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99Technetium bone scanning in experimental osteomyelitis.

A rabbit model of experimental osteomyelitis was used in an attempt to clarify the natural history of bone infection associated with positive scintigraphic and negative radiological findings. In this model a pathogenic strain of Staphylococcus aureus is injected in the proximal metaphysis of the tibia of a rabbit, 15 minutes following the injection of a sclerosing agent. Scintigraphies were performed at 3, 5, 12, and 19 days following this procedure; 99m-Technetium phosphate compounds were used indifferently. On days 5, 12, and 19 a roentgenogram of the lower limbs was taken. Animals were sacrificed at random 6, 14, and 21 days following the procedure. Against expectations, the standard radiological procedure was more sensitive than the scintigraphic technique. The probability of finding a positive bone scintigrapy in the presence of osteomyelitis P(S+/O+) was 15/19 or 0.78. For the roentgenograms P(X+/O+) = 16/17 = 0.94. On pathological review the scintigraphic findings remained unexplained when fibrosis, periosteal reaction, granulocytic infiltration, and new bone formation were considered separately. In half of the cases the early scintigraphies revealed decreased uptake on the affected side, but this finding did not predict whether the final scintigraphy was positive. Finally, positivity was obvious in all cases, and a continuous range from negative to positive could not be documented. Present findings are a characteristic feature of the model. The physiological mechanism remains to be explained by independent measurements of relative bone blood flow made simultaneously with the scintigraphy and other bone tissue specific factors.

Animals↗

Technetium-99m-labeled monoclonal antibodies: influence of technetium-99m binding sites.

UNLABELLED: A number of 99mTc-labeled monoclonal antibodies (Mabs) are being evaluated for diagnostic applications. Preparations are carried out using both direct and indirect (bifunctional chelating agent, BFCA) labeling procedures in which nonspecific 99mTc binding has been postulated. METHODS: By using the ascorbic acid (AA) reduction mediated direct labeling procedure and diaminotetrathiol (N2S4) as a BFCA method, we examined the role of specific binding sites and aliphatic E amino groups of lysine as nonspecific binding sites for 99mTc. RESULTS: Labeling yields for the direct and N2S4 "regular" preparations averaged 73% +/- 2.8% and 91% +/- 2%, for the "specific" preparations, 60% +/- 3.5% and 75% +/- 2% and for the "nonspecific" preparations 13% +/- 1.0% and 16% +/- 1% respectively. All preparations were evaluated in tumor-bearing mice. The control and specific preparations permitted excellent scintigraphic visualization of tumors; the percentages of specific preparations in the tumors being 2.1% +/- 0.5% and 3.1% +/- 0.4%, respectively. With nonspecific preparations, tumors were not visualized and the percentages of administered radioactivity per gram of tumor were only 0.9% +/- 0.2% and 0.9% +/- 0.3%, respectively. CONCLUSIONS: In these 99mTc labeling procedures, the amino group-mediated nonspecific binding of 99mTc to Mabs can be as high as 16% and contributes to increased liver uptake and decreased tumor uptake of radioactivity.

Animals↗

[Simultaneous assessment of wall motion and myocardial perfusion by technetium-99m methoxy isobutyl isonitrile].

The aim of this study was to assess whether or not myocardial uptake of Technetium-99m methoxy isobutyl isonitrile (Tc-MIBI) indicated myocardial viability. We performed simultaneous Tc-MIBI angiography and myocardial SPECT at rest on 12 patients with suspected coronary artery disease. Left ventricle was divided into 3 segments, and regional wall motion was graded as normal, hypokinesis and akinesis/dyskinesis. Myocardial uptake of Tc-MIBI was assessed as normal, reduced and absent in each segment. In segments with normal and reduced Tc-MIBI uptake, 7% (2 of 28) and 33% (2 of 6) showed wall motion abnormalities of akinesis/dyskinesis, respectively. However, all segments with absent Tc-MIBI uptake had asynergy of akinesis/dyskinesis (2 of 2, 100%). Myocardial Tc-MIBI uptake at rest indicated wall motion abnormalities and was considered to be useful for the evaluation of myocardial viability. First-pass radionuclide angiography followed by myocardial SPECT with Tc-MIBI demonstrated to be useful for the simultaneous assessment of the left ventricular wall motion and myocardial perfusion.

