Preparation and biological distribution of technetium diphosphonate radiotracers synthesized without stannous ion.

Two HEDP complexes of technetium (either Tc-99 or a mixture of Tc-99 and Tc-99m) have been prepared without the use of stannous ion. The first, Tc(NaBH4)-HEDP, is synthesized by reduction of TcO4- with NaBH4 in the presence of excess HEDP; this is analogous to the preparation of Tc(Sn)-HEDP in commercial kits wherein SN(II) functions as the reductant. The second, Tc-HEDP, is prepared by substitution of HEDP onto the pre-formed, pre-reduced, technetium center TcBr62-. The HEDP-to-Tc ratio in Tc-HEDP was found to be 1.0 by double-labeling procedures (Tc-99 and [3H]HEDP), implying that in solution this material is polymeric or at least dimeric. Preparations of Tc(NaBH4)-HEDP and Tc-HEDP with Tc-99m are excellent bone-imaging agents in both rats and dogs. Tissue distribution studies in rats show that uptake of Tc(NaBH4)-HEDP and Tc-HEDP by the bone is at least equivalent to that achieved by Tc(Sn)-HEDP prepared in commercial kits with Sn(II) as the reductant. Tin is therefore not necessary for the bone-seeking properties of Tc(Sn)-HEDP, and the in vivo distribution of a given HEDP radiotracer seems to depend primarily on the presence of the HEDP ligand and not on the exact nature of the technetium complex itself. Synthesis of technetium radiotracers by a substitution route, rather than by redox, is practicable; this route has the potential of introducing hitherto unattainable flexibility and subtlety into the preparation of technetium radiotracers.

Development of nonreducible technetium-99m(III) cations as myocardial perfusion imaging agents: initial experience in humans.

A series of 15 nonreducible technetium-99m(III) complexes of formula tr-[99mTcL(Y)2]+ has been prepared by a general synthetic route based on reductive addition of Y to the technetium-99m (99mTc) intermediate [99mTcL(O)]+. In these complexes, selected for potential use as myocardial imaging agents, L represents one of the two tetradentate Schiff base ligands N,N'-ethylenebis(acetylacetone iminato), (en), or N,N'-propylene-1,2-bis(acetylacetone iminato), (pn), while Y represents a monodentate phosphine, phosphite or isonitrile ligand as exemplified by P(CH3)3, P(OCH3)3 and CN-C(CH3)3. Of these 15 complexes, several with octanol/saline partition coefficients in the range 0.04-20 exhibit significant myocardial uptake in rats and dogs. Of these, none exhibit detectable myocardial washout, providing strong support for the hypothesis that myocardial washout occurs only for those 99mTc(III) cations that undergo in vivo reduction to the neutral 99mTc(II) form. Evaluation of the prototypical complex tr-[99mTc(en)(P(CH3)3)2]+ in seven normal volunteers and patients establishes that it is only a mediocre myocardial imaging agent in man.

Evaluation in dogs and humans of three potential technetium-99m myocardial perfusion agents.

The biodistribution of the three cationic 99mTc complexes [99mTc(TMP)6]+, [99mTc(POM-POM)3]+, and [99mTc(TBIN)6]+--where TMP represents trimethylphosphite, POM-POM represents 1,2-bis(dimethyoxyphosphino)ethane, and TBIN represents t-butylisonitrile--have been evaluated in humans and dogs. Each agent was studied in three normal volunteers at rest, while [99mTc(POM-POM)3]+ and [99mTc(TBIN)6]+ were each studied in one normal volunteer at exercise. Even though all three agents yield good myocardial images in dogs, none appear suitable for clinical use as myocardial perfusion imaging radiopharmaceuticals. In humans, [99mTc(TMP)6]+ and [99mTc(POM-POM)3]+ clear very slowly from the blood and provide myocardial images only several hours after injection. [99mTc(TBIN)6]+ clears rapidly from the blood, but accumulation in the lung obscures the myocardial image for the first hour after injection; at later times, activity in the liver and spleen masks the apical wall. These results correlate with the blood-binding properties of the three complexes. [99mTc(TMP)6]+ and [99mTc(POM-POM)3]+ bind tightly to the plasma of human blood, but not to the plasma of dog blood; [99mTc(TBIN)6]+ does not bind tightly to the plasma of either dog or human blood. Among the Tc(I) complexes studied to date in humans, [99mTc(TBIN)6]+ appears to be unique in biodistribution pattern, blood-binding properties, and the fact that exercise improves the ultimate myocardial image. All the Tc(I) complexes appear to undergo myocardial accumulation by a mechanism different from that utilized by Tc(III) complexes. Animal studies alone are not adequate to evaluate the potential utility of 99mTc cationic complexes for myocardial perfusion studies.

Effect of coronary blood flow on uptake and washout of Tc-99m DMPE and Tl-201.

