hofheinz — 2012-04-24T00:00:00Z

Background: As is well known, limited spatial resolution leads to partial volume effects (PVE) and consequently to limited signal recovery. Determination of the mean activity concentration of a target structure is thus compromised even at target sizes much larger than the reconstructed spatial resolution. This leads to serious size-dependent underestimates of true signal intensity in hot spot imaging. For quantitative PET in general and in the context of therapy assessment in particular it is, therefore, mandatory to perform an adequate partial volume correction (PVC). The goal of our work was to develop and to validate a model-free PVC algorithm for hot spot imaging. Methods: The algorithm proceeds in two automated steps. Step 1: estimation of the actual object boundary with a threshold based method and determination of the total activity A measured within the enclosed volume V. Step 2: determination of the activity fraction B, which is measured outside the object due to the partial volume effect (spill-out). The PVE corrected mean value is then given by Cmean = (A+B)/V. For validation simulated tumours were used which were derived from real patient data (liver metastases of a colorectal carcinoma and head and neck cancer, respectively). The simulated tumours have characteristics (regarding tumour shape, contrast, noise, etc.) which are very similar to those of the underlying patient data, but the boundaries and tracer accumulation are exactly known. The PVE corrected mean values of 37 simulated tumours were determined and compared with the true mean values. Results: For the investigated simulated data the proposed approach yields PVE corrected mean values which agree very well with the true values (mean deviation (+/- s.d.): (0.8 +/- 2.5)% Conclusions: The described method enables accurate quantitative partial volume correction in oncological hot spot imaging.

Quantitative assessment of brown adipose tissue metabolic activity and volume using 18F-FDG PET/CT and β3-adrenergic receptor activation

Mohammed Mirbolooki — 2011-12-01T00:00:00Z

Background: Brown adipose tissue [BAT] metabolism in vivo is vital for the development of novel strategies in combating obesity and diabetes. Currently, BAT is activated at low temperatures and measured using 2-deoxy-2-18F-fluoro-D-glucose [18F-FDG] positron-emission tomography [PET]. We report the use of β3-adrenergic receptor-mediated activation of BAT at ambient temperatures using (R, R)-5-[2-[2,3-(3-chlorphenyl)-2-hydroxyethyl-amino]propyl]-1,3-benzodioxole-2,2-dicarboxylate, disodium salt [CL316,243] (a selective β3-adrenoceptor agonist) and measured by 18F-FDG PET/computed tomography [CT]. Methods: Control and CL316,243-treated (2 mg/kg) male Sprague-Dawley rats were administered with 18F-FDG for PET/CT studies and were compared to animals at cold temperatures. Receptor-blocking experiments were carried out using propranolol (5 mg/kg). Dose effects of CL316,243 were studied by injecting 0.1 to 1 mg/kg 30 min prior to 18F-FDG administration. Imaging results were confirmed by autoradiography, and histology was done to confirm BAT activation. Results: CL316,243-activated interscapular BAT [IBAT], cervical, periaortic, and intercostal BATs were clearly visualized by PET. 18F-FDG uptake of IBAT was increased 12-fold by CL316,243 vs. 1.1-fold by cold exposure when compared to controls. 18F-FDG uptake of the CL-activated IBAT was reduced by 96.0% using intraperitoneal administration of propranolol. Average 18F-FDG uptake of IBAT increased 3.6-, 3.5-, and 7.6-fold by doses of 0.1, 0.5, and 1 mg/kg CL, respectively. Ex vivo 18F-FDG autoradiography and histology of transverse sections of IBAT confirmed intense uptake in the CL-activated group and activated IBAT visualized by PET. Conclusion: Our study indicated that BAT metabolic activity could be evaluated by 18F-FDG PET using CL316,243 at ambient temperature in the rodent model. This provides a feasible and reliable method to study BAT metabolism.

Straightforward thiol-mediated protein labelling with DTPA: Synthesis of a highly active 111In-annexin A5-DTPA tracer

Harald Kratz — 2012-04-27T00:00:00Z

Background: Annexin A5 (anxA5) has been found useful for molecular imaging of apoptosis and other biological processes. Methods: Here, we report an optimised two-step synthesis of annexin A5-diethylene triamine pentaacetic acid (DTPA) (anxA5-DTPA) for positron emission tomography (PET) and single-photon emission computed tomography (SPECT) imaging with a single purification step. The use of a recombinant annexin A5 (cys-anxA5) with a single thiol group allowed regionally specific coupling, without affecting the binding domain of cys-anxA5. Results: The metal complexing capacity of anxA5-DTPA was investigated by labelling with 111In3+ and Eu3+. Binding of modified anxA5-DTPA to apoptotic cells was tested in competition experiments with a fluorescent anxA5 derivative (anxA5-FITC) using flow cytometry and compared with that of wildtype anxA5 or non-binding anxA5-DTPA (M1234-anxA5-DTPA). The binding affinity to apoptotic cells of the anxA5-DTPA conjugate does not differ from that of wildtype anxA5. Conclusions: This two-step synthesis of annexin A5-DTPA resulted in biologically active anxA5-DTPA, which can be labelled with radionuclides for use in SPECT and PET imaging.

