Joel Lazewatsky

Phase II safety and clinical comparison with single-photon emission computed tomography myocardial perfusion imaging for detection of coronary artery disease: flurpiridaz F 18 positron emission tomography.

OBJECTIVES This was a phase II trial to assess flurpiridaz F 18 for safety and compare its diagnostic performance for positron emission tomography (PET) myocardial perfusion imaging (MPI) with Tc-99m single-photon emission computed tomography (SPECT) MPI with regard to image quality, interpretative certainty, defect magnitude, and detection of coronary artery disease (CAD) (≥50% stenosis) on invasive coronary angiography (ICA). BACKGROUND In pre-clinical and phase I studies, flurpiridaz F 18 has shown characteristics of an essentially ideal MPI tracer. METHODS One hundred forty-three patients from 21 centers underwent rest-stress PET and Tc-99m SPECT MPI. Eighty-six patients underwent ICA, and 39 had low-likelihood of CAD. Images were scored by 3 independent, blinded readers. RESULTS A higher percentage of images were rated as excellent/good on PET versus SPECT on stress (99.2% vs. 88.5%, p < 0.01) and rest (96.9% vs. 66.4, p < 0.01) images. Diagnostic certainty of interpretation (percentage of cases with definitely abnormal/normal interpretation) was higher for PET versus SPECT (90.8% vs. 70.9%, p < 0.01). In 86 patients who underwent ICA, sensitivity of PET was higher than SPECT (78.8% vs. 61.5%, respectively, p = 0.02). Specificity was not significantly different (PET: 76.5% vs. SPECT: 73.5%). Receiver-operating characteristic curve area was 0.82 ± 0.05 for PET and 0.70 ± 0.06 for SPECT (p = 0.04). Normalcy rate was 89.7% with PET and 97.4% with SPECT (p = NS). In patients with CAD on ICA, the magnitude of reversible defects was greater with PET than SPECT (p = 0.008). Extensive safety assessment revealed that flurpiridaz F 18 was safe in this cohort. CONCLUSIONS In this phase 2 trial, PET MPI with flurpiridaz F 18 was safe and superior to SPECT MPI for image quality, interpretative certainty, and overall CAD diagnosis.

Phase I, First-in-Human Study of BMS747158, a Novel 18F-Labeled Tracer for Myocardial Perfusion PET: Dosimetry, Biodistribution, Safety, and Imaging Characteristics After a Single Injection at Rest

18F-labeled BMS747158 is a novel myocardial perfusion imaging tracer that targets mitochondrial complex 1. The objectives of this phase I study were to evaluate radiation dosimetry, biodistribution, human safety, tolerability, and early elimination of 18F activity in urine after injection of a single dose of the tracer at rest in healthy subjects. Methods: Thirteen healthy subjects were injected with 170–244 MBq (4.6–6.6 mCi) of BMS747158 intravenously. Dynamic PET was obtained over the heart for 10 min, followed by sequential whole-body imaging for 5 h. Blood samples and urinary excretion were collected for up to 8 h. Heart rate, electrocardiogram, and blood pressure were monitored before and during imaging. The residence times were determined from multiexponential regression of organ region-of-interest data normalized by injected dose. Absorbed dose estimates for all target organs were determined using MIRD schema with OLINDA/EXM software. Results: The organ receiving the largest mean absorbed dose was the kidneys at 0.066 mSv/MBq (0.24 rem/mCi), followed by the heart wall at 0.048 mSv/MBq (0.18 rem/mCi). The mean effective dose was 0.019 mSv/MBq (0.072 rem/mCi). The heart exhibited high and sustained retention of BMS747158 from the earliest images through approximately 5 h after injection. There were no drug-related adverse events, and the tracer was well tolerated in all subjects. Mean urinary excretion was 4.83 percentage injected dose (range, 0.64–12.41 percentage injected dose). Conclusion: These preliminary data suggest that 18F-labeled BMS747158 appears to be well tolerated and has a unique potential for myocardial perfusion PET.

