Abstract:

Aim: was to make preclinical and imaging tests of the trans-1,2-diaminocyclohexane-N,N,N',N'-tetraacetic acid (DCTA) complex as a universal contrast agent for MRI and single-photon emission imaging, with Mn (Cyclomang) and ^99mTc- (Cyclotech), respectively.

Material and Methods: the complex of trans-1,2-diaminocyclohexane-N,N,N',N'-tetraacetic acid (DCTA) was synthesized at the department of organic chemistry of National Research Tomsk Polytechnic university, using the original technology in the nanopowder phase using manganese (II) carbonate, or generator eluate ^99mTc, and NaH₂DCTA, resulting in a 0.5 M solution of Мn-DCTA or ^99mTc-DCTA. LD50 values were determined in experiments on laboratory mice. A visualization study was performed in 4 cats and 3 dogs with malignant neoplasms of chest organs and in one dog with a tumor of the left pontocerebellar angle. All of them underwent consecutively MRI with contrast enhancement with Mn-DCTA and SPECT - with ^99mTc-DCTA.

Results: for Cyclotech LD50 >18/ml/kg, for 0.5 M Mn-DCTA (Cyclomang) solution, the LD50 index significantly exceeds 16.9 ml/kg BW. Changes in the content of manganese in the blood plasma of rats when they were administered Mn-DCTA, did not occur. LD50 values allow us to assign the drug in accordance with Russian regulation GOST 12.1.007-76. to group 4 (low-hazard substances). In both cases, in the range of physiological pH, the thermodynamic stability constant is >19.3. In studies in animals with MRI, the enhancement index of T1-weighted spin-echo image of the tumor in all cases exceeded 1.7 (mean 1.82±0.10). When calculating the «tumor/back-ground» index for ^99mTc-DCTA, it was 2.6-7.3 (mean 4.12±1.05).

Conclusion: DCTA complexes with manganese (II) - for enhancement in MRI and with ^99mTc- for SPECT- have very close pharmacokinetic properties, are non-toxic, do not dissociate in physiological environments and can be further used for contrast enhancement in multimodal MRI-SPECT studies. Chelate agents of the ^99mTc with thermodynamic stability constants over 16 may be employed in the nearest future as important source for the development of paramagnetic contrast agents binding Mn.

References

1.     Panov VO, Shimanovskiy NL. The diagnostic efficacy and safety of macrocyclic gadolinium-based magnetic resonance contrast agents. Russian J Radiol. 2017; 98(3): 159-166 [In Russ].

http://doi.org/10.20862/0042-4676-2017-98-3-159-166

2.     Shimanovskiy NL, Epinetov MA, Melnikov MYa. Molecular and nanopharmacology. Moscow, 2009; 624 [In Russ].

3.     National guidebook on nuclear medicine. Vol.1. Ed. by Lishmanov YuB, Chernov VI. Tomsk. STT Publ. 2010; 432 [In Russ].

4.     Litvinenko IV. The possibility of SPECT-CT in the diagnosis of coronary artery stenoses. Medical Visualization. 2015; (2): 53-66 [In Russ].

5.     Narkevich BYa, Ryzhkov AD, Komanovskaya DA et al. Estimation of radiation risks in SPECT/CT of skeletal bones. Medical Physics. 2019; 3 (83): 66-74 [In Russ].

6.     Madru R, Kjellman P, Olsson F et al. ^99mTc-labeled superparamagnetic iron oxide nanoparticles for multimodality SPECT/MRI of sentinel lymph nodes. J Nucl Med. 2012; 53(3): 459-463.

http://doi.org/10.2967/jnumed.111.092437

7.     Onoprienko AV, Kostenikov NA, Velichko OB, et al. Use of Fused Images Combining Contrast-Enhanced MRI and ^99mTc-MIBI SPECT in Diagnosis of Recidive Gliomas. Medical Visualization. 2004; (5): 38-46 [In Russ].

