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There have been many attempts to develop zinc-containing radiopharmaceuticals for use as pancreas-seeking agents, but little consideration has been given to Zn-complex structure as being a factor that contributes to Zn utilization by the pancreas. In the present study, various ligands having N-O donor groups (amino acids and aminopolycarboxylic acids) with variable numbers of coordination sites (2-6) were investigated with regard to the coordination of the radiometal Zn. As an experimental model, freshly prepared slices of rat pancreas were studied, and Sephadex-column chromatography analysis was also performed. The structure and stability of Zn complexes were found to affect the accumulation of Zn in pancreas slices. In particular, the administration of tetradentate ligand complexes of 65Zn-ethylenediamine-N,N'-diacetic acid (EDDA) and 65Zn-nitrilotriacetic acid (NTA) resulted in high Zn utilization in the pancreas. Also, Zn complexes of intermediate stability (as demonstrated by elution behavior at Sephadex-column chromatography) produced the best results.

Gallium-67 labeled fibrinogen was prepared as a new deep-vein thrombus imaging agent, using deferoxamine (DF) as a bifunctional chelating agent. Excellent physicochemical and biological properties of 67 Ga-DF-fibrinogen were obtained. The isotopic clottability was 85.3%. High stability in vivo as well as in vitro was observed. Studies carried out in rabbits with induced thrombi in the femoral vein showed thrombus to blood radioactivity ration of 11.7, comparable to the value estimated with conventional 131I-fibrinogen 24 h after injection. Remarkable visualization of these thrombi with a scintillation camera provided good evidence for the selective mechanism of this new radiopharmaceutical.

A newly developed thrombus imaging agent, 67Ga-DFO-DAS-fibrinogen (67Ga-fibrinogen), was used for 22 studies in 20 cases of suspected deep venous thrombosis. Increased accumulation of 67Ga-fibrinogen in venous thrombi was depicted at 48 h after injection in 10 of the 15 cases (10 of 17 studies) who showed abnormal findings in radionuclide venography. A hot spot in the lung emboli was visualized in two cases. Seven of the eight cases having anticoagulant therapy showed increased 67Ga-fibrinogen uptake, while follow-up 67Ga-fibrinogen scintigraphy after the administration of heparin and urokinase did not reveal an abnormal hot spot in one case. 67Ga-fibrinogen can be made available simply by adding 67Ga solution to a vial containing fibrinogen-DAS-DFO conjugate. In conclusion, 67Ga-fibrinogen is considered to be a promising agent for detecting active venous thrombi and to assess the effect of anticoagulant therapy.

While 131I-meta-iodobenzyl guanidine (131I-MIBG) scanning has made possible the scintigraphic visualization of pheochromocytoma and neuroblastoma, an accumulation of this agent has recently been reported in medullary thyroid cancer. We present the case of a patient with Sipple's syndrome (multiple endocrine neoplasia type IIa), in whom we were able to identify distant metastases and local invasion of medullary thyroid cancer as well as primary thyroid tumour and right adrenal pheochromocytoma, using 131I-MIBG scans. This case highlights the usefulness of 131I-MIBG in the detection of metastatic medullary thyroid cancer and suggests that this agent may also be of therapeutic use in the treatment of tumours.

Serum ferritin levels were measured in 72 normal subjects and in 214 cases with various diseases by an immunoradiometric assay. In normal subjects, the serum ferritin levels were 27-230 mg/ml. Elevated serum ferritins were observed in most cases with iron excess and acute hepatitis. Markedly elevated levels were found in the majority of cases with acute leukemia, malignant lymphoma, hepatoma, and pancreatic cancer. High ferritin levels were also found in other malignant diseases. However, the range overlapped broadly with that of nonmalignant diseases. The serum ferritin correlated significantly with serum iron in normals and in those with iron deficiency anemia. In most nonmalignant cases, the serum ferritin and iron levels distributed on a regression line obtained from levels in normals and those with iron deficiency anemia. However, 92% of the malignant cases showed a serum ferritin to iron ratio higher than that of normal subjects. The estimation of the serum ferritin to iron ratio is a useful means for screening patients or in the differential diagnosis of a suspected malignant lesion.