Design, Synthesis, and Evaluation of Radiolabeled Integrin αvβ3 Receptor Antagonists for Tumor Imaging and Radiotherapy

The goal of this research is the development of tumor imaging and radiotherapeutic agents based on targeting of the integrin αvβ3 (vitronectin receptor). Macrocyclic chelator DOTA has been conjugated to peptidomimetic vitronectin receptor antagonist SH066 to give TA138. TA138 and 89Y-TA138 retain antagonist properties and high affinity for integrin αvβ3 (IC50 = 12 and 18 nM, respectively), and good selectivity versus integrin αIIbβ3 (IC50 > 10,000 nM). TA138 forms stable complexes with 111In and 90Y in > 95% RCP. 111In-TA138 demonstrates high tumor uptake in the c-neu Oncomouse® (Charles River Laboratories [Charles River, Canada]) mammary adenocarcinoma model (9.39% ID/g at 2 hours PI) and low background activity. Blood clearance is rapid and excretion is renal. Tumors are visible as early as 0.5 hours PI. Radiotherapy studies in the c-neu Oncomouse® model demonstrated a slowing of tumor growth at a dose of 15 mCi/m2, and a regression of tumors at a dose of 90 mCi/m2.

Evaluation of LMI1195, a Novel 18F-Labeled Cardiac Neuronal PET Imaging Agent, in Cells and Animal Models

Background—Heart failure has been associated with impaired cardiac sympathetic neuronal function. Cardiac imaging with radiolabeled agents that are substrates for the neuronal norepinephrine transporter (NET) has demonstrated the potential to identify individuals at risk of cardiac events. N-[3-Bromo-4-(3-[18F]fluoro-propoxy)-benzyl]-guanidine (LMI1195) is a newly developed 18F-labeled NET substrate designed to allow cardiac neuronal imaging with the high sensitivity, resolution, and quantification afforded by positron emission tomography (PET). Methods and Results—LMI1195 was evaluated in comparison with norepinephrine (NE) in vitro and 123I-meta-iodobenzylguanidine (MIBG) in vivo. The affinity (Ki) of LMI1195 for NET was 5.16±2.83 &mgr;mol/L, similar to that of NE (3.36±2.77 &mgr;mol/L) in a cell membrane–binding assay. Similarly, LMI1195 uptake kinetics examined in a human neuroblastoma cell line had Km and Vmax values of 1.44±0.76 &mgr;mol/L and 6.05±3.09 pmol/million cells per minute, comparable to NE (2.01±0.85 &mgr;mol/L and 6.23±1.52 pmol/million cells per minute). In rats, LMI1195 heart uptake at 15 and 60 minutes after intravenous administration was 2.36±0.38% and 2.16±0.38% injected dose per gram of tissue (%ID/g), similar to 123I-MIBG (2.14±0.30 and 2.19±0.27%ID/g). However, the heart to liver and lung uptake ratios were significantly higher for LMI1195 than for 123I-MIBG. In rabbits, desipramine (1 mg/kg), a selective NET inhibitor, blocked LMI1195 heart uptake by 82%, which was more effective than 123I-MIBG (53%), at 1 hour after dosing. Sympathetic denervation with 6-hydroxydopamine, a neurotoxin, resulted in a marked (79%) decrease in LMI1195 heart uptake. Cardiac PET imaging with LMI1195 in rats, rabbits, and nonhuman primates revealed clear myocardium with low radioactivity levels in the blood, lung, and liver. Imaging in rabbits pretreated with desipramine showed reduced heart radioactivity levels in a dose-dependent manner. Additionally, imaging in sympathetically denervated rabbits resulted in low cardiac image intensity with LMI1195 but normal perfusion images with flurpiridaz F 18, a PET myocardial perfusion imaging agent. In nonhuman primates pretreated with desipramine (0.5 mg/kg), imaging with LMI1195 showed a 66% decrease in myocardial uptake. In a rat model of heart failure, the LMI1195 cardiac uptake decreased as heart failure progressed. Conclusions—LMI1195 is a novel 18F imaging agent retained in the heart through the NET and allowing evaluation of the cardiac sympathetic neuronal function by PET imaging.