After intravenous administration of Tc-99m DMPE the flow-dependent kinetics were studied in dogs during induced ischemia and during induced maximal reactive hyperemia. A control group was also studied. Mean time-activity curves obtained from the myocardial wall were compared within the same intervention group and also with other groups. During reactive hyperemia, there was a rapid and absolute increase in uptake followed by a rapid washout, whereas during ischemia there was a slow and decreased uptake followed by a slow washout. The magnitude of Tc-99m DMPE uptake during reactive hyperemia was slightly less than that of Tl-201, but the decreased uptake with ischemia was about equal for the two agents. Following maximal uptake in the myocardium the effective half-life of Tc-99m DMPE was one-third to one-fourth that of Tl-201. The similar kinetics of Tc-99m DMPE compared to Tl-201 suggests its usefulness in the evaluation of ischemic heart disease.

Basal kinetic studies of Tc-99m DMPE as a myocardial imaging agent in the dog.

Newly synthesized Tc-99m dichlorobis(1,2-dimethylphosphino)ethane (DMPE) was investigated as a myocardial imaging agent with respect to its kinetics (dependent on both time and regional coronary blood flow), its percent organ uptake, and its imaging characteristics in the anesthetized dog. Most of these data are compared with those of Tl-201. Blood clearance of the two agents is essentially the same. Compared with Tl-201, Tc-99m DMPE shows faster overall kinetics, higher heart-to-lung ratio, equally good correlation with a wide range of regional blood flows, and higher liver uptake. At the time of peak myocardial uptake, the mean heart uptake of Tl-201 is 4.3%, compared with 2.9% for Tc-99m DMPE, yet only 0.9% uptake of Tc-99m DMPE is found in the lung as compared with 3.3% for Tl-201. These differences result in a heart-to-lung ratio of 2:1 for Tc-99m DMPE and 1:1 for Tl-201, based on the data obtained from the time-activity curve. The quantitative findings are supported by the superior quality of Tc-99m DMPE images of both normal and infarcted dog heart. The high hepatic uptake of Tc-99m DMPE is not a serious problem if images are obtained within 5-60 min after dose. These basic kinetic studies suggest that Tc-99m DMPE is a promising myocardial imaging agent.

Neutral technetium(II)-99m complexes as potential brain perfusion imaging agents.

A series of eight neutral technetium(II)-99m complexes of general formula tr-[99mTcIID2X2]0, where D represents a chelating ditertary phosphine or arsine ligand and X represents a halide or pseudohalide ligand, has been prepared and characterized by HPLC comparisons to the known 99Tc analogs. Several members of this series exhibit significant brain uptake in rats, with maximum uptake (1.2% dose/brain at 1 min after injection) being exhibited by tr-[99mTcII (DIARS)2Cl2]0 where DIARS represents o-phenylenebis(dimethylarsine). Surprisingly, several cationic Tc(III) analogs, tr-[99mTcD2X2]+, also exhibit significant brain uptake, presumably via a mechanism which involves in vivo reduction to the neutral Tc(II) form. The complicated interrelationships among the chemical and biological properties of the tr-[99mTcIII/IID2X2]+/0 couples, and the dependencies of these properties on the nature of D and X, provide possible means by which this class of complexes might be manipulated to yield an effective 99mTc brain perfusion imaging agent.

HPLC separated fractions of 99mTc(NaBH4)-HEDP as myocardial infarct imaging agents.

Component fractions of 99mTc(NaBH4)-HEDP mixtures, isolated by anion exchange high performance liquid chromatography (HPLC), have been evaluated as myocardial infarct imaging agents in two animal models. Results from both the isoproterenol-induced myocardial infarction model, and the heat-induced myocardial necrosis model, show that the several HPLC isolated components exhibit significantly different abnormal/normal heart uptake ratios. In addition, the HPLC isolated component of shortest chromatographic retention time exhibits a higher abnormal/normal heart uptake ratio than does 99mTc(Sn)-PyP, the current agent of choice for clinical myocardial infarct imaging.

The chemistry of rhenium and technetium as related to the use of isotopes of these elements in therapeutic and diagnostic nuclear medicine.

The beta emitting isotopes 186Re and 188Re are logical choices on which to base therapeutic radiopharmaceuticals that might be expected to be analogous to diagnostic radiopharmaceuticals based on 99mTc. However, the chemistry of rhenium is sufficiently different from that of technetium so that the development of Re radiopharmaceuticals often cannot be predicated on the known chemistry and biological behavior of 99mTc radiopharmaceuticals. The relevant chemical differences involve the greater stability of the higher oxidation states of Re (and thus the greater tendency of reduced Re radiopharmaceuticals to undergo re-oxidation to perrhenate), and the greater substitution inertness of reduced Re complexes. These differences are illustrated in the preparation and use of 186Re (Sn)-HEDP and 99mTc(Sn)-HEDP diphosphonate radiopharmaceuticals designed, respectively, for palliative therapy and diagnosis of metastatic cancer to bone, and in the preparation and biodistribution of tr[186Re(DMPE)2Cl2]+ and [186Re(DMPE)3]+, analogs to the potential myocardial perfusion imaging agents tr-[99mTc(DMPE)2Cl2]+ and [99mTc(DMPE)3]+. [HEDP = (1-hydroxyethylidene)diphosphonate; DMPE = 1,2-bis(dimethylphosphino)ethane].