A multigated blood-pool study was performed to assess regional and global emptying and filling in 16 patients with hypertrophic cardiomyopathy (HCM), 43 patients with ischemic heart disease (IHD), and 14 controls. The regional volume curve was fitted using second-order harmonics in the Fourier series, while the global left-ventricular volume curve was fitted using third-order harmonics. As asynchronous indices, the standard deviations (SD) in distribution histograms of time to end-systole (TES), time to peak ejection (TPE), and time to peak filling (TPF) were obtained in the left ventricle. In patients with IHD, the TPF-SD was higher (14.4 +/- 11.3 degrees) than the TES-SD (7.8 +/- 5.1 degrees) and TPE-SD (8.1 +/- 5.9 degrees), suggesting the presence of asynchronous filling. In patients with HCM, the TPF-SD was also higher (11.6 +/- 11.1 degrees) than the TES-SD (3.5 +/- 2.4 degrees) and TPE-SD (6.2 +/- 4.4 degrees). The phase delay was localized in the anteroseptal or apical region in all 5 HCM patients with abnormal wall motion, while it corresponded with the region of abnormal wall motion in the patients with IHD. The TPF-SD was inversely correlated with the left-ventricular ejection fraction (r = -0.46), peak filling rate (r = -0.50), and the ratio of peak filling rate to peak ejection rate (r = -0.52), suggesting that asynchronous filling is related to global diastolic disturbance. We conclude that asynchronous filling is often present in patients with IHD and HCM, and that our technique can be used to obtain a quantitative assessment of regional asynchronous emptying and filling in these diseases.

Synthetic human calcitonin gene-related peptide (CGRP) was examined for the action on the bone in vitro. Human CGRP inhibited bone resorption stimulated by both human parathyroid hormone and basal. The mode of inhibitory action of human CGRP seemed to be similar to that of calcitonin and the relative potency of human CGRP to inhibit bone resorption is one five-hundredth of that of human calcitonin. Thus, a novel pharmacological action of CGRP was demonstrated.

Fractional myocardial uptake of thallium-201 was estimated by routine scintigraphic evaluation at rest and during exercise in 10 control subjects, 15 patients with coronary artery disease (CAD) and 12 patients with hypertrophic cardiomyopathy (HCM). Fractional myocardial uptake of the total dose administered at rest was 3.59 +/- 0.98% in the controls, 4.43 +/- 1.17% in patients with CAD and 5.68 +/- 1.29% in patients with HCM, and uptake during exercise was 5.07 +/- 1.23% in the controls, 4.67 +/- 1.04% in the CAD group and 7.50 +/- 1.68% in the HCM group. The value in the HCM group was significantly higher than in the controls (P < 0.001 at rest) or in the CAD group (P < 0.02 at rest). A percentage increment of fractional uptake during exercise was significantly smaller in the CAD group than in the controls or the HCM group (P < 0.01). Thus, assessment of the fractional uptake appears to be a valuable adjunct to myocardial imaging when attempting a clinical assessment of CAD or HCM.

To estimate tricuspid regurgitation (TR) quantitatively, a curve fitting method by computer has been employed. Transport in the right cardiac chambers after intravenous bolus injection of macro-aggregated albumin labeled with technetium 99m (99mTc-MAA) was recorded in anterior view by a gammacamera system. Disturbance of the dilution curves from the left heart can be avoided by using 99mTc-MAA injection. To know the radioisotope activity during the transport, time-activity curves are recorded for the superior vena cava, right atrium, and right ventricle. Parametric differential equations, obtained from compartmental analysis, interpret these curves mathematically. The rate of regurgitation is determined by comparison, using an iterative process, between the original and simulated curves. The whole process is performed automatically by computer. The calculated regurgitation value correlated well with the value from the analog simulation. The method clearly separated those with TR from those without TR. This digital simulation for estimating parameters using a compartmental model is a feasible tool in detecting and quantifying TR.

The microstructure of reactive endosteal new bone was examined using undecalcified ground sections in five pathologic conditions (bone metastasis from prostate cancer in seven cases, intervertebral osteochondrosis in five, Paget disease in four, chronic suppurative osteomyelitis in two, and fracture healing in one). To determine a basic form of rapid intramembranous bone formation, fetal rat calvaria and primitive bones made in clonal osteogenic cell culture were also observed. In slow bone-forming conditions, lamellar new bone was deposited on pre-existing trabecular surface and caused trabecular thickening on radiographs. In contrast, in rapid bone-forming conditions, woven bone was deposited as spicules extending from trabecular surface so as to form new networks in intertrabecular space. This causes obscurity of trabecular margins radiographically. Reactive endosteal bone formation may be nonspecific and have a significance for assessing the virulence of underlying pathologic conditions like periosteal reactions.

