Initial Evaluation of 99mTc(CO)3(ASMA) as a Renal Tracer in Healthy Human Volunteers

Purpose

Preclinical studies in rats showed that two of ^99mTc(CO)₃(ASMA) isomers (rac- and L-ASMA) had pharmacokinetic properties equivalent to that of ¹³¹I-OIH, the radiopharmaceutical standard for the measurement of effective renal plasma flow. The aim of this study was to evaluate the pharmacokinetics of ^99mTc(CO)₃(ASMA) isomers in healthy human subjects.

Methods

Three ASMA ligands (rac-, L- and D-ASMA) were labeled with ^99mTc(CO)₃ using an IsoLink kit (Covidien), and each formed ^99mTc(CO)₃(ASMA) tracer was co-injected with ¹³¹I-OIH into healthy human subjects followed by sequential imaging, plasma clearance measurements and timed urine collection. Plasma protein binding, red cell uptake and percent injected dose in the urine were determined. Urine from each group of volunteers was analyzed for metabolites by HPLC.

Results

Image quality was excellent with all three agents. Each ^99mTc(CO)₃(ASMA) preparation was excreted unchanged in the urine. The plasma clearance ratio (^99mTc(CO)₃(ASMA)/¹³¹I-OIH) was 81 ± 3 % for D-ASMA compared to only 20 ± 4 % for L-ASMA and 37 ± 7 % for rac-ASMA; the 81 % clearance ratio for D-ASMA isomer is still ∼ 30 % higher than the ^99mTc-MAG3/¹³¹I-OIH clearance ratio (∼50-60 %). Red cell uptake was similar for all three tracers (6-9 %), and all tracers had a relatively rapid renal excretion; at 3 h, the ^99mTc(CO)₃(ASMA)/¹³¹I-OIH urine ratio was 100 ± 3 % for D-ASMA, 80 ± 2 % for L-ASMA and 88 ± 1 % for rac-ASMA.

Conclusions

The renal excretion characteristics of ^99mTc(CO)₃(D-ASMA) in humans are superior to those of the other two ^99mTc(CO)₃(ASMA) isomers studied, but are still inferior to ¹³¹I-OIH, even though there was no difference in the clearance of two of ^99mTc(CO)₃(ASMA) isomers and ¹³¹I-OIH in rats. The work described here demonstrates the sensitivity in in vivo biological behavior of ^99mTc(CO)₃(ASMA) isomers to their subtle structural differences.     

A micro-autoradiographical study of the localization of 99mTc(Sn)-MDP and 99mTc-MDP in undecalcified bone sections

The localization of ^99mTc(Sn)-MDP in bone tissue was compared with ^99mTc-MDP by means of microautoradiography of undecalcified bone sections. Sections of good histological quality were obtained by a rapid embedding method in methylmethacrylate. No differences were found in the localization of these radiopharmaceuticals in fetal rat calvariae after incubation in vitro or in rat femora after administration in vivo. In the incubation experiment, hydrolyzed ^99mTc was formed. The uptake was high in areas of new bone formation. No uptake was seen in cells or in resorbing areas. In compact bone ^99mTc(Sn)-MDP was predominantly taken up in the vicinity of blood vessels.     

The Clinical Usefulness of 99mTc HMPAO Leukocyte/99mTc Phytate Bone Marrow Scintigraphy for Diagnosis of Prosthetic Knee Infection: A Preliminary Study

Purpose

The preferred radionuclide imaging procedure for diagnosing prosthetic joint infection is combined radiolabeled leukocyte/^99mTc sulfur colloid bone marrow scintigraphy, which has an accuracy of over 90 %. Unfortunately, sulfur colloid is no longer available in South Korea. In this study, we evaluated the usefulness of ^99mTc phytate, a substitute for ^99mTc sulfur colloid, when combined with radiolabeled leukocyte scintigraphy in suspected prosthetic knee infections.

Methods

Eleven patients (nine women, two men; mean age 72 ± 6 years) with painful knee prostheses and a suspicion of infection underwent both ^99mTc HMPAO leukocyte scintigraphy (LS) and ^99mTc phytate bone marrow scintigraphy (BMS). The combined images were interpreted as positive for infection when radioactivity in the LS at the site of clinical interest clearly exceeded that of the BMS (discordant); they were interpreted as negative when the increased activity in the LS was consistent with an increased activity in the BMS (concordant). The final diagnosis was made with microbiological or intraoperative findings and a clinical follow-up of at least 12 months.