The biological distributions of some technetium-MDP components isolated by anion exchange high performance liquid chromatography.

Individual components of 99mTc(NaBH4)-MDP mixtures, separated by anion exchange HPLC, have been evaluated as skeletal imaging agents in rats. Biodistribution data show that the evaluated components exhibit markedly different bone uptakes and soft tissue localizations. The component with the highest bone uptake and the highest bone/muscle and bone/blood ratios, is the major component of carrier-added 99mTc(NaBH4)-MDP formulations prepared at pH 8.2. Comparative scintiphotos illustrate the enhanced imaging performance of this component vs unseparated reaction mixtures.

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.

In vivo distributions of some component fractions of Tc(NaBH4)-HEDP mixtures separated by anion exchange high performance liquid chromatography.

Anion exchange high performance liquid chromatography has been utilized to separate the component Tc-HEDP complexes of "carrier added" as well as "no carrier added" 99mTc(NaBH4)-HEDP reaction mixtures. The chromatographically separated "carrier added" Tc-HEDP components exhibit distinctly different biodistributions which are directly related to the chromatographic characteristics of the individual components. The Tc-HEDP complexes with shortest retention times, and therefore the lowest negative "charge density" have the maximum uptake on the bone, minimum uptake in the kidney, and fastest blood clearance.

Re-186(Sn) HEDP for treatment of multiple metastatic foci in bone: human biodistribution and dosimetric studies.

Investigation of the biodistribution of subtherapeutic amounts of a new, chromatographically purified rhenium-186(tin) hydroxyethylidene diphosphonate radiopharmaceutical have been completed in five patients with metastatic carcinoma to bone. The new agent localizes in metastatic foci in bone in the same manner as do standard technetium-99m diphosphonate bone-scanning agents and appears able to deliver therapeutic radiation doses of thousands of rads (tens of grays) to these metastatic foci while limiting the total red marrow dose to less than 75 rad (0.75 Gy). The simultaneous treatment of multiple metastatic foci in bone appears feasible with this new agent.

Myocardial scintigraphy with 99mTc-tris-DMPE in man.

Cardiac scintigraphy was performed in six patients with a documented previous myocardial infarction, in one patient with mitral regurgitation, and in four healthy volunteers following administration of 99mTc-tris-DMPE. An intense early blood pool phase permitted gated blood pool scintigraphy and left ventricular ejection fraction calculation. A myocardial phase 12-14 h later permitted myocardial perfusion imaging. The rest myocardial perfusion image quality with 99mTc-tris-DMPE appeared to be superior to the resting image quality obtained with 99mTc-dichloro-DMPE but was inferior to the resting image quality obtained with 201Tl.

Re-186(Sn) HEDP for treatment of painful osseous metastases: initial clinical experience in 20 patients with hormone-resistant prostate cancer.

Rhenium-186(tin) hydroxyethylidene diphosphonate (HEDP) is a new radiopharmaceutical that localizes in areas of osseous metastases in a manner similar to that of standard bone-scanning agents. It also emits beta particles with sufficient energy to be therapeutically useful. A single intravenous injection of about 33 mCi (1,221 MBq) was given to each of 20 elderly patients with advanced skeletal metastases from hormonally resistant prostate cancer. Prompt, significant relief of pain occurred 80% of the time with no significant side effects and only minimal, transient marrow toxicity. Re-186(Sn) HEDP appears to be a useful new agent for the palliation of painful osseous metastases in prostate cancer.

Myocardial perfusion imaging with 99mTc-DMPE in man.

Technetium-99m DMPE (99mTc-DMPE) is a newly synthesized myocardial perfusion imaging agent that shows intense myocardial accumulation in the dog. In the present study, dosimetry and potential clinical usefulness of this agent were assessed in four human subjects. Absorbed radiation doses were low, with the highest doses consisting of 200 mrad/mCi (54 microGy/MBq) to the gallbladder and 160 mrad/mCi (43 microGy/MBq) to the liver. No evidence of clinical toxicity was found. Technetium-99m DMPE did image the myocardium, but the ratio of target to nontarget activity was less favorable than that observed in the dog. Intense hepatic 99mTc-DMPE activity interfered with clinical imaging of the cardiac apex in two of the four subjects. We conclude that the prototype radiopharmaceutical, 99mTc-DMPE, is capable of myocardial perfusion imaging in man but the planar myocardial images produced are of inferior quality compared with 201Tl myocardial images. Further work is justified to develop related compounds to overcome the clinical limitations described.