In our search for a platelet-specific labeling agent, metaraminol (MA), a low-toxic pharmaceutical for the treatment of hypotension and cardiogenic shock, attracted our attention. Its active incorporation and accumulation by platelets have been recognized. At first, the preparation of 125I radioiodinated metaraminol (125I-MA) was carried out using the chloramine-T method. Then, upon the harvest of platelets as platelet-rich plasma (PRP), their labeling with this new radiopharmaceutical was easily performed by incubation for 10 min at 37 degrees C. The cell-labeling efficiency was dependent on cell density, reaching 63.0% +/- 3.1% at 2.4 X 10(9) cells/ml. The specific incorporation of 125I-MA by an active transport system similar to that of 5-hydroxytryptamine (5-HT) as well as by passive diffusion was demonstrated. In in vitro studies, the unaltered state of 125I-MA-labeled platelets with their cellular functions fully retained was estimated. In vivo studies carried out in rabbits with induced thrombi in the femoral artery showed a rather rapid disappearance of the radioactivity from circulating blood, reaching a high thrombus-to-blood activity ratio of 19.8 +/- 4.3 within 30 min of the administration of 125I-MA-labeled autologous platelets. Thus, with the potential availability of 123I, 123I-MA-labeled platelets appear to be a promising agent for thrombus imaging using single-emission computed tomography (CT) studies.

201Tl perfusion scintigraphy of the legs was evaluated to define intermittent claudication quantitatively, based on Sapirstein's indicator fractionation principle. After intravenous injection of 201Tl with or without exercise, the distribution of the radiotracer throughout the body was obtained using the whole blood scanner. Regional blood flow of cardiac output for three segments of the leg was estimated as a regional fractional uptake (rFU) distributed in these segments compared with the whole body distribution. The validity of the principle was confirmed by a comparative study with 99mTc-MAA (r = 0.979). Normal rFUs (%) for each section at rest and after stress, respectively, were 5.49 +/- 0.69 and 19.40 +/- 2.04 (whole leg); 3.57 +/- 0.49 and 12.26 +/- 1.91 (thigh); 1.59 +/- 0.34 and 6.58 +/- 0.61 (calf). The rates of rFU change from the state of rest to stress (delta rFU) in normals were 3.41 +/- 0.45 (whole leg), 3.44 +/- 0.61 (thigh), and 4.30 +/- 1.03 (calf). Although rFU was within normal limits in patients with arteriosclerosis obliterans (ASO) and thromboangitis obliterans (TAO), delta rFU of the whole leg was significantly decreased from the normal value of 3.41 +/- 0.45 to 1.95 +/- 0.40 for ASO (P less than 0.001) and 1.82 +/- 0.47 for TAO (P less than 0.001). A defect or decreased activity on the stress scintigraph was well correlated with the angiographic findings.

Studies on 99mTc-Penicillamine (Tc-Pen) have given us some insight into the significance of the technetium coordination state in hepatobiliary clearance behavior. A 99mTc-complex of pyridoxal and glutamate (Tc-PG) prepared by Baker et al. (1975) using an autoclaving process or by a Sn-Resin kit method (Horiuchi 1981) was compared with a 99mTc-complex of pyridoxal and isoleucine (Tc-PI) prepared by the method of Kato and Hazue (1978) through an intermediate compound of stannous ion, at room temperature. Tc-PG and TcPI complexes analyzed by thin layer chromatography, sephadex column chromatography (G-15), octanol extraction, and ligand exchange reaction showed different chemical properties. Their biological evaluation also demonstrated great differences in biodistribution in mice, metabolic studies, protein binding, and rat bile excretion. Tc-PG was estimated as an hepatobiliary agent with strong metal-ligand binding, inert to ligand exchange reaction with Pen at physiological pH; the likely occurrence of technetium in a mononuclear or dinuclear state providing the great stability observed in its biological and in vivo behavior was compared with the relatively weaker binding observed in Tc-PI, a highly lipophilic complex of high liver partition but of low stability, denoting its different chemical characteristics. The technetium coordination state in radiopharmaceuticals is responsible for the integrity of the molecule while in the blood pool and its relevance in impaired liver uptake is discussed.

The value of stress thallium 201 myocardial emission computed tomography (ECT) in the assessment of coronary artery disease (CAD) was analyzed in 75 patients admitted for coronary arteriography. The ECT provided contiguous transaxial, short-axis, and long-axis sections of the myocardium and the myocardial images were divided into nine segments. The sensitivity and specificity in the diagnosis of CAD were 95% and 93%, respectively. Using selected segments, the ECT identified 97 of 111 (83%) major vessels involved: 89% for right coronary artery (RCA), 88% for left anterior descending (LAD), and 70% for left circumflex (LCx). Among the 75 cases, 35 underwent stress conventional planar imaging within 3 months. The planar imaging provided high sensitivity (90%) and specificity (100%) for the detection of CAD patients as well, but it showed lower sensitivity (57%, P less than 0.001) in identifying individual vessels involved: 55% for RCA (P less than 0.01), 70% for LAD, and 36% for LCx (P less than 0.05). Stress ECT detected vessel involvement more in two-vessel disease (85%) and three-vessel disease (78%) than the planar imaging (50%: P less than 0.05 and 44%: P less than 0.01, respectively). Thus, segmental analysis of stress ECT yielded as high sensitivity and specificity in the diagnosis of CAD as the planar imaging. This can improve sensitivity in identifying individual vessels involved in deep myocardial regions, especially in those with multivessel disease.

