Albert Windhorst

Differential association of [11C]PIB and [18F]FDDNP binding with cognitive impairment

Objective: To evaluate associations of [11C]Pittsburgh compound B (PIB) and [18F]FDDNP with impairment in specific cognitive domains over the broader spectrum comprising cognitively normal elderly subjects, patients with mild cognitive impairment (MCI), and patients with Alzheimer disease (AD). Methods: Twelve patients with AD, 13 patients with MCI, and 15 cognitively normal elderly subjects were included. Paired [11C]PIB and [18F]FDDNP PET scans were performed in all subjects. Binding potential (BPND) was calculated using parametric images of BPND for global, frontal, parietal, and temporal cortex; medial temporal lobe; and posterior cingulate. Cognitive functions were assessed using a battery of neuropsychological tests. Linear regression analyses were used to assess associations of [11C]PIB and [18F]FDDNP binding with cognitive measures. Results: Adjusted for age, sex, and [18F]FDDNP binding, higher global [11C]PIB binding was associated with lower scores on the Mini-Mental State Examination, immediate and delayed recall of the Rey Auditory Verbal Learning Task (RAVLT), Visual Association Task, and Trail Making Test part B. Conversely, higher [18F]FDDNP binding was independently associated with lower scores on immediate recall of the RAVLT. After additional adjustment for diagnosis, higher [11C]PIB binding remained independently associated with delayed recall (standardized β = −0.39, p = 0.01), whereas higher [18F]FDDNP binding remained independently associated with immediate recall (standardized β = −0.32, p = 0.03). When regional binding was assessed using stepwise models, both increased frontal [11C]PIB and temporal [18F]FDDNP binding were associated with memory, whereas increased parietal [11C]PIB binding was associated with nonmemory functions. Conclusion: Increased [18F]FDDNP binding is specifically associated with impairment of episodic memory, whereas increased [11C]Pittsburgh compound B binding is associated with impairment in a broader range of cognitive functions.

SAT0650 [18F]FLUORO-PEG-FOLATE pet: a novel imaging technique to visualize rheumatoid arthritis

Background Imaging arthritis activity in rheumatoid arthritis (RA) patients using PET macrophage tracers holds promise for both early diagnostics and monitoring response to therapy (1,2). Previously, (R)-[11C]PK11195 has been used, but this macrophage tracer is limited due to high background uptake, especially in bone and bone marrow. Recently, a novel macrophage tracer, [18F]fluoro-PEG-folate, was developed, which showed excellent targeting of the folate receptor beta on activated macrophages in synovial tissue in a preclinical arthritic rat model (3). Objectives To assess the value of [18F]fluoro-PEG-folate PET-CT for imaging inflamed joints in patients with clinically active RA. Methods Nine RA patients with at least two clinically inflamed hand joints were included. PET-CT scans of the hands were acquired after intravenous administration of either 185 MBq of [18F]fluoro-PEG-folate (n=6) or 425 MBq of (R)-[11C]PK11195 (n=3). Volumes of Interest (VOI) were drawn over joints with visually marked uptake and Standardized Uptake Values (SUVs) were calculated. Background VOIs were drawn on metacarpal bone in order to calculate Target-to-Background (T/B) ratios. Results No side effects were observed, establishing the safety of [18F]fluoro-PEG-folate for use in humans. [18F]fluoro-PEG-folate clearly showed uptake in arthritic joints, as shown in Figure 1. In patients scanned with [18F]fluoro-PEG-folate, 25 positive joints were seen, with a minimum of two joints per patient. Clinical arthritis was confirmed in 10 of these 25 joints, and was absent in 15 positive joints, suggesting the presence of subclinical inflammation. Whilst both [18F]fluoro-PEG-folate and (R)-[11C]PK11195 accumulated in arthritic joints, [18F]fluoro-PEG-folate showed a significantly lower background uptake than (R)-[11C]PK11195 (SUV of 0.18 vs 0.75; p<0.001) respectively. T/B-ratios were significantly higher for [18F]fluoro-PEG-folate (3.60vs 1.72, p=0.009). Conclusions This first in patient study clearly demonstrates the potential of [18F]fluoro-PEG-folate PET-CT as macrophage tracer to image both clinically and sub-clinically affected joints in RA patients. [18F]fluoro-PEG-folate showed better characteristics for arthritis imaging than the established tracer (R)-[11C]PK11195 because of its lower background signal. References Gent YY, et al. J Rheumatology. 2014; 41: 2145–52. Gent YY, et al. Arthritis Rheum. 2012; 64: 62–6. Gent YY, et al. Arthritis Res Ther. 2013; 15: R37. Disclosure of Interest None declared

