Quantification of myocardial perfusion using BMS-747158-02

Background

BMS-747158-02 ([¹⁸F]BMS-747158-01, [¹⁸F]flurpiridaz, 2-tert-Butyl-4-chloro-5-[4-(2-[¹⁸F]fluoroethoxymethyl)-benzyloxy]-2H-pyridazin-3-one, [¹⁸F]BMS) is a PET perfusion imaging agent which binds to the mitochondrial complex 1 (MC1) of the electron transport chain with high affinity. The tracer has high first-pass extraction and high retention in heart and kidney, and because of the high density of mitochondria in the myocardial muscle the image contrast is very good (see the references below).

Modelling

Input

The model input can be estimated from a ROI placed on LV. Metabolite correction is not needed (Nekolla et al., 2009).

Compartmental model

Regional tissue curves (0-20 min after tracer injection) can be fitted using 3-compartmental model (two tissue compartments) with assumption of irreversible trapping (k₄=0), using geometrical recovery and spill-over correction (Nekolla et al., 2009). K₁ is assumed to represent blood flow. Nekolla et al. (2009) noticed a modest underestimation of myocardial blood flow (MBF), and discussed possible reasons for that.

FUR

Fractional uptake rates (FURs, retention) correlated well with MBF calculated using compartmental model, (Sherif et al., 2010), although FUR estimates will need a conversion factor to achieve quantitative MBF.

Patlak plot

Feasible FUR analysis suggests that also Patlak plot (MTGA for trapped tracers), if linear, could be used to analyze the data. Patlak analysis provides net influx value (K_i), which is usually close to FUR estimate, and relates to compartment model parameters as K_i = K₁ * k₃/(k₂+k₃). If k₂<<k₃, then K_i≅K₁ (which is assumed to represent MBF with this tracer). If k₂>>k₃, then K_i≅(K₁/k₂)*k₃, which would probably not correlate with MBF. The k₂ and k₃ estimates reported by Nekolla et al. (2009; Table 4) would suggest that the former could be the case, but the level of FUR values (Sherif et al., 2010) would suggest something in between.

SUV

Standardized uptake values (SUVs) calculated 5-10 min after injection correlated well with MBF calculated using compartmental model, which would allow injecting tracer outside the PET scanner and performing a physical stress test (Sherif et al., 2010). Dual-gated imaging (Le Meunier et al., 2010) would probably further enhance the SUV estimates.

Rest-stress studies

In rest-stress studies, the radioactivity that is remaining from the first study must be subtracted from the next image data. PET scanning in the second study can be started shortly before tracer injection, and the concentrations in the first frame are then subtracted from every frame (Nekolla et al., 2009). Lazewatsky et al. (2010) have developed a method for optimizing dose ratio and required inter-injection interval. Case et al. (2010) developed a method for automatic registration of rest and test perfusion images.

References:

Case J, Lazewatsky, Hsu B-L, Maddahi J, Berman D, Bateman T. Automatic registration of F-18 labeled BMS-747158 stress and rest myocardial perfusion images using 6D cross-correlation optimization. J Nucl Med. 2010; 51 (Suppl. 2): 1687.

Higuchi T, Nekolla SG, Huisman MM, Reder S, Poethko T, Yu M, Wester HJ, Casebier DS, Robinson SP, Botnar RM, Schwaiger M. A new ¹⁸F-labeled myocardial PET tracer: myocardial uptake after permanent and transient coronary occlusion in rats. J Nucl Med. 2008; 49(10): 1715-1722.

Huisman MC, Higuchi T, Reder S, Nekolla SG, Poethko T, Wester HJ, Ziegler SI, Casebier DS, Robinson SP, Schwaiger M. Initial characterization of an ¹⁸F-labeled myocardial perfusion tracer. J Nucl Med. 2008; 49(4): 630-636.

Lazewatsky J, Maddahi J, Berman D, Bhat G, Sinha S, Devine M, Case J, Ehlgren A. J Nucl Med. 2010; 51 (Suppl. 2): 600.

Le Meunier L, Slomka P, Ramesh A, Thomson L, Hayes S, Tamarappoo B, Cheng V, Lazewatsky J, Germano G, Berman D. Enhanced dual gated cardiac perfusion PET using a new F-18 imaging agent (BMS747158). J Nucl Med. 2010; 51 (Suppl. 2): 522.

Leung K. 2-tert-Butyl-4-chloro-5-[4-(2-[¹⁸F]fluoroethoxymethyl)-benzyloxy]-2H-pyridazin-3-one. Molecular Imaging & Contrast Agent Database (MICAD).

Nekolla SG, Reder S, Saraste A, Higuchi T, Dzewas G, Preissel A, Huisman M, Poethko T, Schuster T, Yu M, Robinson S, Casebier D, Henke J, Wester HJ, Schwaiger M. Evaluation of the novel myocardial perfusion positron-emission tomography tracer ¹⁸F-BMS-747158-02: comparison to ¹³N-ammonia and validation with microspheres in a pig model. Circulation 2009; 119(17): 2333-2342.

Saraste A, Nekolla S, Schwaiger M. Nuclear cardiology needs new "blood". J Nucl Cardiol. 2009; 16(2): 180-183.

Sherif H, Nekolla S, Saraste A, Reder S, Yu M, Robinson S, Schwaiger M. Simplified quantification of myocardial blood flow with 18F BMS-747158-02: comparison to kinetic modeling and microspheres in a pig model. J Nucl Med. 2010; 51 (Suppl. 2): 263.

Sherif HM, Saraste A, Weidl E, Weber AW, Higuchi T, Reder S, Poethko T, Henriksen G, Casebier D, Robinson S, Wester H-J, Nekolla SG, Schwaiger M. Evaluation of a novel ¹⁸F-labeled positron-emission tomography perfusion tracer for the assessment of myocardial infarct size in rats. Circ Cardiovasc Imaging 2009; 2(2): 77-84.

Yu M, Guaraldi MT, Bozek J, Kagan M, Azure M, Radeke H, Cdebaca M, Robinson SP. Effects of food intake and anesthetic on cardiac imaging and uptake of BMS747158-02 in comparsion with FDG. J Nucl Cardiol. 2009; 16: 763-768.

Yu M, Guaraldi MT, Mistry M, Kagan M, McDonald JL, Drew K, Radeke H, Azure M, Purohit A, Casebier DS, Robinson SP. BMS-747158-02: A novel PET myocardial perfusion imaging agent. J Nucl Cardiol. 2007; 14: 789-798.