Simon P. Robinson

Initial Characterization of an 18F-Labeled Myocardial Perfusion Tracer

PET allows for quantitative, regional myocardial perfusion imaging. The short half-lives of the perfusion tracers currently in use limit their clinical applicability. Here, the biodistribution and imaging quality of a new 18F-labeled myocardial perfusion agent (18F-BMS-747158-02) in an animal model are described. Methods: The biodistribution of 18F-BMS-747158-02 was determined at 10 and 60 min after injection. The first-pass extraction fraction of the tracer was measured in isolated rat hearts perfused with the Langendorff method. Small-animal PET imaging was used to study tracer retention. Results: The biodistribution at 10 min after injection demonstrated high myocardial uptake (3.1 percentage injected dose per gram [%ID/g]) accompanied by little activity in the lungs (0.3 %ID/g) and liver (1.0 %ID/g). The tracer showed a high and flow-independent myocardial first-pass extraction fraction, averaging 0.94 (SD = 0.04). PET imaging provided excellent delineation of myocardial structures. The heart-to-lung activity ratio increased from 4.7 to 10.2 between 1 and 15 min after tracer injection (at rest). Adenosine infusion (140 μg/kg/min) led to a significant increase in myocardial tracer retention (from 1.68 [SD = 0.23]) s−1 to 3.21 [SD = 0.92] s−1; P = 0.03). Conclusion: The observation of a high and flow-independent first-pass extraction fraction promises linearity between tracer uptake and myocardial blood flow. Sustained myocardial tracer uptake, combined with high image contrast, will allow for imaging protocols with tracer injection at peak exercise followed by delayed imaging. Thus, 18F-BMS-747158-02 is a promising new tracer for the quantitative imaging of myocardial perfusion and can be distributed to imaging laboratories without a cyclotron.

Assessment of atherosclerotic plaque burden with an elastin-specific magnetic resonance contrast agent

Atherosclerosis and its consequences remain the main cause of mortality in industrialized and developing nations. Plaque burden and progression have been shown to be independent predictors for future cardiac events by intravascular ultrasound. Routine prospective imaging is hampered by the invasive nature of intravascular ultrasound. A noninvasive technique would therefore be more suitable for screening of atherosclerosis in large populations. Here we introduce an elastin-specific magnetic resonance contrast agent (ESMA) for noninvasive quantification of plaque burden in a mouse model of atherosclerosis. The strong signal provided by ESMA allows for imaging with high spatial resolution, resulting in accurate assessment of plaque burden. Additionally, plaque characterization by quantifying intraplaque elastin content using signal intensity measurements is possible. Changes in elastin content and the high abundance of elastin during plaque development, in combination with the imaging properties of ESMA, provide potential for noninvasive assessment of plaque burden by molecular magnetic resonance imaging (MRI).

A comparison of PET imaging characteristics of various copper radioisotopes

PurposePET radiotracers which incorporate longer-lived radionuclides enable biological processes to be studied over many hours, at centres remote from a cyclotron. This paper examines the radioisotope characteristics, imaging performance, radiation dosimetry and production modes of the four copper radioisotopes, 60Cu, 61Cu, 62Cu and 64Cu, to assess their merits for different PET imaging applications. MethodsSpatial resolution, sensitivity, scatter fraction and noise-equivalent count rate (NEC) are predicted for 60Cu, 61Cu, 62Cu and 64Cu using a model incorporating radionuclide decay properties and scanner parameters for the GE Advance scanner. Dosimetry for 60Cu, 61Cu and 64Cu is performed using the MIRD model and published biodistribution data for copper(II) pyruvaldehyde bis(N4-methyl)thiosemicarbazone (Cu-PTSM). Results60Cu and 62Cu are characterised by shorter half-lives and higher sensitivity and NEC, making them more suitable for studying the faster kinetics of small molecules, such as Cu-PTSM. 61Cu and 64Cu have longer half-lives, enabling studies of the slower kinetics of cells and peptides and prolonged imaging to compensate for lower sensitivity, together with better spatial resolution, which partially compensates for loss of image contrast. 61Cu-PTSM and 64Cu-PTSM are associated with radiation doses similar to [18F]-fluorodeoxyglucose, whilst the doses for 60Cu-PTSM and 62Cu-PTSM are lower and more comparable with H215O. ConclusionThe physical and radiochemical characteristics of the four copper isotopes make each more suited to some imaging tasks than others. The results presented here assist in selecting the preferred radioisotope for a given imaging application, and illustrate a strategy which can be extended to the majority of novel PET tracers.

A New 18F-Labeled Myocardial PET Tracer: Myocardial Uptake After Permanent and Transient Coronary Occlusion in Rats

Conventional myocardial perfusion PET tracers require onsite tracer production because of their short radioactive half-lives. To investigate the potential of a new 18F-labeled pyridazinone analog (18F-BMS-747158-02), we characterized this tracer in a rat model of permanent and transient coronary occlusion using small-animal PET. Methods: Myocardial 18F-BMS-747158-02 distribution in healthy rats (n = 7), rats with transient (3-min) left coronary artery occlusion (n = 11), and rats with permanent left coronary occlusion (n = 11) was analyzed with a dedicated small-animal PET scanner. Results: Normal hearts demonstrated intense and almost homogeneous tracer uptake throughout the left ventricle for more than 2 h. During permanent coronary occlusion, PET demonstrated perfusion defects, which remained unchanged (37.6% ± 8.8%, 37.4% ± 10.2%, and 36.2% ± 9.8% left ventricle at 15, 45, and 115 min, respectively, after tracer injection). After transient ischemia, the induced defect size decreased significantly after reperfusion (16.2% ± 9.3%, 6.0% ± 6.5%, and 1.4% ± 1.3% left ventricle). Tracer reinjection after transient ischemia resulted in normalization of the induced defect. Conclusion: Coronary occlusion yielded distinct myocardial 18F-BMS-747158-02 uptake defects in the area of ischemia, which demonstrated normalization of activity after reperfusion and reinjection. These promising kinetic parameters may allow for assessment of flow using exercise–rest protocols similar to those used in combination with exercise and rest perfusion SPECT.

