99mTc-complexes of a pentadentate amine-oxime ligand.

Synthesis and characterization of a new pentadentate amine-oxime ligand, 3,3,11,11-tetramethyl-7-benzyl-4,7,10-triazatridecane-2,12- dionedioxime is reported. The technetium complexes of this ligand was formed by direct reduction of TcO4- in the presence of the ligand at pH 9. The radiochemical yield of the complex is greater than 95% with 10(-7) M 99TcO4-. The technetium complex formed is a positively charged chelate that elutes as a single peak on a reverse phase HPLC. Biodistribution studies in rats showed an uptake of 1.4% of the injected activity at 15 sec p.i. in heart, but the wash-out was fast. The high radiochemical purity and stability of this 99mTc-chelate indicate that these types of chelates hold potential for development of bifunctional chelating agents (BFCAs).

Synthesis, characterization and biodistribution studies of a neutral-lipophilic Tc-99m N3S2 chelate.

Diaminedithiols (DADT) are known to form neutral-lipophilic complexes with 99mTc in aqueous solutions, where they are readily formed in high yields and demonstrate excellent stability. A new triaminedithiol (TADT) ligand was synthesized, characterized and shown to form a neutral-lipophilic 99mTc-chelate. The biodistribution of this 99mTc chelate in rats showed that its uptake in brain or heart following i.v. injection of the 99mTc chelate was low, but activity taken up was retained over a long period of time. The in vivo and in vitro properties of this chelate indicate the possibility that chemical modification of this TADT ligand may produce ligand systems that form 99mTc chelates with suitable diagnostic properties.

Biolocalization and cell labeling properties of neutral-lipophilic 99mTc-amine-phenol chelates.

99mTc-diamine-diphenol chelates are neutral lipophilic chelates exhibiting good stability in aqueous solutions. The cell labeling and biolocalization properties of four different 99mTc-amine-phenol complexes were determined. All four chelates readily labeled leukocytes and RCBs in high yields. Even though 99mTc was retained by the cells, the elution rate of 99mTc from the labeled cells in plasma at 37 degrees C was unacceptably high for potential utility in scintigraphic imaging. The uptake of 99mTc in brain or heart following i.v. injection of the chelates in rats was low and clearance of activity from the blood was slow.

Labeling of human IgG with rhodium-105 using a new pentadentate bifunctional ligand.

We report the labeling of human gamma globulin with the 105Rh complex of a new pentadentate bifunctional ligand, 1,7-bis(2-hydroxybenzyl)-4-(p-aminobenzyl)diethylenetriamine. Complexes of this ligand with 105Rh were prepared by refluxing rhodium carrier spiked with 105Rh at pH9 in bicarbonate buffer. The complex was treated with an excess concentration of thiophosgene to prepare the isothiocyanate derivative which was extracted into CHCl3. The CHCl3 extract was dried and dissolved in DMF and reacted with a borate solution of human gamma globulin. Labeling yields were generally high and varied from 73% to 93%, depending upon the concentration of human gamma globulin and the isothiocyanate derivative of the complex used. The overall recovery of rhodium activity varied from 59% to 75% without taking into account activity lost due to decay. The conjugation reaction was complete by 4 h. From 0.4 to 8.5 atoms of Rh could be incorporated per molecule of protein by this method. The activated isothiocyanate complex did not show any degradation when stored at room temperature for up to 4 days and then used for conjugation.

Labeling of proteins using [105Rh]Rh-4-(p-aminobenzyl)-diethylenetriamine.

A bifunctional ligand 4-(p-aminobenzyl)-diethylenetriamine has been synthesized. 105Rh complexes with this ligand were prepared with an overall yield of 79% at pH 9.0 in bicarbonate buffer. The preformed complex was converted to the isothiocyanate derivative using thiophosgene. Conjugation yields of 75% with IgG and 85% with HSA could be obtained for a 4 h conjugation reaction. Affinity chromatography of human-IgG coupled to the rhodium complex in an anti-human IgG agarose gel indicated no denaturation of the labeled protein. The procedure reported here can be adapted for the preparation of 105Rh-labeled antibodies for therapeutic applications.

Labeling of human serum albumin with 105Rh-cysteine complexes.

The conjugation of a complex formed by reacting RhCl3 with cysteine to human serum albumin has been investigated. Approximately 50% of the rhodium (labeled with 105Rh) was converted to the complex. Conjugation of the complex to HSA via the ECDI method resulted in yields of approximately 40% of the total rhodium or approximately 80% of the Rh-cysteine complex. No conjugation was observed in the absence of the ECDI. At approximately equal molar concentrations of rhodium and HSA, an average of approximately 0.4 rhodium atoms per HSA molecule was achieved.

Labeling of hematoporphyrin with 105Rh and binding studies with human gamma globulin.

Labeling of hematoporphyrin with 105Rh at stoichiometric concentrations is described. Labeling efficiencies of up to 93% could be obtained at pH 9.0 in bicarbonate buffer. Solvent extraction of 105Rh-hematoporphyrin into methyl isobutyl ketone was used to estimate the complex yield. The complex showed high stability and no loss of 105Rh was seen throughout the 6 days of study. 105Rh-hematoporphyrin when incubated with human gamma globulin was seen to be quantitatively bound to the protein. This procedure may be used for labeling monoclonal antibodies with 105Rh for therapeutic applications.