8.     Onoprienko A.V., Velichko O.B., Minin S.M. et al. Imaging of a Successful Medical Treatment of a Multiforme Glioblastoma by Means of Combination of Contrast-enhanced MRI and SPECT with ^99mTc-Technetril. Medical Visualization. 2006; (2); 99-103 [In Russ].

9.     Ussov WYu, Belyanin ML, Bezlepkin Al et al. Magnetic Resonance Imaging of Brain Involvement in Dogs Using Paramagnetic Contrast Enhancement with Mn(II)-DCTA. Bull.Exp.Biol.Med. 2016; 161: 715-718.

http://doi.org/10.1007/s10517-016-3492-1

10.   Belyanin ML, Fedoushchak TA, Filimonov VD et al. Solid-nanophase synthesis and evaluation of manganese (II) complex with diethylentriaminpentaacetic acid as contrast agent for magnetic resonance imaging. Siberian medical journal (Tomsk). 2008; 23(2): 33-36 [In Russ].

11.   Zevatskiy YuE, Samoilov DV. Empiric method of quantification of influence of dissolvent on dissociation constants of carbonic acids. Zhurnal organicheskoi chimii. 2008; 44(1): 59-68 [In Russ].

12.   Kaviani S, Shahab S, Sheikhi M, Ahmadianarog M. DFT study on the selective complexation of meso-2,3-dimercaptosuccinic acid with toxic metal ions (Cd2+, Hg2+ and Pb2+) for pharmaceutical and biological applications. Journal o f Molecular Structure. 2019; (1176): 901-907.

13.   Mironov AN. Guidelines for conducting preclinical research of drugs. M. Grit and К Publ.house. 2012; 944 [In Russ].

14.   Rossotti F, Rossotti X. Determination of stability constants and other equilibrium constants in solutions. M. Mir Publ.house. 1965; 564 [In Russ].

15.   Medixant. RadiAnt DICOM Viewer [Software]. Version 2020.1. Mar 9, 2020.

URL: https://www.radiantviewer.com

16.   Ehman EC, Johnson GB, Villanueva-Meyer JE et al. PET/MRI: Where might it replace PET/CT? J Magn Reson Imaging. 2017; 46(5): 1247-1262.

http://doi.org/10.1002/jmri.25711

17.   Hochhegger B, Alves GR, Irion KL et al. PET/CT imaging in lung cancer: indications and findings. J.Bras.Pneumol. 2015; 41 (3): 264-274.

http://doi.org/10.1590/S1806-37132015000004479

18.   Ansheles AA., Sergienko VB. Interpretation of myocardial perfusion SPECT with attenuation correction. Russian Journal of Radiology. 2020; 101(1): 6-18 [In Russ].

http://doi.org/10.20862/0042-4676-2020-101-1-6-18

19.   Ussov WYu., Sinitsyn VE., Obradovich V. et al. Patterns of cerebral blood flow reactivity in adenosine stress­test in patients with carotid stenosis, evaluated with MRI and ^99mTc-HMPAO SPECT brain study. Russian Journal of Radiology.2000; 81 (6): 4-9 [In Russ].

20.   Berry DJ, Torres Martin de Rosales R, Charoenphun P, Blower PJ. Dithiocarbamate complexes as radiopharmaceuticals for medical imaging. Mini Rev Med Chem. 2012; 12(12): 1174-1183.

http://doi.org/10.2174/138955712802762112

21.   Burilova EA, Ziyatdinova AB, Zyavkina Yul, Amirov RR. Influence of waterso;uble polymers on the formation of Manganese(II) complexomated in solutions. I Complexes with EDTA. Research proceedings of the Kazan University. Natural Sceinces. 2013; 155(2); 10-25 [In Russ].

22.   Belyanin ML, Prvulovich M, Karpova GV et al. Synthesis and evaluation of mangapentetate as paramagnetic contrast agent for magnetic resonance imaging. Diagnostic and Interventional Radiology. 2008; 2(1): 75-86 [In Russ].

23.   Meerovich IG, Gulyaev MV, Meerovich GA et al. Study of contrast agents based on phthalocyanin derivatives for magnetic resonance imaging. Russian chemical journal. 2013. 57(2): 110-114 [In Russ].