Results

Five of eleven patients were diagnosed as having an infected prosthesis. The overall sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and diagnostic accuracy of the combined LS/BMS were 100 %, 83 %, 83 %, 100 % and 91 %, respectively.

Conclusion

We find that combined ^99mTc HMPAO LS/^99mTc phytate BMS shows comparable diagnostic performance to other studies utilizing sulfur colloid. Combined ^99mTc HMPAO LS/^99mTc phytate BMS is therefore expected to be an acceptable alternative to combined radiolabeled LS/^99mTc sulfur colloid BMS for diagnosing prosthetic knee infections.     

Clinical evaluation of 99mTc(V)-dimercapto succinic acid (DMSA) for imaging medullary carcinoma of thyroid and its metastasis

^99mTc(V)-DMSA kits developed by the Radiopharmaceutical Division, Bhabha Atomic Research Centre, have been evaluated for potential use in scanning medullary carcinoma of the thyroid and its metastases. There were 15 patients with proved medullary carcinoma and 6 patients with other differentiated thyroid carcinoma. Amongst the 15 patients with medullary carcinoma, 12(80%) showed positive localisation either in the primary or one or more metastatic sites. None of the six patients with carcinoma other than medullary showed increased concentration of ^99mTc (V)-DMSA. Of the 37 known metastatic sites in 15 patients with medullary carcinoma, 24 showed concentration of ^99mTc (V)-DMSA (64.9%). In addition, ^99mTc(V)-DMSA concentration was seen in 14 sites where no evidence of metastasis was revealed. The incidence of ^99mTc (V)-DMSA concentration in soft tissue and bone metastasis was similar.Isopharm, Radiopharmaceutical Division, BARC, Bombay-400 705, India     

99mTc(V)-DMSA seintigraphy in monitoring the response of bone disease to vitamin D3 therapy in renal osteodystrophy

Renal osteodystrophy (ROD) is a common and serious complication for uremic patients and patients are treated with 1,25-dihydroxyvitamin D3. The bone scanning agent 99mTc-phosphate has also been used to evaluate in ROD but it is not clear that bone scintigraphy has a role in the follow-up of treatment. In this study 99mTc(V)-DMSA scintigraphy was performed in eleven patients [age 40.7 +/- 17.3 (mean +/- SD) yr] with ROD before and after vitamin D3 therapy. Images were obtained after hemodialysis performed following tracer injection to maintain normal blood levels of the radiopharmaceutical and to reduce soft tissue activity. Lumbar vertebra-to-soft tissue uptake ratios (LUR) were quantified with the planar 99mTc(V)-DMSA images. Alkaline phosphatase and parathyroid hormone levels after treatment had significantly decreased compared with pre-therapy. In all patients there was visually decreased uptake in bone structures after treatment. After treatment the mean LUR ratio was significantly lower than those of before treatment (3.59 +/- 2.63 vs. 1.65 +/- 0.62; p = 0.01). LUR values were correlated with pre-therapy alkaline phosphatase and parathyroid hormone. These findings indicate that 99mTc(V)-DMSA scintigraphy is sensitive in evaluating the response of ROD to vitamin D3 therapy.     

Preparation and evaluation of 99mTc(V)-DMSA complex: Studies in medullary carcinoma of thyroid

Consequent to the promising results reported with ^99mTc(V)-DMSA for imaging certain types of soft tissue tumors, we have developed methods to prepare this radiopharmaceutical in three ways:-(i) from freshly prepared reagents, (ii) through the use of a two component kit and (iii) use of the standard renal DMSA kit by a modified recipe. The ^99mTc(V)-DMSA complex has been subjected to paper electrophoretic and chromatographic procedures and also biodistribution studies. The distinctly different behaviour of this new product compared to that of the well known renal DMSA complex has been clearly established. Scintiimaging in a preliminary clinical trial in patients with medullary carcinoma of the thyroid has been encouraging.     

Isolation and labelling of human leukocytes with 99mTc

The role of the leukocyte isolation procedure on cell labelling with ^99mTc has been evaluated. Separation of leukocytes was performed by two procedures: (1) sedimentation on methyl cellulose, followed by discontinuous gradient centrifugation; (2) methyl cellulose sedimentation and hypotonic haemolysis of residual red blood cells. After washing the cells in saline and incubation with a stannous pyrophosphate agent, the leukocytes were labelled with 5–10 mCi ^99mTc. Procedure 1 gave a higher purity but lower recovery of polymorphonuclear leukocytes, and a minor contamination of red blood cells. ^99mTc labelling of cells was slightly more efficient with this method, probably due to the presence of red blood cells. Procedure 1 is recommended for in vitro studies on cell kinetics and procedure 2 is recommended for clinical use.     