Biodistribution and Radiation Dosimetry of LMI1195: First-in-Human Study of a Novel 18F-Labeled Tracer for Imaging Myocardial Innervation

A novel 18F-labeled ligand for the norepinephrine transporter (N-[3-bromo-4-(3-18F-fluoro-propoxy)-benzyl]-guanidine [LMI1195]) is in clinical development for mapping cardiac nerve terminals in vivo using PET. Human safety, whole-organ biodistribution, and radiation dosimetry of LMI1195 were evaluated in a phase 1 clinical trial. Methods: Twelve healthy subjects at 3 clinical sites were injected intravenously with 150–250 MBq of LMI1195. Dynamic PET images were obtained over the heart for 10 min, followed by sequential whole-body images for approximately 5 h. Blood samples were obtained, and heart rate, electrocardiogram, and blood pressure were monitored before and during imaging. Residence times were determined from multiexponential regression of organ region-of-interest data normalized by administered activity (AA). Radiation dose estimates were calculated using OLINDA/EXM. Myocardial, lung, liver, and blood-pool standardized uptake values were determined at different time intervals. Results: No adverse events due to LMI1195 were seen. Blood radioactivity cleared quickly, whereas myocardial uptake remained stable and uniform throughout the heart over 4 h. Liver and lung activity cleared relatively rapidly, providing favorable target-to-background ratios for cardiac imaging. The urinary bladder demonstrated the largest peak uptake (18.3% AA), followed by the liver (15.5% AA). The mean effective dose was 0.026 ± 0.0012 mSv/MBq. Approximately 1.6% AA was seen in the myocardium initially, remaining above 1.5% AA (decay-corrected) through 4 h after injection. The myocardium-to-liver ratio was approximately unity initially, increasing to more than 2 at 4 h. Conclusion: These preliminary data suggest that LMI1195 is well tolerated and yields a radiation dose comparable to that of other commonly used PET radiopharmaceuticals. The kinetics of myocardial and adjacent organ activity suggest that cardiac imaging should be possible with acceptable patient radiation dose.

Dual-Gated Motion-Frozen Cardiac PET with Flurpiridaz F 18

A novel PET radiotracer, Flurpiridaz F 18, has undergone phase II clinical trial evaluation as a high-resolution PET cardiac perfusion imaging agent. In a subgroup of patients imaged with this agent, we assessed the feasibility and benefit of simultaneous correction of respiratory and cardiac motion. Methods: In 16 patients, PET imaging was performed on a 4-ring scanner in dual cardiac and respiratory gating mode. Four sets of data were reconstructed with high-definition reconstruction (HD•PET): ungated and 8-bin electrocardiography-gated images using 5-min acquisition, optimal respiratory gating (ORG)—as developed for oncologic imaging—using a narrow range of breathing amplitude around end-expiration level with 35% of the counts in a 7-min acquisition, and 4-bin respiration-gated and 8-bin electrocardiography-gated images (32 bins in total) using the 7-min acquisition (dual-gating, using all data). Motion-frozen (MF) registration algorithms were applied to electrocardiography-gated and dual-gated data, creating cardiac-MF and dual-MF images. We computed wall thickness, wall/cavity contrast, and contrast-to-noise ratio for standard, ORG, cardiac-MF, and dual-MF images to assess image quality. Results: The wall/cavity contrast was similar for ungated (9.3 ± 2.9) and ORG (9.5 ± 3.2) images and improved for cardiac-MF (10.8 ± 3.6) and dual-MF images (14.8 ± 8.0) (P < 0.05). The contrast-to-noise ratio was 22.2 ± 9.1 with ungated, 24.7 ± 12.2 with ORG, 35.5 ± 12.8 with cardiac-MF, and 42.1 ± 13.2 with dual-MF images (all P < 0.05). The wall thickness was significantly decreased (P < 0.05) with dual-MF (11.6 ± 1.9 mm) compared with ungated (13.9 ± 2.8 mm), ORG (13.1 ± 2.9 mm), and cardiac-MF images (12.1 ± 2.7 mm). Conclusion: Dual (respiratory/cardiac)-gated perfusion imaging with Flurpiridaz F 18 is feasible and improves image resolution, contrast, and contrast-to-noise ratio when MF registration methods are applied.