105Rh as a potential radiotherapeutic agent.

The production of 35.5-h 105Rh (560- and 250-keV betas) by neutron activation of 104Ru followed by beta decay of 4.4-h 105Ru is discussed. A simple procedure for producing 105Rh in 10-100 mCi quantities at specific activities of 700-10,000 Ci/mmol is described.

Chemical and physical properties of radionuclides.

There are many radionuclides with a wide range of energies and half-lives available for use as non-sealed radiotherapeutic agents. To date, no single radionuclide has emerged as being clearly superior to all others, in the way that 99mTc predominates in diagnostic imaging. It is unlikely that one will emerge. Instead, if a particular application demands certain decay properties, the radionuclide which will be used will be the one for which appropriate chemistry can be developed and which can be produced and distributed most economically.

153Sm radiotherapeutic bone agents.

Samarium-153 is a radionuclide which can be produced in high yield by neutron irradiation and which has nuclear properties that make it attractive for use as a radiotherapeutic agent. Several phosphonate complexes of 153Sm were synthesized and characterized by electrophoresis and HPLC. A procedure based on cation exchange chromatography was developed for measuring complex yields. The complexes could be produced in yields greater than 99%, were anionic, and most exhibited a single HPLC peak.

A bifunctional ligand for Pd(II).

A bifunctional ligand, 6-(5-carboxyl pentyl)-5,7 dioxo-1,4,8, 11-tetraazaundecane, has been shown to produce a neutral, inert complex with Pd(II). The complex is formed in high yield and is stable over a wide pH range. It can be conjugated to proteins through the carboxylic acid side arm using a carbodiimide coupling reagent and may be useful for labeling antibodies or other large molecules.

A neutral lipophilic complex of 99mTc with a multidentate amine oxime.

Propylene amine oxime, 3,3'-(1,3-propanediyldiimino)bis(3-methyl-2-butanone)dioxime, (PnAO) forms a neutral lipophilic complex with 99mTc in greater than 95% yield at room temperature at pH 5-10. The complex can be prepared with generator produced 99mTc using 10(-5) M SnC4H4O6 as the reducing agent at ligand concentrations as low as 3 X 10(-5) M. It is stable in saline solutions for as long as 24 h. [99mTc]PnAO may be useful as an imaging agent which passively diffuses across the blood brain barrier.

99mTc-propylene amine oxime (99mTc-PnAO); a potential brain radiopharmaceutical.

Propylene amine oxime (PnAO) forms a neutral lipid soluble complex with 99mTc. 99mTc-PnAO can be prepared by simple reduction of 99mTc-pertechnetate with stannous ion in the presence of excess PnAO in saline at or near neutral pH. This agent will passively penetrate biological membranes including the intact blood-brain barrier (BBB) as evidenced by the high brain uptake observed shortly after IV injection. The first-pass extraction efficiency in baboons was estimated to be 80% at normal blood flow. This agent or a derivatized form of 99mTc-PnAO may be useful in assessment of regional cerebral blood flow (rCBF) in humans.

Biodistribution of lipophilic 99mTc complexes of cyclam derivatives.

Several n-alkyl-cyclam derivatives were synthesized which form stable single component cationic chelates with 99mTc. These results suggest that the cyclam moiety in these derivatives complexes 99mTc in the same manner as the underivatized macrocycle. Biodistribution studies in mice show that all of these chelates are cleared from circulation by both the kidneys and liver. The ratio and rates of clearance by these organ systems is related to lipid solubility. None of the lypophilic-cationic-99mTc agents show any significant myocardial uptake. Also, these chelates show no significant ability to penetrate the blood-brain-barrier.

The behavior of neutral amine oxime chelates labelled with Tc at tracer level.

Neutral 99mTc-chelates were formed with propylene amine oxime, 3,3'-(1,3-propanediyldiimino)bis-(3-methyl-2-butanone)-dioxime and other PnAO analogues. Even though the other amine oxime ligands form neutral chelates with 99mTc, the stability, lipophilic and the brain uptake characteristics are less desirable than [99mTc]-PnAO. These results demonstrate that slight modifications in the amine oxime ligand backbone produces significant effects on the chemical and biological behavior of the [99mTc]dioxime chelates.

Complexing of Tc-99m with cyclam: concise communication.

The macrocyclic amine, cyclam, has been found to be an efficient complexing agent for Tc-99m. Complexes can be formed in yields of higher than 95% at pH 11 in 10(-3) M cyclam using 5 x 10(-6) M SnC4H4O6 as a reducing agent. The complex is positively charged and is stable in air. It is not decomposed by dilution, by 0.05 M NaOH, or 0.05 M H2O2, but does show slight decomposition in 0.05 M HCl. In unanesthetized mice the complex is cleared rapidly from the blood by the kidneys and liver. Preliminary studies show that derivatives of cyclam also complex Tc-99m.