Klein, Andreas Theodor Josef
Produktion von n.c.a. 51Mn zur in vivo PET_Evaluierung von Kontrastmitteln für die Magnetresonanztomographie (MRT)
229 S., 1998
Magnetic resonance imaging (MRI) is finding increasing application in diagnostic studies by virtue of its high spacial resolution and radiation-free character. The contrast is often enhanced using paramagnetic agents. Most commonly applied agents are chelated high spin metal ions, especially GdIII, but also the manganese ions MnII / MnIII are interesting. However, exact distribution data and quantitative uptake kinetics of those magnetopharmaceuticals in individual organs are not available since the paramagnetic centers can only be localized indirectly in MRI by their effect to detectable water protons. Such exact pharmacokinetics are of strong interest regarding the optimization of these chemical compounds (drug design) and of MRI protocols.
The likewise non invasive positron emission tomographic (PET) technique could provide the desired pharmacokinetics in man using contrast agents labelled with suitable PET nuclides. The aim of this work was therefore, to produce the positron emitter 51Mn (t1/2 = 46 min, E[[beta]]+ = 0.935 MeV, I[[beta]]+ = 98 %) and to label relevant manganese based contrast agents with it in order to enable an in vivo evaluation of the labelled magnetopharmaceuticals via PET. The steps involved were: 1.) electrolytic preparation of thin and isotopically enriched chromium targets, 2.) development of a rapid and complete radiochemical separation of 51Mn from irradiated chromium targets, 3.) quantitative studies of the nuclear reactions, which generate the interesting nuclide as well as studies of interfering side reactions, 4.) development of a suitable target system for the production of the desired 51Mn in relatively high activities and 5.) labeling of interesting magnetopharmaceuticals with the produced nuclide.
For preparing an irradiation target, enriched chromium was plated electrochemically on a gold backing with a current efficiency of about 45 %, yielding an optimum layer thickness of 88 umol/cm2 after 13.3 min of electrolysis. A process was established, which generates highly enriched 50CrO3aq electrolytes for electrodeposition, starting from purchased forms of 50Cr as well as from used baths. The yield in each case was over 90 %. Quantitative determination of chromium, i.e. of chromate, could be realized by spectrophotometry at 350 nm in the absorbance plateau area, with pH between 1 and 4.
The rapid separation of n.c.a. radiomanganese from chromium targets was studied in detail using several different techniques. The most suitable one consisted of the precipitation of n.c.a. radiomanganese together with added non-isotopic carrier FeIII, after oxidation of chromium(III) to chromate(VI) in alkaline media using H2O2. The final solution of n.c.a. 51Mn was obtained in 99.0 % overall radiochemical yield and high chemical ( 0,10 % Fe) and radiochemical ( 0,05 % [51Cr]Cr) purity.
Excitation functions of the most promising nuclear reactions 50Cr(d,n)51Mn and 52Cr(p,2n)51Mn as well as of the competing side reactions were determined with a view to optimize the product process. 51Mn had to be detected by indirect methods after radiochemical separation such as multidecay analysis of the annihilation peak and quantification of its daughter 51Cr, since the nuclide possesses just a weak characteristic [[gamma]]-line (E[[gamma]] = 749 keV, I[[gamma]] = 0.265 %). Integral yields of 51Mn, derived from the excitation functions, are: 1100 MBq/uAh for the (d,n) process in the range 14 0 MeV and 3230 MBq/uAh for the (p,2n) process in the range 40 20 MeV. However, using highly enriched 50Cr, the first reaction leads to 51Mn of high radioisotopic purity, whereas in the second one the 52Cr(p,n)52m,gMn reactions compete. For medium scale production a sandwiched target system (Al4[50Cr]CrCl3) as well as a remotely controlable separation unit was developed.
For the tumor localizing metalloporphyrin MnIIITPPS4, used as a contrast agent in MRI, the labeling procedure was optimized, guaranteeing radiochemical yields of 99.9 % after 5 min of reaction time. Solid phase extraction methods were applied to separate and to purify the desired [51Mn]MnTPPS4 by RP columns. Quality control was enabled by a HPLC method using gradient elution. Finally, [51Mn]MnTPPS4 was obtained with high purity in isotonic saline solution, ready for injection into living systems, thus allowing an in vivo PET evaluation of the magnetopharmaceutical. Furthermore, the availability of the positron emitting 51Mn offers the opportunity to use labelled manganese based MRI contrast agents as new PET radiopharmaceuticals.