Automatic 3D registration of dynamic stress and rest 82Rb and flurpiridaz F 18 myocardial perfusion PET data for patient motion detection and correction

PURPOSE The authors aimed to develop an image-based registration scheme to detect and correct patient motion in stress and rest cardiac positron emission tomography (PET)/CT images. The patient motion correction was of primary interest and the effects of patient motion with the use of flurpiridaz F 18 and (82)Rb were demonstrated. METHODS The authors evaluated stress/rest PET myocardial perfusion imaging datasets in 30 patients (60 datasets in total, 21 male and 9 female) using a new perfusion agent (flurpiridaz F 18) (n = 16) and (82)Rb (n = 14), acquired on a Siemens Biograph-64 scanner in list mode. Stress and rest images were reconstructed into 4 ((82)Rb) or 10 (flurpiridaz F 18) dynamic frames (60 s each) using standard reconstruction (2D attenuation weighted ordered subsets expectation maximization). Patient motion correction was achieved by an image-based registration scheme optimizing a cost function using modified normalized cross-correlation that combined global and local features. For comparison, visual scoring of motion was performed on the scale of 0 to 2 (no motion, moderate motion, and large motion) by two experienced observers. RESULTS The proposed registration technique had a 93% success rate in removing left ventricular motion, as visually assessed. The maximum detected motion extent for stress and rest were 5.2 mm and 4.9 mm for flurpiridaz F 18 perfusion and 3.0 mm and 4.3 mm for (82)Rb perfusion studies, respectively. Motion extent (maximum frame-to-frame displacement) obtained for stress and rest were (2.2 ± 1.1, 1.4 ± 0.7, 1.9 ± 1.3) mm and (2.0 ± 1.1, 1.2 ±0 .9, 1.9 ± 0.9) mm for flurpiridaz F 18 perfusion studies and (1.9 ± 0.7, 0.7 ± 0.6, 1.3 ± 0.6) mm and (2.0 ± 0.9, 0.6 ± 0.4, 1.2 ± 1.2) mm for (82)Rb perfusion studies, respectively. A visually detectable patient motion threshold was established to be ≥2.2 mm, corresponding to visual user scores of 1 and 2. After motion correction, the average increases in contrast-to-noise ratio (CNR) from all frames for larger than the motion threshold were 16.2% in stress flurpiridaz F 18 and 12.2% in rest flurpiridaz F 18 studies. The average increases in CNR were 4.6% in stress (82)Rb studies and 4.3% in rest (82)Rb studies. CONCLUSIONS Fully automatic motion correction of dynamic PET frames can be performed accurately, potentially allowing improved image quantification of cardiac PET data.