Coronary Circulation↗

Technetium labeling of monoclonal antibodies with functionalized BATOs. 1. TcCl(DMG)3PITC.

BATO (boronic acid adduct of technetium dioximes) complexes, TcCl(dioxime)3BR, were prepared in which the boron substituent (R) was the protein-reactive m-phenyl isothiocyanate (PITC). The 99TcCl(dioxime)3PITC complexes [dioxime = dimethylglyoxime (DMG) or cyclohexanedione dioxime (CDO)] were prepared from 99Tc(dioxime)3(mu-OH)SnCl3 and characterized. The X-ray crystal structure of 99TcCl(DMG)3PITC was determined. The 99mTc complexes were prepared from 99mTcO4- in a process using a freeze-dried kit, either in a one-step procedure or via 99mTcCl(dioxime)3. Initial labeling studies with 99mTcCl(dioxime)3PITC were performed on glycine and polylysine and, subsequently, on mouse IgG and the B72.3 monoclonal antibody. Covalent attachment of 99mTcCl(DMG)3PITC to B72.3 was demonstrated by SDS-PAGE electrophoresis. B72.3 labeled with 99mTcCl(DMG)3PITC displayed high binding to a TAG 72 affinity column and had a distribution in normal mice similar to that reported for iodine-labeled B72.3.

Animals↗

Design, preparation, and biodistribution of a technetium-99m triaminedithiol complex to assess regional cerebral blood flow.

A new ligand (N-piperidinylethyl-DADT, 5) has been prepared which forms two complexes with 99mTc when stannous chloride is used as a reducing agent for [99mTc] pertechnetate. Biodistribution studies of one of the complexes in mice showed that 2.2% of the injected dose of the tracer was in the brain at 5 min postintravenous injection with 0.53% of the dose remaining in the brain at 30 min postinjection. Brain-to-blood ratios at these times were 5.3 and 3.0, respectively. Biodistribution studies of the other complex showed similar behavior with a slightly lower initial uptake by and faster clearance from the brain. Imaging studies of the more promising of the two complexes were conducted in a monkey and a baboon. In both cases, rapid uptake of the tracer in the brain was observed and clear brain images were obtained. Time-activity curves showed peak uptake in the brain at approximately 5 to 7 min postintravenous injection followed by a plateau of about 11 min. The half-lives for clearance of the tracer from the brains of the monkey and baboon were found to be 63 and 58 min, respectively. These results suggest that this tracer may be useful for brain imaging in humans.

Animals↗

Pharmacokinetics, biodistribution and dosimetry of 99Tcm(V)DMSA in humans with squamous cell carcinoma.

Technetium-99m (99Tcm)(V) dimercaptosuccinic acid (DMSA) is a new tumour imaging agent which has been used to evaluate squamous carcinoma (SCC) of the head and neck. This study evaluated the pharmacokinetics and biodistribution of 99Tcm(V)DMSA in patients with SCC and calculated the bone mass of a New Zealand White (NZW) rabbit. This data was then used to calculate the effective dose equivalent in man. A total of 16 patients were studied (5 with no tumour, 11 with tumour). 99Tcm(V)DMSA had a fast bi-exponential blood clearance in patients with no tumour (30 and 401 min) and patients with tumour (30 and 387 min) with no significant difference (p greater than 0.05) between the two groups. 99Tcm(V)DMSA had a fast cumulative urine excretion with mean half-times in non-tumour and tumour patients of 183 min and 244 min respectively. There was no significant difference (p greater than 0.05) between these two latter groups. The effective dose equivalent of 99Tcm(V)DMSA in man is 5.1 microSv/MBq.

Aged↗

99Tcm (v) DMSA: a clinical, planar and SPECT study to evaluate patients with head and neck squamous carcinoma.

