Preparation and characterization of technetium complexes with Schiff base and phosphine coordination. 1. Complexes of technetium-99g and -99m with substituted acac2en and trialkyl phosphines (where acac2en = N,N'-ethylenebis[acetylacetone iminato]).

A series of 23 technetium(III) complexes of the type [TcL(PR3)2]+, where L represents a tetradentate Schiff base ligand in the equatorial plane and PR3 represents the axial phosphine ligands, are reported. Full ligand syntheses and characterizations are included. The technetium complexes were prepared with 99mTc to study the organ distribution in guinea pigs at 5 and 60 min postinjection. Four prototypical complexes of the series were also prepared with either 99gTc or 99gTc/99mTc (designated as carrier-added) to allow macroscopic characterization. Equivalence of the 99gTc and 99mTc complexes was demonstrated by dual detection high performance liquid chromatography (HPLC) techniques. The development of a one-step preparation from the standard two-step method is discussed for some complexes. Biodistribution data are related to structure and lipophilicity. None of the complexes in the series exhibited a tendency for in vivo reduction. Myocardial uptake was favorable for a number of complexes. The optimal agent from this series for further imaging development was chosen based on myocardial uptake, rapid blood and liver clearance, and ability to be formulated as a one-step kit.

Characterization of polyethyleneglycol-stabilized, manganese-substituted hydroxylapatite (MnHA-PEG). A potential MR blood pool agent.

PURPOSE: To optimize the performance (or efficacy) of a potential particulate blood pool agent for MR angiography by varying the particle size. The colloidal system under investigation was polyethylene glycol-stabilized manganese-substituted hydroxylapatite (MnHA-PEG). MATERIAL AND METHODS: Several MnHA-PEG formulations were prepared using various length PEGs (MW = 140-2000). Products were characterized in vitro by dynamic light scattering (DLLS), field flow fractionation (FFF), and relaxometry; and in vivo by blood clearance kinetics in rabbits, and by analytical electron microscopy (EM). RESULTS: The particle size distribution (PSD) consisted only of small particles (approximately 10-nm diameter) when approximately 40 mo1% PEG was used. At approximately 20 mo1% PEG, larger particles (approximately 100 nm), which are aggregates of the small ones, were also present. The water proton relaxation profiles of the particles in plasma were different from that of the free Mn2+. In plasma, the large aggregates were broken down into the smaller particles which were stable. Although the small particles were efficient relaxation enhancing agents, they were cleared from the blood approximately 3 times faster than the approximately 100-nm diameter aggregates, probably as a consequence of leakage into the extravascular space. Variation of PEG size had no effect on particle characteristics or on blood clearance. Analytical EM of rabbit liver specimens indicated some retention of Mn in mitochondria at the time point when Mn content of other subcellular structures returned to baseline. CONCLUSION: DLLS and FFF are complementary techniques for sizing particulate MR contrast media. Small MnHA particles are more efficient T1-shortening agents than large ones but they are prone to leakage from the vascular space. Within the MW range explored, the length of PEG molecule had no effect on blood clearance of the MnHA particles. Larger aggregates of MnHA-PEG break down into stable small particles in plasma. Mn clears from the subcellular structures within hepatocytes within 60 min after i.v. MnHA-PEG administration except from the mitochondria in which it appears to accumulate.

Preliminary evaluation of a polyethyleneglycol-stabilized manganese-substituted hydroxylapatite as an intravascular contrast agent for MR angiography.

A blood-persistent particulate paramagnetic contrast agent has been formulated via size stabilization of manganese-substituted hydroxylapatite by a polyethylene glycol (PEG) bearing a terminal diphosphonate. At high PEG surface densities (35-40 mol%), particles with mean diameter 8 +/- 2 nm were obtained. Relaxivities of autoclaved samples (at 20 MHz proton Lamor frequency) were R1 = 18.7 +/- .8 mM-1 sec-1 and R2 = 22.3 +/- .7 mM-1 sec-1. The formulation persisted in rabbit blood with a biphasic clearance profile. Half-lives (with amplitudes in parenthesis) were 4 +/- 1 minutes (55%), and 49 +/- 3 minutes (45%), respectively, for the two phases. A dose of 40 mumol Mn/kg body weight enhanced the signal from rabbit vasculature for more than 45 minutes on MR angiograms. Thus, PEG-modified MnHA particles may find use as T1 agents for MR angiography.