24.   Ussov WYu, Belyanin ML, Kodina GE et al. Magnetic resonance imaging of myocardium with paramagnetic contrast enhancement with Mn-methoxyisobutylisonitrile (Mn-MIBI) in an experiment. Medical visualization. 2016; (1): 31-38 [In Russ].

25.   Ussov VYu, Bezlepkin Al, Kovalenko AYu et al. Preclinical study of paramagnetic contrast enhancement with Mn(II)-dimercaptosuccinate complex in magnetic resonance imaging of primary tumor and metastatic spread of breast cancer. Diagnostic Radiology and Radiation Therapy. 2020; (1 (11)): 70-77 [In Russ].

http://doi.org/10.22328/2079-5343-2020-11-1-70-77

26.   Ussov VYu, Belyanin ML, Filimonov VD et al. Theoretical basis and experimental study of the Mn(II) complex with hexamethylpropylenaminoxim as a paramagnetic contrast agent for visualization of malignant tumors. Diagnostic Radiology and Radiation Therapy. 2019; (2 (10)): 42-49 [In Russ].

http://doi.org/10.22328/2079-5343-2019-10-2-42-49

27.   Serebrennikov W. Chemistry of rare earth elements (scandium, yttrium, lanthanides). Tomsk. TSU Publ. House. 1959; 531 [In Russ].

28.   Batyreva VA, Kozik W, Serebrennikov W, Yakunina GM. Synthesis of compounds of rare earth elements. Tomsk. TSU Publ. House. 1983; 144 [In Russ].

29.   Ussov VYu, Belyanin ML, Bezlepkin Al etal. Evaluation of Manganese-trans-1,2-Diaminocyclohexane-N,N,N’,N’-tetraacetate Complex (Cyclomang) as Paramagnetic Contrast Agent for Magnetic Resonance Imaging. Eksperimentalnaya i klinicheskaya farmakologiya. 2013; 76(10): 32-38 [In Russ].

Abstract:

Purpose. Was to estimate the informative value of scintigraphy (SG) with labeled leukocytes (LL) in detection of osteomyelitis in patients with various forms of diabetic foot syndrome (DFS)

Materials and methods. This study includes results of scintigraphy with labeled leukocytes of 39 patients with diabetes mellitus and with suspicion of osteomyelitis in diabetic foot. Results were compared with morphological study in 22 patients

Results. SG with LL has high informative value rate in diagnostics of inflammatory process: sensitivity - 100%, specificity - 100% accuracy - 100%; and also high in the diagnostics of osteomyelitis: sensitivity - 100%, specificity - 64,7%, accuracy - 84,6%.

Conclusions. LL CG is a highly effective method of identifying the presence of an inflammatory process. During high rate of sensitivity the level of specificity decreases in case of intraosseous inflammation. The reason of decreased specifity is in that SG has low resolution in differentiation of radiopharmaceutical accumulation in bones and soft tissues.

References 

1.    Senneville E. et al. Needle puncture and transcutaneous bone biopsy cultures are inconsistent in patients with diabetes and suspected osteomyelitis of the foot. Clin. Infect. Dis. 2009; 48: 888-893.

2.    Gil H.C. MR imaging of diabetic foot infection. H.C. Gil, W.B. Morrison. Semin. Musculoskelet. Radiol. 2004; 8(3): 189-198.

3.    Craig J.G. et al. Osteomyelitis of the diabetic foot: MR imaging-pathologic correlation. Radiology. 1997; 203 (3): 849-855.

4.    Vesco L. et al. The value of combined radionuclide and magnetic resonance imaging in the diagnosis and conservative management of minimal or localized osteomyelitis of the foot in diabetic patients. Metabolism. 1999; 48 (7): 922-927.

5.    Hopfner S. et al. Preoperative imaging of Charcot neuroarthropathy. Does the additional application of (18) F-FDG-PET make sense? Nuklearmedizin. 2010; 45 (1):15-20.

6.    Завадовская В.Д., Зоркальцев М.А., Килина О.Ю., Шульга О.С. Возможности радионуклидной диагностики синдрома диабетической стопы (часть 1). Диагностическая и интервенционная радиология. 2010; 4 (4): 31-40.