OC-0129: Nitroglycerin decreases the hypoxic fraction of non-small cell lung cancer lesions

ESTRO 35 2016 _____________________________________________________________________________________________________ It is well known that MR data contains detailed information with high tissue contrast and that PET imaging gives molecular/biochemical information with high molecular sensitivity but what is the added value? A major goal with treatment planning is to delineate the tumor volume, which can be done with both MR and PET, but since the both modalities show different characteristics of the tumor the volume might differ between them. Challenges from the imaging point of view will be discussed. The availability to PET/CT is much higher and the challenges with this method are fewer. Some comparison of the two hybrid modalities will be done. The majority of PET studies are done with the tracer fluorodexyglucose, FDG, but beyond FDG a large number of tracer are available, all giving information about different biochemical properties of the tumor. A few of these tracers will be presented and discussed.

Molecular Imaging of Inflammation Reveals Differences Between Drug-Resistant and Drug-Sensitive Animals in a Chronic Model of Temporal Lobe Epilepsy

Molecular Imaging of Inflammation Reveals Differences Between Drug-Resistant and Drug-Sensitive Animals in a Chronic Model of Temporal Lobe Epilepsy

AB0761 Synthesis and evaluation of the novel folate receptor ligand [18f]fluoro-peg-folate for macrophage targeting in a rat model of arthritis

Background Detection of (subclinical) synovitis is relevant for both early diagnosis and monitoring of therapy of rheumatoid arthritis (RA). Previously, the potential of imaging of (sub)clinical arthritis was demonstrated by targeting the translocator protein in activated macrophages using (R)-[11C]PK11195 and positron emission tomography (PET)1. Images, however, also showed significant peri-articular background activity. The folate receptor (FR)-β has been recognized as a potential alternative target for imaging of activated macrophages as the receptor features high (nanomolar) binding affinities for folates and folate-conjugated therapeutic compounds. Objectives Synthesis of the novel PET tracer [18F]fluoro-PEG-folate and its evaluation in both in vitro and ex vivo studies using a methylated BSA induced arthritis model. Methods [18F]fluoro-PEG-folate was synthesized in a two-step procedure. Relative binding affinities of non-radioactive fluoro-PEG-folate, folic acid and naturally circulating 5-methyltetrahydrofolate (5-Me-THF) to FR were determined using KB cells with high expression of FR. Both in vivo [18F]fluoro-PEG-folate PET and ex vivo tissue distribution studies were performed in arthritic rats on standard (high folate) or folate-deficient chow and in normal rats. Results were compared with those of the macrophage tracer (R)-[11C]PK11195. Results [18F]fluoro-PEG-folate was synthesized with a purity >97%, a yield of 300-1700 MBq and a specific activity between 40-70 GBq/µmol. Relative in vitro binding affinity for FR of F-PEG-folate was 1.8 fold lower than that of folic acid, but 3 fold higher than that of 5-Me-THF. [18F]fluoro-PEG-folate PET images clearly visualized arthritic rat knees. Confirming the PET data, [18F]fluoro-PEG-folate uptake (in %ID/gram tissue) as determined by tissue distribution studies in arthritic knees (0.34±0.08) was increased compared with both contralateral knees (0.24±0.08) and knees of normal rats (0.16±0.04, p<0.01). Ex vivo uptake in arthritic knees could be blocked (0.03±0.02) by an excess of glucosamine-folate, consistent with [18F]fluoro-PEG-folate being specifically bound to FR. Ex vivo arthritic knee-to-bone and arthritic knee-to-blood ratios of [18F]fluoro-PEG-folate (1.64±0.15 and 23.1±14.3, respectively) were increased compared with those of (R)-[11C]PK11195 (1.14±0.18 and 10.0±1.9, respectively). Reduction of 5-Me-THF levels in rat plasma to those mimicking human levels with folate-deficient chow increased absolute [18F]fluoro-PEG-folate uptake in arthritic joints, but without improving arthritic knee-to-bone ratios. Conclusions The novel PET tracer [18F]fluoro-PEG-folate, designed to target FR on activated macrophages, provided improved contrast in a rat model of arthritis compared with the clinically established macrophage tracer (R)-[11C]PK11195. These results warrant further exploration of [18F]fluoro-PEG-folate as a putative PET tracer for imaging (sub)clinical arthritis in RA patients. References Gent et al. Arthritis & Rheumatism 2012, 64, 62-66 Disclosure of Interest None Declared

