Quantification of myocardial perfusion using [18F]Flurpiridaz
[18F]Flurpiridaz (BMS-747158-02, [18F]BMS-747158-01, 2-tert-Butyl-4-chloro-5-[4-(2-[18F]fluoroethoxymethyl)-benzyloxy]-2H-pyridazin-3-one, [18F]BMS) is a myocardial perfusion imaging (MPI) radioligand which binds to (inhibits) the mitochondrial complex 1 (MC-1) of the electron transport chain with high affinity. It is a structural analogue of the insecticide pyridaben, which competes for MC-1 binding with ubiquinone. Yet, Flurpiridaz does not affect the viability of cardiomyocytes. [18F]Flurpiridaz can be safely used for clinical MPI (Maddahi et al. 2011 and 2018). [18F]Flurpiridaz and related compounds have shown promise in quantification of MC-1 activity in the brain (Fukumoto et al., 2012; Tsukada et al., 2014), and later also in the liver (Rokugawa et al., 2017) and kidney.
The radiotracer has high first-pass extraction, >0.9 over the physiological perfusion values (Huisman et al., 2008), and high retention in the heart and kidney, and because of the high density of mitochondria, in the myocardial muscle the image contrast is very good. Myocardial uptake is not dependent on food intake (Yu et al., 2009). Instead it is partly dependent on mitochondrial membrane potential, especially when it is reduced, which was seen as underestimated perfusion values in pig studies with ligated arteries (Nekolla et al., 2009).
The model input function can be estimated from a ROI placed on LV chamber. Metabolite correction is not needed (Nekolla et al., 2009). In porcine studies the LV cavity ROI was about 2×2×2 cm3 in size, and provided more reliable input TAC than arterial sampling (Guehl et al., 2017a). Obtaining the good quality input curve from the cavity still demands optimization of the imaging protocol and image reconstruction parameters.
In a pig study, Petibon et al. (2017a and 2017b) report that the image-derived blood TAC was transformed to plasma TAC using a factor based on previous pig studies, but the factor is not given in the referred abstract. Based on the rat study by Tsukada et al. (2014), plasma-to-blood ratio of [18F]Flurpiridaz can be calculated to be steadily 1.28 during 60 min after injection.
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). In a 5-min pig study even assumption k3=0 could be made (Petibon et al., 2017b). K1 is assumed to represent blood flow, either directly, or after division by extraction fraction E=0.94 (Petibon et al., 2017a). Extraction fraction can be assumed to be flow-independent in this case (Nekolla et al., 2009). Nekolla et al. (2009) noticed a modest underestimation of myocardial blood flow (MBF), and discussed possible reasons for that.
In practise, it has been difficult to estimate k2 and k3 independently in the myocardium. To improve parameter identifiability, Alpert et al. (2012) and Guehl et al (2017a) fixed k3 at a nominal physiologically plausible value of 0.026 min-1. Setting k3 to different values in the range 0 - 0.1 min-1 has only minimal effect on K1 (Alpert et al., 2012; Guehl et al., 2017a).
Fractional uptake rates (FURs, retention) correlated well with MBF calculated using compartmental model (Sherif et al., 2011), although FUR estimates will need a conversion factor to achieve quantitative MBF.
Feasible FUR analysis suggests that also Patlak plot, if linear, could be used to analyze the data. Patlak analysis provides net influx rate (Ki), which is usually close to FUR estimate, and relates to compartment model parameters as
If k2 << k3, then Ki ≅ K1 (and K1 is assumed to represent MBF with this tracer). If k2 >> k3, then Ki ≅ (K1/k2) × k3, which would not correlate well 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 estimates reported by Alpert et al. 2012, and the level of FUR values (Sherif et al., 2011) would suggest something in between.
Standardized uptake values (SUVs) calculated 5-10 min p.i. correlated well with MBF calculated using compartmental model. This would allow tracer administration outside the PET scanner and performing a physical stress test (Sherif et al., 2011). Dual-gated imaging (Le Meunier et al., 2010) would probably further enhance the SUV estimates.