Phase II Safety and Clinical Comparison With Single-Photon Emission Computed Tomography Myocardial Perfusion Imaging for Detection of Coronary Artery Disease

OBJECTIVES This was a phase II trial to assess flurpiridaz F 18 for safety and compare its diagnostic performance for positron emission tomography (PET) myocardial perfusion imaging (MPI) with Tc-99m single-photon emission computed tomography (SPECT) MPI with regard to image quality, interpretative certainty, defect magnitude, and detection of coronary artery disease (CAD) (≥50% stenosis) on invasive coronary angiography (ICA). BACKGROUND In pre-clinical and phase I studies, flurpiridaz F 18 has shown characteristics of an essentially ideal MPI tracer. METHODS One hundred forty-three patients from 21 centers underwent rest-stress PET and Tc-99m SPECT MPI. Eighty-six patients underwent ICA, and 39 had low-likelihood of CAD. Images were scored by 3 independent, blinded readers. RESULTS A higher percentage of images were rated as excellent/good on PET versus SPECT on stress (99.2% vs. 88.5%, p < 0.01) and rest (96.9% vs. 66.4, p < 0.01) images. Diagnostic certainty of interpretation (percentage of cases with definitely abnormal/normal interpretation) was higher for PET versus SPECT (90.8% vs. 70.9%, p < 0.01). In 86 patients who underwent ICA, sensitivity of PET was higher than SPECT (78.8% vs. 61.5%, respectively, p = 0.02). Specificity was not significantly different (PET: 76.5% vs. SPECT: 73.5%). Receiver-operating characteristic curve area was 0.82 ± 0.05 for PET and 0.70 ± 0.06 for SPECT (p = 0.04). Normalcy rate was 89.7% with PET and 97.4% with SPECT (p = NS). In patients with CAD on ICA, the magnitude of reversible defects was greater with PET than SPECT (p = 0.008). Extensive safety assessment revealed that flurpiridaz F 18 was safe in this cohort. CONCLUSIONS In this phase 2 trial, PET MPI with flurpiridaz F 18 was safe and superior to SPECT MPI for image quality, interpretative certainty, and overall CAD diagnosis.

IMPROVED ASSESSMENT OF CAD IN OBESE SUBJECTS WITH FLURPIRIDAZ F18 PET MYOCARDIAL PERFUSION IMAGING: A SUBSET ANALYSIS OF THE FLURPIRIDAZ F18 301 PHASE 3 STUDY

Non-invasive assessment of CAD in the obese (WHO definition BMI > 30) is challenging, often resulting in suboptimal image quality. Flurpiridaz F-18 is a novel PET tracer in Phase 3 development, the primary endpoint being accuracy vs Tc99m-labeled SPECT. This study reports on a pre-specified

Radiation dose to abdominal organs of the mouse due to 90Y in the urinary bladder.

Radiation dosimetry estimates in mice have proven useful in evaluating therapeutic radiopharmaceuticals. Current models for mice do not take into account the dose to abdominal organs from radioactivity in the urinary bladder. Although the dose from this source is probably low for slowly clearing compounds such as antibodies, it may be considerable for small molecule (90)Y conjugates undergoing rapid renal clearance. To evaluate this possibility, we modeled the mouse bladder as a 6 mm sphere, surrounded by a 0.5 mm thick shell. We then calculated the radiation dose that might be received by the shell and by more distant points, using the point kernel method with the Loevinger analytical point kernel. A Monte Carlo calculation using EGS4 was also performed. Surface dose calculations were compared with in vitro experimental data. LiF TLD dosimeters were placed directly under five separated, flat-bottomed, 6-mm diameter wells containing (90)Y on a 96-well plate. Dose versus distance from the mouse urinary bladder was calculated using kinetic data from imaging studies of a renally cleared (111)In analog compound currently under investigation. From this, it was estimated that whole body administration of 34.8 MBq of the (90)Y analog compound would yield a bladder wall dose estimate of approximately 98 Gy. Structures within 2 mm of the bladder would receive additional estimated doses of at least 15 Gy. This radiation dose approaches that which is known from external beam data to cause fibrosis in mice. Because of the greater size of the human bladder compared with that of the mouse relative to the range of (90)Y beta particles, the radiation exposure from the same residence time in man was estimated to be considerably lower. This highlights a potential practical limitation of extrapolating radiotoxicity findings in the mouse to human subjects.