Evaluation of a Novel 18 F-Labeled Positron-Emission Tomography Perfusion Tracer for the Assessment of Myocardial Infarct Size in Rats

Background—The goal of this study was to evaluate a new 18F-labeled positron-emission tomography (PET) perfusion tracer, 18F BMS747158-02, for the assessment of myocardial infarct (MI) size. Methods and Results—Wistar rats were studied 24 hours after ligation of the left coronary artery either permanently (n=15) or transiently (n=16) for 30 minutes. Seven nonoperated rats were studied as controls. The rats were injected with 37 MBq of 18F BMS747158-02 and imaged with a small animal PET scanner for 20 minutes. Polar maps were generated for measurement of PET defect size, and left ventricular systolic and diastolic volumes were assessed in gated images. As a reference, MI size was determined by 2,3,5-triphenyltetrazolium chloride staining of left ventricular tissue samples. Permanent or transient ligation of the left coronary artery produced transmural or subendocardial MI of variable sizes, respectively. In normal rats, PET imaging demonstrated intense and homogeneous uptake of 18F BMS747158-02 throughout the myocardium. After ligation, sharply defined perfusion defects were present. Throughout the imaging period, the defect size correlated closely with the MI size either after permanent (r=0.88; P<0.01; mean difference, 1.86%) or transient (r=0.92; P<0.01; mean difference, 2.16%) ligation of the left coronary artery. Moreover, reduction of left ventricular systolic function measured with PET correlated with the MI size (r=−0.81; P<0.01; n=23). Conclusions—Myocardial 18F BMS747158-02 PET imaging provides excellent image quality and uptake properties, enabling accurate evaluation of MI size and left ventricular function in rats. It is a promising technique for evaluation of MI size in clinical trials.

The Next Generation of Cardiac Positron Emission Tomography Imaging Agents: Discovery of Flurpiridaz F-18 for Detection of Coronary Disease

Myocardial perfusion imaging (MPI) with thallium 201 ((201)Tl) or (99m)Tc based imaging agents has become a major tool for noninvasive identification of coronary artery disease (CAD). However, single photon emission computed tomography (SPECT) imaging with the current agents is vulnerable to artifacts associated with soft tissue attenuation, proximal gastrointestinal activity, image quality, and suboptimal sensitivity and is limited by the degree of first-pass myocardial extraction. The development of (18)F-based flurpiridaz F-18 takes advantage of positron emission tomography (PET) to overcome many of the imaging issues and structural design to achieve an ideal MPI agent profile. Flurpiridaz F-18 was designed to bind to mitochondrial complex I with high affinity and demonstrates high heart uptake in multiple species with clear delineation of perfusion deficits. It exhibits rapid uptake in the myocardium, prolonged retention, and superior extraction versus flow profiles compared with (201)Tl and (99m)Tc-sestamibi. A first in man study has established the safety and dosimetry of flurpiridaz F-18 and confirmed high sustained cardiac uptake. Subsequent studies performed in CAD patients established the dose and timing needed to detect perfusion deficits when the agent is administered under rest and stress conditions. This review compares the current preclinical and clinical data with an ideal MPI agent profile. The assessment indicates flurpiridaz F-18 represents a new generation of PET MPI agents and demonstrates significantly improved molecular and imaging characteristics.

Peptide based P21RAS farnesyl transferase inhibitors : systematic modification of the tetrapeptide CA1A2X motif

Abstract A systematic study of CVFM, a CAAX-derived farnesyl transferase inhibitor, was undertaken to determine the structural elements important for intrinsic activity as well as substrate character. Results indicate a narrowly defined profile for nonsubstrate FT inhibition.

RATIONAL DESIGN OF POTENT CARBOXYLIC ACID BASED BISUBSTRATE INHIBITORS OF RAS FARNESYL PROTEIN TRANSFERASE

Abstract Bisubstrate analog inhibitors in which a substrate mimetic tripeptide is attached to a homologated farnesyl carboxylic acid were synthesized and evaluated for in vitro inhibition versus ras farnesyl protein transferase (FPT). Our results demonstrate that such bisubstrate analogs are potent inhibitors of FPT.

140 Molecular MRI of vascular remodeling in a swine model of coronary injury using an elastin-binding contrast agent

Address: 1Cardiology Division, Technische Universität München, München, Germany, 2Center for Preclinical Research, Technische Universität München, München, Germany, 3Diagnostic Radiology, Cologne University, Cologne, Germany, 4Nuclear Medicine, Technische Universität München, München, Germany, 5Diagnostic Radiology, University Saarland, Homburg, Germany and 6Bristol-Myers Squibb Medical Imaging, North Billerica, MA, USA * Corresponding author

153 MR vessel wall imaging of the descending aorta using an elastin-binding contrast agent in an ApoE -/- TFDeltact double knockout mouse model of advanced atherosclerosis

Introduction A novel elastin-binding, Gadolinium-based low molecular weight contrast agent, BMS753951 (Bristol Myers Squibb, Billerica, MA) may be useful for visualization of the artery wall by delayed-enhancement magnetic resonance imaging (MRI). Synthesis and degradation of the extracellular matrix (ECM), including elastin, plays a central role in the natural progression of atherosclerosis. In particular, excessive ECM degradation in the advanced plaques has been suggested to be associated with plaque instability.