Chemical,radiochemical, and radionuclide purity of eluates from different commercial fission99Mo/99mTc generators

Seven⁹⁹Mo/^99mTc generators (using fission⁹⁹Mo) obtained from seven different manufactures were studied in 1984 and 1985 to test the quality of the eluates. We present the findings concerning the elution efficiency, radionuclide purity,⁹⁹Mo breakthrough, radiochemical purity, pH, and aluminium content of the eluates. One generator was overloaded with⁹⁹Mo by about 40%, while one generator had^99mTc yields of only about 80%. The eluates generally (although with some exceptions) exhibited a high and satisfactory radionuclidic purity and good radiochemical purity. The low-level determination of⁹⁹Mo break-through using a commercially available dose calibrator with a⁹⁹Mo assay shiled indicated a misleadingly high⁹⁹Mo content. All of the eluates had pH values of between 5.0 and 5.5, and the aluminium content was always below the detection limit of 1 g per milliliter of eluate. The generators performed well and proved their capability of functioning as reliable sources of sodium pertechnetate Tc99m. In all cases, the pertechnetate produced met the requirements of the European Pharmacopeia.This report is based on work conducted within the scope of a research poject devised by the Ministry of the Interior of the Federal Republic of Germany (Hammermaier et al. 1985). The present report reflects the opinions of the authors and does not necessarily express the views of the Federal Ministry of the Interior     

Evaluation of a new leukocyte labeling procedure with 99mTc-HMPAO

A technique for labeling leukocytes with ^99mTc using hexamethylpropylene-amineoxime (HMPAO) was evaluated in vitro. The labeling procedure resulted in a cell bound fraction of radioactivity of 56% after ^99mTc incubation and 96% after 1 washing of cells. In the final cell suspension 84% of the radioactivity was attached to the polymorphonuclear (PMN) leukocytes constituting 94% of white cells. Only 5% was bound to residual red blood cells. The stability evaluated in autologous plasma showed a decline of cell bound activity from 96% to 84% over 3 h. The chemotactic function of PMN leukocytes was unaffected by the labeling procedure. These findings demonstrate that HMPAO, albeit cell unspecific, is efficient for labeling PMN leukocytes with ^99mTc. The stability of the labeling procedure is high and the technique does not affect cell function. No other current ^99mTc leukocyte labeling technique possesses all these qualities.     

Uptake of 99mTc labelled (Fab')2 fragments of monoclonal antibody 225.28S by a benign ocular naevus

Malignant melanoma is one of the most common primary intraocular neoplasms. Recently, ^99mTc radiolabelled (Fab')₂ fragments of monoclonal antibody 225.28S raised against cutaneous melanomas have been used for imaging uveal melanomas. We report here a case where uptake of radiolabelled antibody was observed in a choroidal melanoma of the right eye and a benign choroidal naevus of the left.     

Use of pertechnetate 99mTc for abdominal scanning in localising an ileal duplication cyst: case report and review of the literature

A 10-year-old boy presented with periumbilical postprandial pain and some melena. Physical examination was normal. All investigations were negative except a pertechnetate ^99mTc abdominal scan which showed a very large and horn-shaped focus of high activity in the right flank. An ileal duplication was resected. It was lined by antral gastric mucosa with a large ulcer. The patient was treated successfully. The abdominal pertechnetate scan is discussed. Offprint requests to: X. Marchandise     

Semiquantitative assessment of regional cerebral perfusion using 99mTc HM-PAO and emission tomography

A method for the relative quantification of ^99mTc-HM-PAO distribution in brain SPECT is described. The method, applied in 12 normal volunteers and 150 patients suffering from different cerebral diseases, uses circumferential profiles to quantify the relative radionuclide distribution in the brain tomograms as an angular function with the origin at the center of the brain slice.Abnormal ^99mTc-HM-PAO distribution is evaluated by comparing the count content of symmetrical selected parts of the profile curve and comparing each patient's profile with the corresponding limits of normal ones, determined from the pooled profiles of 12 normal subjects.This computerized method allows an accurate, reproducible and objective assessment of the relative HM-PAO distribution in the brain.     