Abstract:

Purpose. Was to еstablish the informative value of 3-phase scintigraphy in assessment of blood flow and identify pyo-inflammatory process in patients with neuropathic, ischemic, and mixed forms of diabetic foot.

Materials and methods. This study includes the results of three-phase scintigraphy of 76 patients with diabetes mellitus and with suspicion of osteomyelitis in diabetic foot. Results were verified with morphological study in 39 patients.

Results. In patients with diabetic foot the depression of the main vessels blood flow and blood flow prevalence the changes intraosseous blood flow. Three-phase scintigraphy revealed a lower specificity (66,7%) in the diagnosis of osteomyelitis in patients with diabetes mellitus at the sensitivity (94,7%) and accuracy (73,7%).

Conclusions. Three-phase scintigraphy is high-performance method in revealing the arterial and peripheral blood flow disorder in patients with diabetes mellitus. The low specificity of the three-phase scintigraphy with high sensitivity indicates the limited possibilities of the method in the identification of pyo-inflammatory process in patients with diabetes mellitus. The observed preservation of blood flow makes it possible to expand indications of methods of nuclear medicines and applies scintigraphy with labeled leukocytes for indication purulent infection in patients with complicated course. 

References

1.    Capriotti G. et al. Nuclear medicine imaging of diabetic foot infection: results of meta-analysis. Nucl. Med. Commun. 2006; 27 (10):757–764.

2.    Kaim A. et al. Chronic complicated osteomyelitis of the appendicular skeleton.Diagnosis with 99mTc labeled monoclonal anti-granulocyte antibody-immunoscintigraphy. Eur. J. Nucl. Med. 1997; 24 (7): 732–738.

3.    Unal S.N. et al. Comparison of 99mTc methylene diphosphonate, 99mTc human immuneglobulin, and 99mTc labeled white blood cell scintigraphy in the diabetic foot. Clin. Nucl. Med. 2001; 26 (12): 101–1021.

4.    Devillers A. et al. Contribution of 99mTc hex-amethylpropylene amine oximelabelled leucocyte scintngraphy to the diagnosis of diabetic foot infection. Eur. J. Nucl. Med. 1998; 25(2): 132–138.

5.    E-Maghraby T.A. Nuclear medicine methods for evaluation of skeletal infection among other diagnostic modalities. J. Nucl. Med. Mol. Imaging. 2006; 50 (3): 167–192.

6.    Soluri A. et al. High resolution mini-gammacamera and 99mTc [HMPAO] leukocytes for diagnosis of infection and radioguided surgery in diabetic foot. G. Chir. 2005; 26 (6–7): 246–250.

7.    Prandini N. et al. Nuclear medicine imaging of bone infections. Nucl. Med. Commun. 2006;27 (8): 633–644.

8.    Christopher J.P. et al. Osteomyelitis: Diagnosis with 99mTc labeled Antigranulocyte Anti-bodies Compared with Diagnosis with 111Inlabeled Leukocytes – Initial Experience. Radiology. 2002; 223: 758–764.

9.    Palestro C.J. et al. Rapid diagnosis of pedal osteomyelitis in diabetics with a technetium-99mTc labeled monoclonal antigranulocyte antibody. J. Foot. Ankle. Surg. 2003; 42 (1): 2–8.

10.  Stephen L.H. et al. The Effects of Peripheral Vascular Disease with Osteomyelitis in the Diabetic Foot. Am. J. of Surg. 1999; 177:282–286.

11.  Завадовская В.Д. Лучевая диагностика остеомиелита Дис. Д-ра мед. наук. Томск. 1995; 290.

Abstract:

Introduction. ¹⁹⁹Tl-chloride scintigraphy is used to visualize tumors. In addition to typical imaging of the musculoskeletal malignancy, unusually types of malignant tumor visualization were revealed by studies of diagnostic potentialities of ¹⁹⁹Tl-chloride scintigraphy, analogue of ²⁰¹Tl-chloride scintigraphy.

