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For the purpose of radiation dose estimates, organ assays and excretion measurements of the Tc-99m and In-111 complexes with DTPA were conducted in dogs at various time intervals up to 24 hr, and the results compared with available human data. The peak concentration of the Tc-99m complex, at 3 min after injection, was 5% of the administered dose for one kidney, 3.5% for the liver, and 3.5% for the small bowel. No organ system except the urinary tract reached a concentration higher than that in blood for several hours after the injection. The biliary excretion of these agents was extremely low, and their elimination in the feces was negligible. In man, it appears that the residual 4-5% of an administered dose not eliminated in the urine by 24 hr is widely distributed in various tissues. The distribution of the In-111 complex is similar but not identical to that of the Tc-99m complex.

Indium-113m complexed with polyfunctional phosphonates EDTMP (an analog of EDTA with carboxylic groups replaced by phosphate groups) and DTPMP (an analog of DTPA) showed preferential skeletal localization in experimental animals. Excellent images of the rabbit skeleton were obtained with both 113mIn and 111In complexes using the scintillation camera. In tissue radioassay using 85Sr as a simultaneous biologic standard, 113mIn-EDTMP compound showed higher concentration in the skeleton than the DTPMP complex and its bone uptake was comparable to that of 85Sr. Renal excretion was greater for the DTPMP complex (70% vs. 50% for EDTMP at 4 hr) and its blood clearance was faster than EDTMP. EDTMP was found to be the superior agent also to two other polyfunctional phosphonates, NTMP and HMDTMP. Because of the excellent skeletal localization with minimal soft-tissue levels, 113mIn-EDTMP may find use in bone scanning in humans wherever 99mTc bone-imaging agents are not available. These compounds may prove useful also in demonstrating acute myocardial infarcts, particularly for repeat studies after 99mTc bone agents have already been administered.

We have used both Tc-99m oxine and In-111 oxine to study the effects in the rabbit of various parameters on platelet labeling and the in vivo survival of platelets harvested by four different methods. For In-111 oxine, platelet labeling in saline produces much higher efficiencies (90%) than labeling in the presence of plasma (20%), with no significant shortening of in vivo survival (1% survival at 5.9 days). For Tc-99m oxine, labeling efficiencies are considerably lower (30%) and survival is shorter (1% survival at 3.8 days). For both radioagents, a 30-min labeling incubation at room temperature is suggested.

Using rabbit platelets harvested and labeled with either Tc-99m or In-111 oxine as described in Part 1, we have successfully imaged experimentally induced fresh venous thrombi and newly injured arterial intima. Visualization of lesions up to 6 hr old is striking. Thrombi and arterial damage 24 hr old, however, were usually not imaged successfully; nor were preformed platelet-poor arterial emboli. The varying rates of platelet deposition in vascular lesions of different ages and types account for these observations. Should human cells prove as effective, widespread clinical application is anticipated.

The biodistributions of In-111 oxine (with and without leukocyte labeling) of Ga-67 citrate and of In-111 chloride were compared in 30 dogs with chemical and bacterial abscesses and acute joint inflammation. Serial blood samples were taken and tissues radioassayed at 24 hr. The concentration of In-111-oxine leukocytes in all three types of inflammatory lesion was invariably much higher than that of Ga-67 injected simultaneously. For bacterial abscesses, the mean abscess-to-muscle concentration ratio was 3,000 for labeled leukocytes and 72 for Ga-67. Aqueous buffered In-111 oxine sulfate solution appeared better for labeling leukocytes than In-111 oxine in ethanol. When In-111 oxine was not incubated with leukocytes before injection, or if the cells were poorly labeled or damaged, the abscess localization was often inferior to that of gallium. Localization of In-111 chloride also appeared inferior to that of gallium. No significant difference in distribution in the major organs or inflammatory lesions was demonstrable between labeled suspensions of "pure"neutrophils harvested by elutriation and "mixed"cell suspensions of leukocytes after erythrocyte sedimentation with hydroxyethyl starch. For both types of leukocyte suspension labeled with In-111 oxine, the average recovery of cell-bound activity in the circulating blood at 4 hr was 32% of the administered activity, inferior to that of DFP-32. It is concluded, therefore, that In-111 oxine is a more effective agent than Ga-67 for the detection of acute focal inflammatory lesions if leukocytes are properly labeled, but current techniques are unsatisfactory for the study of neutrophil kinetics.

The biodistributions of five Tc-99m colloids were compared with the 24-hr distributions of Fe-59 and In-111 in dogs by direct radioassay 1 hr after intravenous injection. One formulation of Tc-99m minmicroaggregated albumin (particle size 30-100 mn), produced the highest marrow concentration, approximately six times that of Tc-99m sulfur colloid, with similar blood, and liver concentrations and a lower splenic uptake. Nevertheless, the best colloid marrow uptake was lower than the 24-hr value for In-11 and much lower than that for Fe-59. The marrow concentration of minimicroaggregated albumin was also higher than that of sulfur colloid in rats at 30 min after injection. The principal disadvantage of Tc-99m antimony sulfide colloid was its slow blood clearance. Clinical evaluation of Tc-99m minimicroaggregated albumin for marrow imaging appears warranted, although its hepatic activity will obscure overlying and immediately adjacent marrow.

Dextrans with average molecular weights of 5,000, 10,000, and 17,500 and inulin were rendered cationic by amination with 2-bromoethylamine hydrobromide. After limited coupling with DTPA cyclic dianhydride, they were labeled with 111In. A good correlation was found between their early renal uptake quantitated by camera-computer techniques and their renal clearance from multiple plasma samples in rats with glomerular damage induced by puromycin aminonucleoside and controls. However, there was poor correlation between the early renal uptake of these agents and the clearance of simultaneously injected [99mTc]DTPA. The 2-hr organ distribution and urinary excretion of these agents were compared with the corresponding values of DTPA. The differences in clearance between rats with glomerular damage and controls were greater with aminated dextran (mol wt 5,000) than with DTPA, confirming previous work with infusions of nonradioactive charged dextrans and neutral inulin. The cationic dextrans appear to reflect the presence or absence of the normal anionic charge of the glomerular membrane as well as changes in filtration rate. Aminated inulin did not differentiate between controls and rats with glomerular disease any better than DTPA, probably because the number of amino groups conjugated was insufficient to produce the charge effect.

Leukocyte suspensions labeled with In-111 oxine or tropolone were administered intravenously to 150 patients for the detection of suspected foci of bacterial infection by gamma camera imaging. The results were correlated with other imaging modalities, and clinical, laboratory, and surgical findings after a minimum follow-up period of six months. Twenty-five of 29 foci of bacterial infection were demonstrated on the leukocyte-labeled images (sensitivity of detection = 86%). Three of the four missed lesions were chronic active osteomyelitis. The specificity of detection proved difficult to define, varying with different criteria for a false positive diagnosis. In every region of the body, a variety of lesions other than foci of bacterial infection produced positive uptake of the labeled leukocytes. An intense focal uptake was uncommon in lesions other than abscesses and hematomas. It was concluded that imaging with labeled leukocytes is valuable for demonstrating sites of infection in conjunction with other diagnostic methods. Detectable leukocytic infiltration, however, may occur in inflammatory lesions of any cause and in some noninflammatory states as well.