Abstract
Purpose
SPECT (e.g., with 99mTc-sestamibi) is routinely used for imaging myocardial damage, even though PET could offer a higher spatial resolution. Using the generator-gained isotope 68Ga would allow a rapid supply of the tracer in the diagnostic unit. For this reason, the aim of the study was to develop 68Ga-labeled PET tracers based on different Schiff base amines and to evaluate the cardiomyocyte uptake in vitro as well as the biodistribution of the tracers in vivo.
Procedures
Fifteen different Schiff bases (basing on 3 different backbones) were synthesized and labeled with 68Ga. Lipophilicity varied between 0.87 ± 0.24 and 2.72 ± 0.14 (logD value). All tracers were positively charged and stable in plasma and apo-transferrin solution. In vitro uptake into cardiomyocytes was assessed in HL-1 cells in the absence and presence of the ionophor valinomycin. In vivo accumulation in the heart and in various organs was assessed by small animal PET imaging as well as by ex vivo biodistribution. The results were compared with 99mTc-sestamibi and 18F-flurpiridaz.
Results
All cationic Schiff bases were taken up into cardiomyocytes but the amount varied by a factor of 10. When destroying the membrane potential, the cellular uptake was markedly reduced in most of the tracers, indicating the applicability of these tracers for identifying ischemic myocardium. PET imaging revealed that the in vivo myocardial uptake reached a constant value approximately 10 min after injection but the intracardial amount of the tracer varied profoundly (SUV 0.46 to 3.35). The most suitable tracers showed a myocardial uptake which was comparable to that of 99mTc-sestamibi.
Conclusions
68Ga-based Schiff bases appear suitable for myocardial PET images with uptake comparable to 99mTc-sestamibi but offering higher spatial resolution. By systematical variation of the backbone and the side chains, tracers with optimal properties can be identified for further clinical evaluation.
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Abbreviations
- HEPES:
-
,4-(2-Hydroxyethyl)piperazine-1-ethanesulfonic acid
- PBS:
-
,Phosphate-buffered saline
- SUV:
-
,Standardized uptake value
References
Murray CJ, Lopez AD (2013) Measuring the global burden of disease. N Engl J Med 369:448–457
Bailey DL, Willowson KP (2013) An evidence-based review of quantitative SPECT imaging and potential clinical applications. J Nucl Med 54:83–89
Bengel FM, Higuchi T, Javadi MS, Lautamäki R (2009) Cardiac positron emission tomography. J Am Coll Cardiol 54:1–15
Yalamanchili P, Wexler E, Hayes M et al (2007) Mechanism of uptake and retention of F-18 BMS-747158-02 in cardiomyocytes: a novel PET myocardial imaging agent. J Nucl Cardiol 14:782–788
Zhernosekov KP, Filosofov DV, Baum RP et al (2007) Processing of generator-produced 68Ga for medical application. J Nucl Med 48:1741–1748
Baum RP, Rösch F (eds) (2013) Theranostics, gallium-68, and other radionuclides. Recent Results Cancer Res 194:3–576
Velikyan I (2011) Positron emitting [68Ga]Ga-based imaging agents: chemistry and diversity. Med Chem 7:345–379
Garcia C, Gebhart G, Flamen P (2012) New PET imaging agents in the management of solid cancers. Curr Opin Oncol 24:748–755
Green MA, Mathias CJ, Neumann WL, Fanwick PE, Janik M, Deutsch EA (1993) Potential gallium-68 tracers for imaging the heart with PET: evaluation of four gallium complexes with functionalized tripodal tris(salicylaldimine) ligands. J Nucl Med 34:228–233