Sorafenib increases 18-FDG colic uptake: demonstration in patients with differentiated thyroid cancer

Renaud Ciappuccini — 2012-05-07T00:00:00Z

Background: To assess 18-fluorodeoxyglucose (FDG) bowel uptake in patients with differentiated thyroidcancer (DTC) treated with sorafenib.FindingsVisual (5-point scale) and high maximum standard uptake value (SUVmax) semi-quantitativeanalyses were conducted in 63 positron emission tomography (PET) studies performed inpatients on sorafenib (group 1, n = 20), in a control group (group 2, n = 28) and in patients onsunitinib or vandetanib (group 3, n = 15).Moderate or high and diffuse bowel uptake (grade 4 or 5) was observed in 90% of the PETscans of group 1 versus none in group 2. Only 20% of PET scans in group 3 were scoredgrade 4. SUVmax values were significantly higher for all colic segments in group 1 than ingroup 2 (P < 0.0001) or 3 (P < 0.0004). This uptake pattern appeared rapidly (one month) anddisappeared after sorafenib withdrawal. Conclusions: FDG uptake is increased in the colon of DTC patients treated by sorafenib.

Imaging technologies for preclinical models of bone and joint disorders

Jordi Tremoleda — 2011-07-29T00:00:00Z

Preclinical models for musculoskeletal disorders are critical for understanding the pathogenesis of bone and joint disorders in humans and the development of effective therapies. The assessment of these models primarily relies on morphological analysis which remains time consuming and costly, requiring large numbers of animals to be tested through different stages of the disease. The implementation of preclinical imaging represents a keystone in the refinement of animal models allowing longitudinal studies and enabling a powerful, non-invasive and clinically translatable way for monitoring disease progression in real time. Our aim is to highlight examples that demonstrate the advantages and limitations of different imaging modalities including magnetic resonance imaging (MRI), computed tomography (CT), positron emission tomography (PET), single-photon emission computed tomography (SPECT) and optical imaging. All of which are in current use in preclinical skeletal research. MRI can provide high resolution of soft tissue structures, but imaging requires comparatively long acquisition times; hence, animals require long-term anaesthesia. CT is extensively used in bone and joint disorders providing excellent spatial resolution and good contrast for bone imaging. Despite its excellent structural assessment of mineralized structures, CT does not provide in vivo functional information of ongoing biological processes. Nuclear medicine is a very promising tool for investigating functional and molecular processes in vivo with new tracers becoming available as biomarkers. The combined use of imaging modalities also holds significant potential for the assessment of disease pathogenesis in animal models of musculoskeletal disorders, minimising the use of conventional invasive methods and animal redundancy.

Bone-seeking TRAP conjugates: surprising observations and their implications on the development of gallium-68-labeled bisphosphonates

Johannes Notni — 2012-03-30T00:00:00Z

Background: Bisphosphonates possess strong affinity to bone. 99mTc bisphosphonate complexes are widely used for bone scintigraphy. For positron emission tomography (PET) bone imaging, Ga-68-based PET tracers based on bisphosphonates are highly desirable.FindingsTwo trimeric bisphosphonate conjugates of the triazacyclononane-phosphinate (TRAP) chelator were synthesized, labeled with Ga-68, and used for microPET imaging of bone in male Lewis rats. Both Ga-68 tracers show bone uptake and, thus, are suitable for PET bone imaging. Surprisingly, Ga-71 nuclear magnetic resonance data prove that Ga(III) is not located in the chelating cavity of TRAP and must therefore be bound by the conjugated bisphosphonate units. Conclusion: The intrinsic Ga-68 chelating properties of TRAP are not needed for Ga-68 PET bone imaging with TRAP-bisphosphonate conjugates. Here, TRAP serves only as a trimeric scaffold. For preparation of Ga-68-based bone seekers for PET, it appears sufficient to equip branched scaffolds with multiple bisphosphonate units, which serve both Ga-68-binding and bone-targeting purposes.