Scintigraphic localization of occult gastrointestinal bleeding using a combination of 111In-labelled platelets and 99mTc sulphur colloid

Repeated scintigraphy was performed for 6 days after the injection of autologous ¹¹¹In-labelled platelets in a patient showing signs of recurrent occult gastrointestinal bleeding. Colonic activity was observed 142 h post injection, at which time a superimposed study using ^99mTc sulphur colloid pinpointed the source of bleeding in the transverse colon.     

Preparation and bioevaluation of a Tc-labeled chlorambucil analog as a tumor targeting agent

Chlorambucil belongs to a group of nitrogen mustards which are used for the treatment of variety of cancers. Hence, a chlorambucil derivative has been radiolabeled with [^99mTc(CO)₃(H₂O)₃]⁺ core and its efficacy as a tumor targeting agent has been evaluated. Radiochemical yield of the complex was >98% as observed by HPLC. The in vitro studies in MCF-7 breast cancer cells showed about 30% inhibition of the radiolabeled complex in presence of the cold chlorambucil derivative. Biodistribution studies in Swiss mice bearing fibrosarcoma tumor showed an uptake of 3.2±0.3% ID/g at 3 h.p.i.     

Diaphyseal medullary stenosis with pleomorphic malignant fibrous histiocytoma of the bone:99mTc hydroxymethylenediphosphonate and201Tl chloride scintigraphy findings

Diaphyseal medullary stenosis (DMS) is an extremely rare hereditary bone dysplasia, which was first described by Arnold in 1973. DMS has a high incidence of pleomorphic malignant fibrous histiocytoma (MFH). In this paper, we report the imaging findings of DMS with pleomorphic MFH of the bone, mainly describing 99mTc hydroxymethylenediphosphonate (HMDP) and thallium-201 (201Tl) chloride scintigraphy findings. On 99mTc HMDP scintigraphy, focal increased uptake area of the right femur corresponded to the area of bone marrow invasion of the tumor and bone infarction. The mechanism of the uptake of 99mTc HMDP to the extraosseous lesion was not clear. On 201Tl chloride scintigraphy, the increased uptake of the periphery of the mass seemed to reflect the aggressiveness of invasion and the cellularity.     

Synthesis and biodistribution of a novel [TcN(PNP5)(DMCHDTC)] complex as a potential myocardial perfusion imaging agent

The [^99mTcN(PNP5)(DMCHDTC)]⁺(DMCHDTC: 2,3-dimethyl cyclohexyl dithiocarbamate, PNP5:bis(dimethoxypropylphosphinoethyl)ethoxyethylamine) complex was synthesized through a ligand-exchange reaction. The two-step procedure involved the initial reaction of ^99mTcO₄⁻ with succinic dihydrazide (SDH) as a donor of nitride nitrogen atom (N³⁻) in the presence of stannous chloride dihydrate as reducing agent and propylenediamine tetraacetic acid (PDTA) as complexant, followed by the addition of the PNP5 ligand and the DMCHDTC ligand. The radiochemical purity (RCP) of the product was over 90% as measured by thin layer chromatography (TLC). No decomposition of the complex at room temperature was observed over a period of 6 h. Its partition coefficient indicated that it was a lipophilic complex. The electrophoresis results showed the complex was cationic. The biodistribution results in mice indicated that [^99mTcN(PNP5)(DMCHDTC)]⁺ was significantly retained into the heart. The heart uptake (ID%/g) was 14.47, 12.23 and 8.76 at 5, 30 and 60 min post-injection, respectively. The heart/liver, heart/lung and heart/blood ratios of the complex were 1.24, 3.62 and 23.05 at 60 min post-injection, suggesting it will be a potential myocardial imaging agent.     

The utilization of Tc-99m-TBI as a myocardial perfusion agent in exercise studies: Comparison with Tl-201 thallous chloride and examination of its biodistribution in humans

Twenty-four patients were studied with both ²⁰¹Tl-thallous chloride and ^99mTc-TBI scintigraphy following exercise. Comparison of the two agents in detecting segmental myocardial ischemia and scar was made in 18 patients with evidence of coronary artery disease on ²⁰¹Tl-thallous chloride scintigraphy. Agreement between the two studies was observed in 77% (125 of 162) of left ventricular segments, suggesting that ^99mTc-TBI can be used as a myocardial perfusion agent. Limitations were related to early high background activity from lungs and liver. The high lung activity and early myocardial redistribution within the 1st hour contributed to the failure of ^99mTc-TBI to detect 16 segmental defects seen in the immediate post-exercise thallous chloride scan. Persistently high liver activity additionally affected accurate interpretation in the left ventricular segments close to the diaphargm. Improvement in the accuracy of ^99mTc-TBI stress studies might be achieved with tomographic imaging to reduce the problem of background activity or by the development of ^99mTc-labeled isonitrile analogues with rapid lung and liver clearance.     