Technetium-99m (99Tcm) (v) dimercaptosuccinic acid (DMSA) is a new tumour imaging agent which has been used to image squamous cell carcinoma (SCC) of the head and neck. This study was undertaken to compare planar versus SPECT 99Tcm (v) DMSA scintigraphy in patients with head and neck SCC. Thirty-four patients were studied. Twenty-eight had SCC, and of these, four had received previous treatment with surgery or irradiation. SPECT was as sensitive and as accurate as clinical examination (but more sensitive and accurate than planar scintigraphy) in detecting which patients had cancer and which patients had primary tumours. SPECT was more sensitive and more accurate than planar scintigraphy (but less sensitive and accurate than clinical examination) in detecting lateral neck compartments with metastatic carcinoma. SPECT correctly upstaged 6% of clinically N0 necks. Although SPECT 99Tcm (v) DMSA scintigraphy improved the image quality, sensitivity and spatial resolution of the investigation, it has no role to play in the routine evaluation of patients with head and neck SCC (to include the clinically N0 neck).

Adult↗

Comparison of technetium-99m aminoalkyl diaminodithiol (DADT) analogs as potential brain blood flow imaging agents.

N-ethyl piperidinyl diaminodithiol (NEP-DADT), complexed with 99mTc has been developed as an agent for the measurement of brain blood flow using SPECT. Studies in patients have shown that 99mTc NEP-DADT enters rapidly into the brain, but also clears rapidly (t1/2 = 17 min). In this study nine new aminoalkyl DADT derivatives were synthesized, labeled with 99mTc and tested in mice with the aim of developing an agent with increased retention in the brain. In addition, relationships between chemical properties of the derivatives and their in vivo localization were investigated. The results were as follows: (a) the R-group and its isomeric configuration has a profound influence on the biodistribution; (b) 99mTc aminoalkyl DADT derivatives with apparent pKa values of greater than 6.9 show poor brain uptake (less than 0.40% dose at 5 min); (c) lengthening of the chain between the DADT moiety and the amino-R group from ethyl to hexyl generally increases the apparent pKa and consequently lowers brain uptake; (d) a correlation (r = 0.71) exists between initial brain uptake and the octanol-buffer partition coefficient; (e) 99mTc-4'-methyl NEP-DADT has the highest partition coefficient, relatively high uptake, and longest retention in the mouse brain. This complex has characteristics suited for brain blood flow measurements.

Animals↗

Technetium-99m methoxyisobutyl isonitrile (RP30) for quantification of myocardial ischemia and reperfusion in dogs.

This study was done to determine whether [99mTc]methoxyisobutyl isonitrile (RP30), a nonredistributing myocardial perfusion agent, could be used to quantify regional myocardial blood flow distribution during ischemia and reperfusion, employing sequential injections of tracer, tomographic imaging, and appropriate image subtraction. Dogs underwent transient (6 min) coronary artery occlusion, followed by two paired injections of RP30 and radioactive microspheres combined with tomographic imaging, the first during coronary occlusion and the second after 60 min of reperfusion. To obtain a true image representative of reperfusion, the first set of images was corrected for 99mTc decay and subtracted from the second. During occlusion, tissue microsphere content and scintigraphic RP30 activity in the center of the ischemic region (both expressed as a fraction of the nonischemic region) were closely correlated, although RP30 consistently exceeded microsphere content (0.43 +/- 0.03 vs. 0.24 +/- 0.04, p less than 0.01). Direct tissue counting of RP30 confirmed its relative excess in ischemic myocardium. Reperfusion was successful in 7/8 dogs, with an increase in RP30 activity to 0.98 +/- 0.04 compared to 0.89 +/- 0.03 for microspheres (p = N.S.). In one dog with microsphere-documented persistent ischemia, the RP30 defect was still present after reflow. Our results indicate that because of the lack of myocardial clearance and redistribution, repeat injections of RP30 can be used to quantify serial changes in regional myocardial blood flow.

Animals↗

Quantitation of renal uptake of technetium-99m DMSA using SPECT.