Synthesis and characterization of novel N3O3-Schiff base complexes of 99gTc, and in vivo imaging studies with analogous 99mTc complexes.

Sixteen novel derivatives of 1,1,1-tris (salicylaldiminomethyl)ethane have been synthesized for the purpose of encapsulating 99mTc(IV) ions and generating new 99mTc radiopharmaceuticals. Two methods for the preparation of the 99gTc(IV) analog complexes are presented; one utilizes SnCl2 reduction on 99gTcO4- and the other a direct substitution route starting with [99gTcCl6]2-. Free ligands (H3L) are characterized by melting points, 1H NMR, 13C NMR, mass spectroscopy, TLC, and/or elemental analyses. [99gTcL]+ complexes are characterized by FAB-ms, UV-VIS, IR and/or CV. An X-ray structural analysis was performed on a crystal of [M(6,6'-[[2-[[((4-Methoxy-2-hydroxyphenyl) methylene)-amino]methyl]-2-methyl- 1,3-propanediyl]bis(nitrilomethylidyne)]-bis-3-methoxyphenol )] tetraphenylborate, where M represents a 1/3 isomorphous mixture of 99gTc/Sn as determined by SEM. The metal coordination site is 6-coordinate, composed of N3O3 donor atoms, and intermediate between octahedral and trigonal prismatic geometry. The [99mTcL]+ complexes were prepared in a stannous environment; equivalence of the 99mTc and 99gTc complexes is demonstrated by HPLC techniques. The [SnL]+ complex was prepared for comparison purposes. An unusual ligand oxidation occurs for one series of ligands in which in situ amine-->imine conversion is observed during the complexation reaction in reducing media. Guinea pig, rat, dog, and human metabolism studies are reported for selected [99mTcL]+ complexes, the myocardial uptake of which approaches 2% of the injected dose.

Technetium-99m-L,L-ethylenedicysteine: a renal imaging agent. I. Labeling and evaluation in animals.

L,L-ethylenedicysteine (L,L-EC) can be labeled efficiently with 99mTc at pH 12 to obtain a highly pure and very stable tracer agent (99mTc-L,L-EC). The biological behavior of 99mTc-L,L-EC was studied in mice and a baboon. In mice, 99mTc-L,L-EC demonstrated a more rapid urinary excretion and less retention in the kidneys, the liver, the intestines, and the blood than did 99mTc-MAG3 at 10 and 60 min p.i. Urinary excretion decreased in probenecid pretreated mice, which indicates active tubular transport. In the baboon, the renograms for 99mTc-MAG3 and 99mTc-L,L-EC were comparable. Plasma-protein binding of 99mTc-L,L-EC was lower than that of 99mTc-MAG3 while its distribution volume and 1-hr plasma clearance were clearly higher. The promising results of the animal experiments suggest that 99mTc-L,L-ethylenedicysteine may be a useful alternative to 99mTc-MAG3 for renal function studies in humans.

Synthesis, characterization and myocardial uptake of cationic bis(arene)technetium(I) complexes.

A series of bis(arene)technetium(I) complexes has been synthesized from 99mTcO4- in order to study their organ distribution. Syntheses using either ultrasound/Al/AlCl3 or Zn/HCl gave products relatively free from transalkylation. The identity of the complexes was verified by comparison to the 99Tc complexes. Equivalence of the 99Tc and 99mTc complexes was demonstrated by HPLC techniques. Biodistribution studies in rats reveal substantial myocardial uptake for many members of the series, especially those containing benzene rings substituted with about four to six carbon atoms. The myocardial uptake is related to the lipophilicity of the complexes as measured by octanol/buffer partition ratios (OBPR). Optimal ranges of lipophilicity for maximal myocardial uptake occur for OBPR from 2 to 9. Rat and human plasma binding of the complexes increases with lipophilicity after a threshold value is exceeded.

Preparation and characterization of [99mTc(DMPE)2X2]+, X = Cl, Br (DMPE = 1,2-bis(dimethylphosphino)ethane).

The preparation of "no-carrier-added" [99mTc(DMPE)2X2]+ (X = Cl, Br) in greater than 95% radiochemical purity, suitable for in vivo evaluation as a myocardial imaging agent, is described. Reaction parameters that lead to the formation of the desired products, as well as those that lead to the formation of the major impurities, are delineated. These 99mTc species are characterized by HPLC using the known 99Tc analogs as standards. Myocardial images obtained in mongrel dogs with [99mTc(DMPE)2X2]+ (X = Cl, Br) are briefly discussed.