The membrane transport properties of twelve Tc-99m complexes were studied by determining each complex's brain uptake index (BUI), extent of protein binding, and octanol-to-saline partition coefficient. The chelating agents used were classified as either N-substituted carbamoylmethyliminodiacetates, substituted oxines, N,N'-diesters of EDTA, or N-substituted derivatives of DTPA. The Tc-99m complexes were found to cross the blood--brain barrier in proportion to their lipophilicity. Of the four types of chelating agents tested, substituted oxines appear to be most suitable for the development of diffusible Tc-99m-labeled compounds for imaging nonexcretory organs.

The chemical structure of Tc-HIDA was determined by synthesizing Tc-HIDA using Tc-99 and Tc-99 m TcO−4, C-14 HIDA and Sn-113 Sn+2 all of known specific activitiy. Tc-HIDA was separated from HIDA and Sn-HIDA by HPLC on a reverse phase column. The identity of Tc-HIDA with and without carrier Tc-99 was confirmed by chromatographic and tissue distribution studies. The oxidation state of the technetium was measured by titration of the excess stannous ion with iodine. Kinetic studies were used to preclude the occurrence of two technetium atoms in the same molecule of HIDA. The Tc-HIDA was found to exist in solution as sodium bis-[N-(2,6-dimethylphenylcarbamoylmethyl)iminodiaceto] technetate (III). Neither stannous nor stannic ion was found in the final radiopharmaceutical. Such knowledge of the chemical structure of radiopharmaceuticals is necessary before their in vivo stability and distribution can be predicted with any degree of certainty.

Prerequisite to the development of technetium-99m containing drug and biochemical analogs is the ability to synthesize radiochemically pure technetium chelates from mixtures of an appropriate chelating agent, pertechnetate, and various reducing agents. This paper reports the synthesis of a series of N-substituted iminodiacetates (IDA) in which the pKa of the imino nitrogen was varied from 5.0 to 8.7. The chelating agents were labeled with Tc-99m using the stannous reduction method at aqueous pH's of 4.0, 5.5 and 8.0 and in absolute methanol. The radiochemical purity of each chelate was examined by high pressure liquid chromatography, paper electrophoresis, paper chroma-tography, and tissue distribution studies. Aqueous radiolabeling conditions resulted in pure technetium chelates only when the pKa of the imino nitrogen was approximately 6. Methanolic labeling conditions resulted in pure radiochemicals for all N-substituted imino-diacetic acids provided the imino nitrogen had a pKa of greater than 6. Under non-aqueous conditions, however, the radiochemical purity deteriorated with time for all compounds in which the pKa of the imino nitrogen was greater than 7. These results indicate that only those IDA derivatives in which the in vivo nitrogen has a pKa of approximately 6 show a high degree of radiochemical purity when radiolabeled using stannous ion as the reducing agent.

99mTc-labeled N-[2,6-dimethylphenylcarbamoylmethyl]iminodiacetic acid (99mTc-HIDA) underwent an acid catalyzed ligand exchange reaction in the presence of EDTA with half-lives of 2.5, 11, and 72 hr at pH values of 2.9, 4.4, and 6.4, respectively. The half-life for dissociation of 99mTc-HIDA in the presence of EDTA at pH 4.4 was found to be substantially independent of EDTA concentration. In addition, the formation constant for 99mTc-EDTA prepared by stannous ion reduction is 300 times larger than the overall formation constant for 99mTc-HIDA. This work indicates that99mTc-(HIDA)2 exists as an anionic bis compound and that the bond between reduced technetium and N-substituted iminodiacetic acids should remain intact for long periods of time at physiologic pH and temperature.

The synthesis, radiochemical labeling, and tissue distribution characteristics of N-(2,6-dimethylphenylcarbamoylmethyl)iminodiacetic acid are described. The radiopharmaceutical prepared by labeling with 99mTc was rapidly eliminated through the hepato-biliary system of mice. Parent 14C compound was eliminated primarily through the kidney. The 99mTc ion appears to have a greater influence than the organic carrier molecule on the distribution of the radiopharmaceutical.