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.

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Abstract:

The preclinical evaluation of the 0,5 M solution of the manganese(II)-DTPA [Mn(II)-DTPA] complex (mangapentetate) has been carried out in order to test the ability of Mangenese to be employed as substiute of potentially toxic Gadolinium in paramagnetic contrast agents for the MRI clinical routines. The toxicologic tests of the Mn(II)-DTPAwere carried out in mice, rats and rabbits. Saline phantoms served for calculation of the R1 -relaxivity of the Mn(II)-DTPA, in comparison to the Gd(III)-DTPA (Magnevist). Normal healthy rabbits (n = 12), healthy dogs (n = 5) and dogs with tumors (n = 5) served for quantification of imaging abilities of the Mn(II)-DTPA in vivo in animals. The LD50 in rats was over 10 ml/kg, essentially close to that one of Gd(III)-DTPA. The increase in intensity oftheTI-weighted images induced by addition of the Mn(II)-DTPA in phantom tests did not differ significantly from the values obtained with gadopentetate. Mn(II)-DTPA delivered prominent enhancement of normal kidneys in healthy rabbits as well as chest tumors in dogs. We conclude the mangapentetate can be employed as paramagnetic contrast agent in routine MRI studies and is worth clinical testing. 

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