However, SUV method is not suitable for measurement of coronary flow reserve (CRF) in rest-stress setting (Johnson & Gould, 2011).
Coronary flow reserve can be calculated as the ratio of the MBF during the pharmacological stress (usually adenosine or dipyridamole) to the MBF at rest:
In rest-stress studies, the radioactivity that is remaining from the first study (rest) must be subtracted from the image data of the second study (stress). PET scanning in the stress study can be started shortly before tracer administration, and the concentrations in the first frame are then subtracted from every image frame (Nekolla et al., 2009). Visual scoring provides good diagnostic certainty even without subtraction (Berman et al., 2013). Lazewatsky et al. (2010) have developed a method for optimizing dose ratio and required inter-injection interval.
Woo et al. (2011) developed a method for automatic registration of rest and stress perfusion images.
Alpert et al. (2012) have developed an analysis method where the rest-stress study with two injections can be performed during a single PET session, without the assumptions that are necessary when using the subtraction method. The model instead has time varying kinetic parameters, accounting for the blood flow change induced by adenosine with a step function. The method has been validated with [18F]Flurpiridaz in a porcine model (Guehl et al., 2017a), suggesting that less than 15 min PET acquisition would be sufficient to accurately measure rest and stress blood flow. Model is also applicable for calculation of parametric images (Guehl et al., 2017b).
- MBF using [15O]H2O and dynamic PET
- MBF using [13N]NH4+
- MBF using 82Rb
- Partial volume and spillover effects in cardiac PET
Alpert N, Dean Fang Y-H, El Fakhri G. Single-scan rest/stress imaging 18F-labeled flow tracers. Med Phys. 2012; 39(11): 6609-6620. doi: 10.1118/1.4754585.
Berman DS, Germano G, Slomka PJ. Improvement in PET myocardial perfusion image quality and quantification with flurpiridaz F 18. J Nucl Cardiol. 2012; 19(Suppl 1): S38-S45. doi: 10.1007/s12350-011-9487-4.
Berman DS, Maddahi J, Tamarappoo BK, Czernin J, Taillefer R, Udelson JE, Gibson CM, Devine M, Lazewatsky J, Bhat G, Washburn D. 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. J Am Coll Cardiol. 2013; 61(4): 469-477. doi: 10.1016/j.jacc.2012.11.022.
Guehl NJ, Normandin MD, Wooten DW, Rozen G, Sitek A, Ruskin J, Shoup TM, Ptaszek LM, El Fakhri G, Alpert NM. Single-scan rest/stress imaging: validation in a porcine model with 18F-Flurpiridaz. Eur J Nucl Med Mol Imaging 2017a; 44(9): 1538-1546. doi: 10.1007/s00259-017-3684-6.
Guehl NJ, Normandin MD, Wooten DW, Rozen G, Ruskin J, Shoup TM, Woo J, Ptaszek LM, El Fakhri G, Alpert NM. Rapid computation of single PET scan rest-stress myocardial blood flow parametric images by table look up. Med Phys. 2017b; 44(9): 4643-4651. doi: 10.1002/mp.12398.
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.
Johnson NP, Gould KL. Letter to editor. J Nucl Med. 2011; 52(11): 1835.
Lazewatsky J, Maddahi J, Berman D, Bhat G, Sinha S, Devine M, Case J, Ehlgren A. Development of a method for the determination of dose ratio and minimum inter-injection interval for a one-day rest-stress protocol with BMS747158 PET myocardial perfusion agent. 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).
Maddahi J. Properties of an ideal PET perfusion tracer: new PET tracer cases and data. J Nucl Cardiol. 2012; 19(Suppl 1): S30-37.
Merisaari H, Huang X, Oikonen V, Teräs M, Tolvanen T, Saraste A, Knuuti J, Han C. Estimation in modelling for dual injection of novel 18F-Labeled myocardial perfusion tracer using background subtraction method. Poster presentation, 2014. figshare.