Quantitative single photon emission computed tomography (SPECT) methodology based on calibration with kidney phantoms has been applied for the assessment of renal uptake of [99mTc]DMSA in 25 normals; 16 patients with a single normal kidney; 30 patients with unilateral nephropathy; and 17 patients with bilateral nephropathy. An excellent correlation (r = 0.99, s.e.e. = 152) was found between SPECT measured concentration and actual concentration in kidney phantoms. Kidney uptake at 6 hr after injection in normals was 20.0% +/- 4.6% for the left and 20.8% +/- 4.4% for the right. Patients with unilateral nephropathy had a statistically significant (p less than 0.001) low uptake in the diseased kidney (7.0% +/- 4.7%), but the contralateral kidney uptake did not differ from the normal group (20.0% +/- 7.0%). The method was especially useful in patients with bilateral nephropathy. Significantly (p less than 0.001) decreased uptake was found in both kidneys (5.1% +/- 3.4% for the left and 6.7% +/- 4.2% for the right). The total kidney uptake (right and left) in this group showed to be inversely correlated (r = 0.83) with serum creatinine. The uptake of [99mTc]DMSA in single normal kidney was higher (p less than 0.001) than in a normal kidney (34.7% +/- 11.9%), however, it was lower than the total absolute uptake (RT + LT = 41.5% +/- 8.8%) in the normal group. The results indicate that SPECT is a reliable and reproducible technique to quantitate absolute kidney uptake of [99mTc]DMSA.

Adolescent↗

Technetium-99m-tetrofosmin in dipyridamole-stress myocardial SPECT imaging: intraindividual comparison with technetium-99m-sestamibi.

UNLABELLED: Tetrofosmin is a new 99mTc-labeled myocardial perfusion imaging agent. Biodistribution studies suggest more favorable heart-to-adjacent organ biokinetics than for 99mTc-sestamibi after injection during exercise. The aim of this work was to determine intraindividually whether tetrofosmin is more suitable than sestamibi for pharmacological stress testing in a 1-day protocol. METHODS: Thirty subjects underwent two similar 1-day, rest and dipyridamole stress imaging protocols: one using tetrofosmin, the other using sestamibi. SPECT was performed 60 min after tracer administration. Myocardial images were analyzed both visually and quantitatively. RESULTS: Heart-to-liver activity ratios measured on the anterior SPECT projections were significantly higher for tetrofosmin than for sestamibi in the rest and stress studies. Heart-to-lung ratios were similar for both tracers. Significant linear correlations between tetrofosmin and sestamibi perfusion indices were found in normals and in patients with proven or suspected coronary artery disease. In segments showing abnormal uptake during stress, the perfusion indices were similar for tetrofosmin and sestamibi at rest and during stress. The degree of reversibility in these segments was also similar for both tracers. Finally, the extent, intensity and severity of perfusion defects were similar for both tracer studies. CONCLUSION: Tetrofosmin has a more optimal biodistribution than sestamibi when used in a 1-day, rest and dipyridamole stress myocardial SPECT imaging protocol. No significant difference in either the quality or diagnostic interpretation of the images could be demonstrated.

Aged↗

Use of technetium-99m sestamibi to determine the size of the myocardial area perfused by a coronary artery.

The value of the new radionuclide tracer, technetium-99m (Tc-99m) sestamibi, to demonstrate myocardial perfusion in areas supplied by specific coronary arteries was evaluated in patients injected with the agent during cardiac catheterization. Tc-99m sestamibi differs from thallium-201 in its physical characteristics (photon energy 140 keV), half-life (6 hours) and lack of significant redistribution, allowing its administration during an episode of chest pain or ischemia occurring outside the nuclear medicine laboratory with later imaging to visualize the distribution. In 13 patients Tc-99m sestamibi was administered intravenously during balloon-occlusion angioplasty. In 11 of 13 patients, defects of the single photon emission computed tomography images corresponded to the area made ischemic during angioplasty. In the remaining 2 patients, abundant collateral flow was present and no defects were seen. In a second study, 15 patients had Tc-99m sestamibi selectively injected into a coronary artery during angiography. Later imaging identified the area supplied by the artery injected. Tc-99m sestamibi imaging can detect perfusion defects associated with short episodes of ischemia, and the area supplied by the different coronary arteries.

Adult↗

Effect of mitochondrial and plasma membrane potentials on accumulation of hexakis (2-methoxyisobutylisonitrile) technetium(I) in cultured mouse fibroblasts.