Green MA, Welch MJ, Mathias CJ, Fox KA, Knabb RM, Huffman JC (1985) Gallium-68 1,1,1-tris (5-methoxysalicylaldiminomethyl) ethane: a potential tracer for evaluation of regional myocardial blood flow. J Nucl Med 26:170–180
Hsiao YM, Mathias CJ, Wey SP, Fanwick PE, Green MA (2009) Synthesis and biodistribution of lipophilic and monocationic gallium radiopharmaceuticals derived from N, N′-bis(3-aminopropyl)-N, N′-dimethylethylenediamine: potential agents for PET myocardial imaging with 68Ga. Nucl Med Biol 36:39–45
Sharma V, Beatty A, Wey SP et al (2000) Novel gallium(III) complexes transported by MDR1 P-glycoprotein: potential PET imaging agents for probing P-glycoprotein-mediated transport activity in vivo. Chem Biol 7:335–343
Tsang BW, Mathias CJ, Green MA (1993) A gallium-68 radiopharmaceutical that is retained in myocardium: 68Ga[(4,6-MeO2sal)2BAPEN]+. J Nucl Med 34:1127–1131
Tsang BW, Mathias CJ, Fanwick PE, Green MA (1994) Structure-distribution relationships for metal-labeled myocardial imaging agents: comparison of a series of cationic gallium (III) complexes with hexadentate bis(salicylaldimine) ligands. J Med Chem 37:4400–4406
Tarkia M, Saraste A, Saanijoki T et al (2012) Evaluation of 68Ga-labeled tracers for PET imaging of myocardial perfusion in pigs. Nucl Med Biol 39:715–723
Yang BY, Jeong JM, Kim YJ et al (2010) Formulation of 68Ga BAPEN kit for myocardial positron emission tomography imaging and biodistribution study. Nucl Med Biol 37:149–155
Fellner M, Dillenburg W, Buchholz HG et al (2011) Assessing p-glycoprotein (Pgp) activity in vivo utilizing 68Ga-Schiff base complexes. Mol Imaging Biol 13:985–994
Zoller F, Riss PJ, Montforts FP, Rösch F (2010) Efficient post-processing of aqueous generator eluates facilitates 68Ga-labelling under anhydrous conditions. Radiochim Acta 98:157–160
Asti M, De PG, Fraternali A et al (2008) Validation of 68Ge/68Ga generator processing by chemical purification for routine clinical application of 68Ga-DOTATOC. Nucl Med Biol 35:721–724
White SM, Constantin PE, Claycomb WC (2004) Cardiac physiology at the cellular level: use of cultured HL-1 cardiomyocytes for studies of cardiac muscle cell structure and function. Am J Physiol Heart Circ Physiol 286:H823–H829
Piwnica-Worms D, Kronauge JF, Holman BL, Davison A, Jones AG (1989) Comparative myocardial uptake characteristics of hexakis (alkylisonitrile) technetium(I) complexes. Effect of lipophilicity. Invest Radiol 24:25–29
Kim YS, He Z, Hsieh WY, Liu S (2007) Impact of bidentate chelators on lipophilicity, stability, and biodistribution characteristics of cationic 99mTc-nitrido complexes. Bioconjug Chem 18:929–936
Kim YS, Wang F, Liu S (2010) Minimizing liver uptake of cationic Tc radiotracers with ether and crown ether functional groups. World J Hepatol 2:21–31
Veltri KL, Espiritu M, Singh G (1990) Distinct genomic copy number in mitochondria of different mammalian organs. J Cell Physiol 143:160–164
Cal-Gonzalez J, Herraiz JL, Espana S et al (2013) Positron range estimations with PeneloPET. Phys Med Biol 58:5127–5152
Acknowledgments
The study was supported by Deutsche Krebshilfe (grant 109136).
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The authors declare that they have no conflict of interest.
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Thews, O., Zimny, M., Eppard, E. et al. In Vitro and In Vivo Structure–Property Relationship of 68Ga-Labeled Schiff Base Derivatives for Functional Myocardial PET Imaging. Mol Imaging Biol 16, 802–812 (2014). https://doi.org/10.1007/s11307-014-0750-3
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DOI: https://doi.org/10.1007/s11307-014-0750-3