11 oral: Preclinical Evaluation Of [18f]Hx4, A Novel and Promising Hypoxia Marker for Pet Imaging

Purpose: Hypoxic tumor cells show resistance to radiotherapy and various chemotherapeutic agents. Pre-treatment quantification of hypoxia may enable selection of patients for intensified treatment regimens. Carbonic Anhydrase IX is an endogenous hypoxia-related marker involved in pHmaintenance and is upregulated under hypoxic conditions in various tumor types. Radiolabeling of a monoclonal antibody against CAIX, such as cG250, could facilitate non-invasive PET-imaging of tumor hypoxia. Labeled F(ab’)2 fragments of cG250 show more rapid covalent binding and blood clearance than intact IgG, potentially making it an attractive PET tracer of hypoxia. Aim of this study was to investigate whether Zr-labeled cG250-F(ab’)2 showed spatial correlation to the microregional distribution of CAIX-expressing cells in a human head-and-neck tumor model assessed by immunohistochemistry and if tumor uptake would be sufficient to achieve visualization using microPET. Materials: Human head-and-neck tumors were transplanted in athymic mice. Micro-PET images were acquired 4 and 24 hours after injection of ZrcG250-F(ab’)2 . PET images were analyzed quantitatively using standardized uptake values (SUV). Tumors, blood and muscle tissue were excised for biodistribution measurements. After tumor excision, autoradiography of tumor sections was followed by immunohistochemical staining to visualize CAIX expression, hypoxia (pimonidazole) and tumor blood perfusion (Hoechst 33342). Spatial correlation analysis methods were performed. Results: At 4h after administration, definite tumor accumulation of ZrcG250-F(ab’)2 was demonstrated by micro-PET imaging, with declining uptake 24h post-injection. Pixel-by-pixel analysis showed a positive and significant spatial correlation between CAIX immunohistochemical and Zr-cG250F(ab’)2 autoradiography signal (r values 0.57 0.74; p<0.0001). Slightly lower correlations were found between pimonidazole and Zr-cG250-F(ab’)2. Tumor SUVmax (mean 1.65± 0.26 at 4h p.i. and 0.57± 0.32 at 24h p.i.) correlated significantly with tumor uptake determined ex vivo (r= 0.93; p= 0.0067), as did fractions of CAIX and pimonidazole signal in tumor sections (r= 0.75; p= 0.03 and r= 0.78; p= 0.02, respectively). Conclusions: In a human head-and-neck tumor model, Zr-labeled cG250F(ab’)2 showed rapid tumor accumulation on micro-PET scan images, with good correlation to CAIX expression on a microregional level.

PET imaging of [11C]docetaxel uptake and tumor perfusion in lung cancer.

2543 Background: Although docetaxel is an effective treatment of lung cancer, a number of patients do not benefit from this therapy due to tumor resistance. Positron emission tomography (PET) is a noninvasive imaging technique that allows for quantification of radiolabeled docetaxel ([11C]docetaxel) kinetics and might be useful for predicting response to treatment. The aim of the present study was to determine the feasibility and reproducibility of [11C]docetaxel PET scans in lung cancer and to investigate whether [11C]docetaxel uptake was related to tumor perfusion. Methods: Fourteen patients with advanced lung cancer underwent a dynamic PET-CT scan with [11C]docetaxel (60 min) and H215O (10 min). In addition, patients underwent a second [11C]docetaxel PET scan to assess test-retest reproducibility. Lesions were delineated on the CT scan and projected onto the dynamic PET frames. [11C]docetaxel uptake in tumors was quantified using the net influx rate (Ki). Tumor perfusion was quantified by applying the ...