Hexakis(2-methoxyisobutylisonitrile) technetium(I) (Tc-MIBI) is representative of a class of 99mTc-based lipophilic cationic myocardial perfusion imaging agents. To test the hypothesis that the mechanism of cellular uptake may involve distribution across biologic membranes in response to membrane potential, Tc-MIBI net uptake and retention were determined in cultured mouse BALB/c 3T3, NIH 3T3, and v-src transformed NIH 3T3 fibroblasts as well as in cultured chick embryo heart cells. Isovolumic depolarization of plasma membrane potentials with 130 mM K 20 mM Cl buffer decreased Tc-MIBI net cell uptake in all preparations. In BALB/c 3T3 cells, depolarizing mitochondrial membrane potential with valinomycin in high K buffer or with the protonophore CCCP inhibited net uptake and retention of Tc-MIBI while hyperpolarizing mitochondrial and plasma membrane potentials with the K+/H+ exchanger nigericin increased Tc-MIBI net uptake. These results indicated that net cellular uptake and retention of Tc-MIBI in fibroblasts were determined by both mitochondrial and plasma membrane potentials; the gamma-emitting properties of Tc-MIBI may therefore raise the possibility of monitoring membrane potential in vivo.

Animals↗

Myocardial infarct imaging in patients with technetium-99m 2,3-dimercaptosuccinic acid. Superiority of technetium-99m pyrophosphate.

Technetium-99m 2,3-dimercaptosuccinic acid (Tc-99m DMSA) has been used successfully for imaging acute myocardial infarction in a canine model. The application in humans, however, has not been previously reported. In order to determine the feasibility of using this agent in clinical studies and to compare the agent to technetium-99m pyrophosphate (Tc-99m PPi), ten patients with proven myocardial infarction were studied. While imaging of transmural infarctions in humans was achieved using Tc-99m DMSA, scores for the Tc-99m DMSA images (1.8 +/- 0.96) were not as high as for Tc-99m PPi (2.5 +/- 0.45) (P less than 0.05). Discordance among four independent interpreters was greater for images obtained with Tc-99m DMSA. The superiority of Tc-99m PPi was evident whether images were obtained early (within 24 hours) or late (within five days). Although DMSA images were not obscured by rib uptake, they were less sensitive (63%) than Tc-99m PPi (97%). A potential advantage of Tc-99m DMSA in imaging acute myocardial infarction is that radiotracer concentration in the infarct occurs primarily in the early postinfarction period. The longer postinfarction that Tc-99m DMSA imaging was attempted, the lower the concentration of radiotracer. Thus, Tc-99m DMSA would not be expected to have the same persistence pattern as Tc-99m PPi into the remote postinfarction period. The persistent positivity of Tc-99m PPi has made it difficult to diagnose reinfarction.

Aged↗

Gated technetium-99m methoxy-isobutylisonitrile perfusion imaging.

Technetium-99m methoxy-isobutylisonitrile, has been shown to be a useful perfusion agent for detecting coronary artery disease. Gated acquisition of perfusion images may remove motion artefact and improve detection. We compared the results of sensitivity and specificity for detecting coronary artery disease using perfusion images from the whole cardiac cycle (ungated) or from end-diastolic (gated) frames in 46 subjects, 31 with significant coronary disease and 15 with normal coronary arteries. There was no significant difference in detection of patients with coronary disease between the ungated and end-diastolic images: 25/31 with the ungated image and 28/31 with the end-diastolic. An improvement was made in detecting defects in the left anterior descending artery territory: 17/20 with the end-diastolic vs 11/20 with the ungated image (P less than 0.05) and in the right coronary artery region: 16/21 vs 10/21 (P less than 0.05), with an overall improvement in detecting regions supplied by stenosed coronary arteries: 45/55 end-diastolic vs 31/55 ungated (P less than 0.01). These results suggest use of the end-diastolic frame can significantly enhance the diagnostic capacity of methoxy-isobutylisonitrile perfusion imaging.

Adult↗

Value of technetium Mibi to detect short lasting episodes of severe myocardial ischaemia and to estimate the area at risk during coronary angioplasty.