99mTc-Pyridoxylidene-glutamate (Tc-PG) was introduced in 1975 by Baker et al. as a cholescintigraphic agent. Nevertheless its routine use has been limited due to the autoclaving process involved. To shorten the labeling procedure, an analysis of Tc-PG complex formation using the stannous chloride method was carried out. Sn-Resin (stannous ion adsorbed onto cation exchange resin) was used for labeling a stable Tc-PG with high efficiency. A preautoclaved complex of pyridoxal and glutamate was required but the labeling procedure took only 10-15 min after the elution of 99m-TcO4- from the generator. Formation of a complex other than a 99mTc-complex of the Schiff -base ligand pyridoxylidene-glutamate is discussed. The new formulation of a Tc-PG kit (Sn-Resin) simplified the labeling method and reproducible data to that already reported by Baker was obtained in chromatographic studies. Its suitability in hospital departments has already been shown in clinical studies.

We examined 17 patients with primary hyperparathyroidism for their serum 1,25 dihydroxyvitamin D levels and for their fractional intestinal calcium absorption rates using a whole body counter and calcium-47. As controls, 10 normal volunteers were examined both before and after administration of 1 alpha-hydroxyvitamin D to increase serum 1,25 dihydroxyvitamin D. Values of serum 1,25 dihydroxyvitamin D were 71.6 +/- 37.6 pg/ml (mean +/- SD) in patients with primary hyperparathyroidism and 75.3 +/- 27.7 pg/ml (mean +/- SD) in normal volunteers after administration of 1 alpha-hydroxyvitamin D, while values of intestinal calcium absorption rate were 61.5 +/- 16.5% (mean +/- SD) in patients with primary hyperparathyroidism and 34.1 +/- 5.1% (mean +/- SD) in normal controls, respectively. There was a positive correlation between values of serum 1,25 dihydroxyvitamin D and intestinal calcium absorption in both groups. However, in patients with primary hyperparathyroidism, intestinal calcium absorption was more increased than that in normal volunteers when compared to their serum values of 1,25 dihydroxyvitamin D. This suggests that another factor than 1,25 dihydroxyvitamin D plays an important role in the intestinal calcium absorption in patients with primary hyperparathyroidism.

The functionality of various zinc complexes of amino acid derivatives as a zinc radiopharmaceutical for pancreas PCT imaging was tested using 65Zn, which has a long half-life, and 62Zn, which has a short half-life. Because of the favorable results obtained in previous in vitro pancreas section studies, the ability of those Zn complexes to retain their integrity in the presence of blood serum or in living organisms was screened using Sephadex column chromatography and mice biodistribution studies. A relationship between the structure and stability of Zn complexes played a determining role on the in vivo availability of Zn for the pancreas or liver. Among the Zn complexes tested, the tetra-coordinated structure of the Zn-EDDA complex at an equimolar ratio showed proper accumulation in the pancreas, inducing an appropriate pancreas PCT image in the dog with the positron emitter 62Zn-EDDA administered at 1 mg Zn/kg body weight.

The in vivo renal volume was determined using SPECT for 99mTc -DMSA renal imaging. The total renal volume was derived by summing the DMSA distribution volumes of the transaxial slices in the whole kidney. In 20 healthy subjects the renal volume in the right kidney was 220 ml for men and 195.2 ml for women, while that in the left kidney was 213 ml for men and 193.7 ml for women. Differences in those values were not statistically significant. A good correlation was found between renal volumes in both kidneys and body surface area. In 106 kidneys including solitary and pathological kidneys, individual renal volume correlated well with individual DMSA renal uptake rate which demonstrates cortical functioning mass, depending on the cortical blood flow. Thus, SPECT enables an accurate noninvasive means of estimating in vivo functioning renal volume.

To depict the three-dimensional distribution of 99mTc-pyrophosphate in the heart, emission computed tomography (ECT) was performed, following the conventional planar imaging, in 32 cases with suspected acute myocardial infarction (AMI). There were 23 cases with evidence of AMI, 7 with unstable angina (UA), and 2 with dilated cardiomyopathy (DCM). While the planar images showed discrete cardiac activity in only 11 of the 23 cases (48%) with AMI, the ECT images delineated focal myocardial uptake clearly in 20 of them (87%). On the other hand, the ECT images revealed cardiac blood-pool activity without significant myocardial uptake in all cases with UA and DCM in which the planar images showed diffuse activity. Thus, the ECT imaging of 99mTc-pyrophosphate seems to be a valuable technique for assessing the presence and localization of myocardial necrosis, especially in cases showing diffuse cardiac activity in the planar imaging.