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.
Packard RRS, Huang S-C, Dahlbom M, Czernin J, Maddahi J. Absolute quantitation of myocardial blood flow in human subjects with or without myocardial ischemia using dynamic Flurpiridaz F 18 PET. J Nucl Med. 2014; 55(9): 1438-1444. doi: 10.2967/jnumed.114.141093.
Petibon Y, Guehl NJ, Reese TG, Ebrahimi B, Normandin MD, Shoup TM, Alpert NM, El Fakhri G, Ouyang J. Impact of motion and partial volume effects correction on PET myocardial perfusion imaging using simultaneous PET-MR. Phys Med Biol. 2017a; 62(2): 326-343. doi: 10.1088/1361-6560/aa5087.
Petibon Y, Rakvongthai Y, El Fakhri G, Ouyang J. Direct parametric reconstruction in dynamic PET myocardial perfusion imaging: in vivo studies. Phys Med Biol. 2017b; 62(9): 3539-3565. doi: 10.1088/1361-6560/aa6394.
Saraste A, Kajander S, Han C, Nesterov SV, Knuuti J. PET: Is myocardial flow quantification a clinical reality? J Nucl Cardiol. 2012; 19(5): 1044-1059.
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 flow reserve with flurpiridaz F 18: validation with microspheres in a pig model. J Nucl Med. 2011; 52(4): 617-624. doi: 10.2967/jnumed.110.083196.
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.
Slomka PJ, Rubeaux M, Le Meunier L, Dey D, Lazewatsky JL, Pan T, Dweck MR, Newby DE, Germano G, Berman DS. Dual-gated motion-frozen cardiac PET with Flurpiridaz F 18. J Nucl Med. 2015; 56(12): 1876-1881.
Tsukada H, Nishiyama S, Fukumoto D, Kanazawa M, Harada N. Novel PET probes 18F-BCPP-EF and 18F-BCPP-BF for mitochondrial complex I: a PET study in comparison with 18F-BMS-747158-02 in rat brain. J Nucl Med. 2014; 55: 473-480. doi: 10.2967/jnumed.113.125328.
Wiyaporn K, Tocharoenchai C, Pusuwan P, Higuchi T, Fung GSK, Feng T, Park MJ, Tsui MBW. Optimization of imaging protocols for myocardial blood flow (MBF) quantification with 18F-flurpiridaz PET. Physica Medica 2017; 42: 127-134. doi: 10.1016/j.ejmp.2017.08.002.
Woo J, Tamarappoo B, Dey D, Nakazato R, Le Meunier L, Lazewatsky J, Germano G, Berman DS, Slomka PJ. Automatic 3D registration of dynamic stress and rest 82Rb and flurpiridaz F 18 myocardial perfusion PET data for patient motion detection and correction. Med Phys. 2011; 38(11): 6313-6326. doi: 10.1118/1.3656951.
Yalamanchili P, Wexler E, Hayes M, Yu M, Bozek J, Kagan M, Radeke HS, Azure M, Purohit A, Casebier DS, Robinson SP. Mechanism of uptake and retention of F-18 BMS-747158-02 in cardiomyocytes: a novel PET myocardial imaging agent. J Nucl Cardiol. 2007; 14: 782-788.
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 comparison 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.
Yu M, Nekolla SG, Schwaiger M, Robinson SP. The next generation of cardiac positron emission tomography imaging agents: discovery of Flurpiridaz F-18 for detection of coronary disease. Semin Nucl Med. 2011; 41: 305-313.
Zhu W, Ouyang J, Rakvongthai Y, Guehl NJ, Wooten DW, El Fakhri G, Normandin MD, Fan Y. A Bayesian spatial temporal mixtures approach to kinetic parametric images in dynamic positron emission tomography. Med Phys. 2016; 43(3): 1222-1234. doi: 10.1118/1.4941010.
Updated at: 2018-12-02
Created at: 2010-11-29
Written by: Vesa Oikonen, Harri Merisaari, Chunlei Han