201Tl has been used for more than a decade in cardiology in spite of its physical properties, which are far from ideal. Other agents, with better physical characteristics, are desirable. Tc99m Mibi has become available. It is different from 201Tl not only because of a better energy, 140 (keV), shorter half-life (6 h), but also because it shows minimal redistribution; it can therefore be administered in a different location from where the nuclear investigation can be performed. In this study, we investigated the value of Tc99m Mibi to detect short-lasting episodes of ischaemia and to determine the area at risk during PTCA, by injecting the substrate in the catheterization laboratory during the first balloon inflation. The 13 patients studied, had single vessel disease, a normal resting ECG and a normal left ventricular contraction pattern. In eight, a PTCA was performed in the LAD, in three, in the circumflex, and in two, in the RCA. In 11 patients, a defect was seen in the single photon emission computer tomography images, which corresponds to the area supplied by the coronary artery, where flow was obstructed during PTCA. Tc99m Mibi is able to detect short-lasting episodes of ischaemia caused by a complete occlusion of the coronary artery. It is also of help to estimate the area at risk during PTCA.

Adult↗

Radionuclide measurement of differential glomerular filtration rate in urinary tract obstruction.

In a previous study using dogs whose renal function was rendered asymmetric by unilateral infarction, the efficacy of technetium-99m (99mTc) DTPA and DMSA in measuring differential glomerular filtration rate (GFR) was demonstrated. The present study was undertaken to determine whether the same techniques were applicable to unilateral ureteral obstruction. Five normal dogs and nine dogs with partial unilateral ureteral obstruction had determination of glomerular filtration rate by standard techniques using constant infusions of iothalamate and creatinine after ureteral catheterization. These results were compared with total GFR as measured by single injection of 99mTc DTPA and analysis of the plasma disappearance curve. Calculated differential GFR was obtained by multiplying total GFR from double exponential analysis of this curve (DTPA2) by each of three measures of differential function. These included the percent differential uptake of 99mTc DTPA and 99mTC DMSA in the posterior projection as well as the geometric mean of 99mTc DMSA uptake. There were good correlations between differential GFR determined by iothalamate clearances at ureteral catheterization and all noninvasive methods involving radionuclides and DTPA2 ( r = 0.93-0.99). Single exponential analysis of the 99mTc DTPA plasma disappearance curve was less satisfactory than double exponential analysis. These results and those reported previously support the use of radionuclides in the determination of differential GFR in a variety of clinical situations.

Animals↗

Pharmacokinetic evaluation of technetium-99-metallothionein-conjugated mouse monoclonal antibody B72.3 in rhesus monkeys.

These studies were conducted to determine the biodistribution and pharmacokinetics of [99mTc]metallothionein-conjugated B72.3 ([ Tc]MT-B72.3) in Rhesus monkeys (Macaca mulatta) that were performed as part of the preclinical evaluation of [Tc]MT-B72.3. The B72.3-MT conjugate was studied at three doses of B72.3 ranging from 0.03 mg/kg to 1 mg/kg to determine whether a relationship existed between the dose of total antibody administered intravenously and the biodistribution and clearance of the radiolabeled protein. Results indicated that [Tc]MT-B72.3 distributes rapidly to central body cavity organs and that there was no difference in the rate of blood elimination for the three doses of B72.3 studied. The terminal phase of blood elimination was found to be 26.2 +/- 6.1 hr for the combined groups of monkeys. Approximately one-half of injected 99mTc activity was recovered in the urine within 24 hr. A second purpose of these studies was to evaluate the overall immunogenicity of the mouse monoclonal B72.3 IgG1 antibody in Rhesus monkeys. These results demonstrated that a single i.v. exposure to mouse monoclonal B72.3 at doses of 0.3 mg/kg or greater elicited antibody production to B72.3 in Rhesus monkeys within 3 wk. Analysis of [Tc]MT-B72.3 biodistribution and clearance in monkeys with circulating levels of antibodies to B72.3 (immunized monkeys) revealed that the liver was the primary site of clearance of the presumed immune complex and that blood elimination was greatly accelerated.

Animals↗