Can technetium 99m bisdiethylphosphinoethanebis-t butylisocyanide (99mTc-DEPIC) be used for routine radionuclide ventriculography?

Radionuclide ventriculography is a useful investigation in the evaluation of cardiac function. Generally, in vivo technetium 99m-labelled red blood cells (RBC) yield good quality images in ventriculography. However, it is widely believed that some drugs have an adverse effect on RBC labelling. Zanelli et al. (1987) developed a radiopharmaceutical (technetium 99m bisdiethylphosphinoethanebis-t-butylisocyanide,^99mTc-DEPIC) to obtain better results in patients using such drugs. We untertook a prospective study of 6 patients with cardiovascular and/or pulmonary disease using several kinds of drugs to evaluate imaging of the cardiac blood pool with^99mTc-DEPIC and in vivo labelled^99mTc-RBC. After injection, blood samples were taken, and gated equilibrium blood pool studies were performed. The radiochemical purity of the injected^99mTc-DEPIC varied from 76.4 to 93.6% (mean 86.4%, SD 5.7%). The protein (pre-albumin) binding was 100%. Biological half-life in blood varied from 3.3 to 4.7 h (mean 4.1 h, SD 0.5 h). For^99mTc-RBC no significant blood disappearance was seen for 8 h. The percentage of RBC-bound^99mTc varied from 96.9% to 98.3% (mean 97.0%, SD 0.5%) and was stable for at least 8 h. The heart-to-lung, heart-to-spleen, and heart-to-liver ratios were higher for^99mTc-RBC than for^99mTc-DEPIC. Furthermore,^99mTc-DEPIC showed a significant decline of the ejection fraction with time. Visually, the images with^99mTc-RBC were superior to those with^99mTc-DEPIC, especially a few hours after injection. According to our findings, in vivo labelling of^99mTc-RBC is still the method of choice for routine radionuclide ventriculography. The decline of the ejection fraction, the short blood half-life, and the intense liver uptake make^99mTc-DEPIC less suitable for this purpose.     

Initial experience with SPECT of the brain using 99mTc-hexamethyl-propyleneamine oxime (99mTc-HM-PAO)

A recently developed ^99mTc radiocompound, hexamethyl-propyleneamine oxime (^99mTc-HM-PAO) exhibits favorable properties for regional cerebral tomograms in man utilizing conventional instrumentation (SPECT). Planar and tomographic studies using a rotating gamma camera equipped with a high sensitivity, low energy, collimator were performed in 5 normal subjects and 20 patients suffering from different cerebral diseases. SPECT abnormalities observed in patients with CVD, brain tumors and hydrocephalus were compared with results from X-ray CT. Our preliminary study demonstrates the feasibility of assessing regional brain perfusion using SPECT and a ^99mTc radiopharmaceutical which is lipid soluble and has a high extraction fraction in the brain.     

The behavior of99mTc-hexamethylpropyleneamineoxime (99mTc-HMPAO) in blood and brain

^99mTc-hexamethylpropyleneamineoxime (^99mTc-HMPAO) is a reagent for scanning cerebral blood flow. We investigated how^99mTc-HMPAO changed in the blood and brain. The^99mTc-HMPAO, which was prepared by adding of^99mTcO _- ⁴ to HMPAO and Sn(II), consisted of primary and secondary complexes, reduced hydrolyzed^99mTc, and^99mTc0pertechnetate. The percentage of the primary complex in^99mTc-HMPAO decreased with time after preparation. The primary complex converted to the secondary one very rapidly in the presence of plasma. When^99mTc-HMPAO was injected into patients,^99mTc activity was immediately partitioned in the plasma fraction, with approximately 60% in whole blood. In plasma,^99mTc was found to be associated with proteins such as albumin and globulin.^99mTc trapped in red cells was not washed out with either plasma or saline. Biodistribution studies showed that the less lipophilic compounds of^99mTc-HMPAO could not pass through the blood brain barrier (BBB), and therefore did not accumulate in the brain. The results of gel chromatography and equilibrium dialysis indicated that no specific^99mTc binding protein was present in the brain. Considering the instability of^99mTc-HMPAO in vivo, we proposed that the speed at which the primary complex converted to the less lipophilic compounds was important in allowing^99mTc-HMPAO to pass through the BBB and to be fixed in the brain.