Aim. Was to study features of malignant tumor visualization of the musculoskeletal system with the help of ¹⁹⁹Tl-chloride scintigraphy.

Materials and methods. 85 patients with diseases of musculoskeletal system underwent ¹⁹⁹Tl-chloride scintigraphy. 107 localizations of malignant tumors (n=57) and benign lesion (n=50) were investigated. During the research in 107 patients malignant tumors were detected, 50 patients had bening tumors.

Results. Malignant tumors were visualized in 98.1%. Three types of malignant tumors' visualization were obtained - positive (82.4%) and rare negative (7.8%) and mixed (9.8%). Types of visualization were associated with tumor histological types, blood-flow, metabolism, and pharmacodynamic features of ¹⁹⁹Tl-chloride. Negative and mixed visual types were high specific for primary and recurrent malignant tumors, but no metastasis.

Conclusion. Accounting to negative and mixed visual types - ¹⁹⁹Tl-chloride scintigraphy sensitivity increased to 98.1% without decreasing of specificity in detection of malignant tumors of musculoskeletal system.

Abstract:

Aim: was to evaluate pedal vascularisation in diabetic patients with using contrast MR-angiography.

Material and methods: 23 patients (15 male, 8 female; mean age 56±14,6) with suspicion on osteomyelitis (OM) underwent MR-angiography (Gadobutrol 15ml). Imaging analysis included blood-flow's speed, vascular architectonic's condition and character of contrast's accumulation, microcirculation was especially estimated. Results were compared with white blood cells-scan in identification of pyoinflamation. Osteomyelitis was verified according to operations in all cases.

Results: all patients were divided in 3 groups: neuropathic (n=9; 39,0%), neuroischemic (n=10; 43,5%), ischemic (n=4; 17,5%) forms of diabetic foot. First-pass MR-angiography detected significant delay in contrast's arrival in ischemic group. There were no significant differences between values of neuropathic and neuroischemic forms of diabetic foot. There were no pedal vessels in patients in ischemic and neuroischemic groups. Contrast MR-angiography revealed three types of contrast distribution in soft tissues: uniform, local increase and local absence. Osteomyelitis was characterized as diffuse enhanced contrast accumulation in all cases.

Conclusions: MRI blood vessel imaging is a promising and valuable method for examining peripheral arterial changes in diabetic foot and may be useful for treatment planning in different forms of diabetic foot. 

References

1.     Ametov A.C. Diabetes mellitus type 2. Problems and Solution. Moscow: GEOTAR-Media. 2014; 1032 [In Russ].

2.     Malhotra R., Chan C.S., Nather A. Osteomyelitis in the diabetic foot. Diabet Foot Ankle. 2014; 30; 5.

3.     Bargellini I., Piaggesi A., Cicorelli A., et al. Predictive value of angiographic scores for the integrated management of the ischemic diabetic foot. J. Vasc. Surg. 2013; 57(5): 1204-12.

4.     Manzi M., Cester G., Palena L.M., et al. Vascular imaging of the foot: the first step toward endovascular recanalization. Radiographics. 2011; 31(6):1623-36.

5.     Rohrl B., Kunz R.P, Oberholzer K., et al. Gadofosveset-enhanced MR angiography of the pedal arteries in patients with diabetes mellitus and comparison with selective intraarterial DSA. Eur Radiol. 2009;19(12): 2993-3001.

6.     Prince M.R., Wang Y, Watts R., et al. Contrast travel times measured on 2D Projection MRA in patients with Peripheral Vascular Disease Proc. Intl. Soc. Mag. Reson. Med. 2001; 9: 47.

7.     Ranachowska C., Lass P., Korzon-Burakowska A., Dobosz M. Diagnostic imaging of the diabetic foot. Nucl Med Rev Cent East Eur. 2010; 13(1): 18-22.

8.     Li J., Zhao J.G., Li M.H. Lower limb vascular disease in diabetic patients: a study with calf compression contrast-enhanced magnetic resonance angiography at 3.0 Tesla. Acad Radiol. 2011; 18(6): 755-63.