(Diethylenetriaminepentaacetic acid)gadolinate (hereinafter abbreviated as to "DTPA-Gd") is the only one practical pharmaceutical which is presently known as a nuclear magnetic resonance imaging (hereinafter sometimes abbreviated as MRI) agent for diagnosis [JP-A 58-29718] and it is considered that the use thereof as an imaging agent for diagnosis in the brain or spinal regions has been almost established. Since, however, DTPA-Gd is complexed, the relaxivity showing the image display index is lower (about 1/2) than that of Gd itself. Therefore, it is necessary to compensate this lowered relaxivity by increasing the dose. In addition, DTPA-Gd is rapidly excreted into the urine after administration [Hiroki Yoshikawa et al., Gazoshindan, 6, pages 959-969 (1986)], and this is very disadvantageous for imaging of several parts of the body by reflecting them in blood stream (blood vessel distribution, blood stream distribution, distribution volume, permeation and the like in a lesion) with a single injection of the pharmaceutical. Further, such rapid excertion also makes distribution properties of DTPA-Gd disadvantageous.
For solving the above-described problems (improvement in the relaxivity), some attempts at polynuclearization by repetition of mononuclear complex are described in JP-A 63-41468, JP-A 2-196776 and the like. Since, however, the poly-nuclearization is limited at best to di-nuclearization or tri-nuclearization, remarkable improvement in relaxivity can not be recognized.
Thereafter, the use of a polynuclear type metal complex compound obtained by introducing a plurality of metal complexes into a carrier polymer material as an imaging agent for diagnosis used as has been investigated. As a result, a MRI agent for diagnosis the carrier of which is human serum albumin (abbreviated as "HSA") [Ogan, M. D., et al., Invest. Radiol., 22, pages 665-671 (1987)], dextran [Brash, R. C., et al., Radiology, 175, pages 483-488 (1990)], starch [JP-A 61-501571], polylysine [JP-A 64-54028] or the like has been proposed and succeeded in improvement of relaxivity. These polymer polynuclear type metal complex compounds are localized in blood vessel for a constant period of time from immediately after administration and have the common distribution properties as retention in blood vessel for a relatively long period of time, which also improves the rapid excretion and penetration properties of DTPA-Gd.
However, the polymer carriers which can be a backbone for these polynuclear type metal complexes, regardless of a natural or synthetic material, is a heterogeneous compound the molecular weight of which has no mono-dispersion and is dealt with as an average value having a certain distribution width. Therefor, there is a problem that pharmaceutical uniformization can not be attained. For this reason, it is very difficult to control the number of metal ion to be introduced at constant and, therefore, heterogeneity arises inevitably in the objective physicochemical properties. Further, since all of the above-described polymers have the molecular weight more than tens of thousands, they have an unnecessarily long retention time in blood such as from ten and a few hours to a few days and have problems on biological acceptability as retention in the body, antigenicity and the like.
USPTO Backgrounds
USPTO Backgrounds