Evolution of Tc-99m in diagnostic radiopharmaceuticals

The progress in diagnostic nuclear medicine over the years since the discovery of 99mTc is indeed phenomenal. Over 80% of the radiopharmaceuticals currently being used make use of this short-lived, metastable radionuclide, which has reigned as the workhorse of diagnostic nuclear medicine. The preeminence of 99mTc is attributable to its optimal nuclear properties of a short half-life and a gamma photon emission of 140 keV, which is suitable for high-efficiency detection and which results in low radiation exposure to the patient. 99mTcO4-, which is readily available as a column eluate from a 99Mo/99mTc generator, is reduced in the presence of chelating agents. The versatile chemistry of technetium emerging from the 8 possible oxidation states, along with a proper understanding of the structure-biologic activity relationship, has been exploited to yield a plethora of products meant for morphologic and functional imaging of different organs. This article reviews the evolution of 99mTc dating back to its discovery, the development of 99Mo/99mTc generators, and the efforts to exploit the diverse chemistry of the element to explore a spectrum of compounds for diagnostic imaging, planar, and single photon emission computed tomography. A brief outline of the 99mTc radiopharmaceuticals currently being used has been categorically presented according to the organs being imaged. Newer methods of labeling involving bifunctional chelating agents (which encompass the "3 + 1" ligand system, Tc(CO)3(+1)-containing chelates, hydrazinonicotinamide, water-soluble phosphines, and other Tc-carrying moieties) have added a new dimension for the preparation of novel technetium compounds. These developments in technetium chemistry have opened new avenues in the field of diagnostic imaging. These include fundamental aspects in the design and development of target-specific agents, including antibodies, peptides, steroids, and other small molecules that have specific receptor affinity.     

Development of technetium-99m-based CNS receptor ligands: have there been any advances?

By virtue of its ideal nuclear physical characteristics for routine nuclear medicine diagnostics and its ready availability, technetium-99m is of outstanding interest in the development of novel radiopharmaceuticals. The potential for the development of 99mTc-based radioligands for the study the receptor function in the central nervous system (CNS) is also well recognised despite the difficulties to be overcome. A fundamental challenge is the pharmacologically acceptable integration of the transition metal technetium, with its specific coordination chemistry, into the molecular entity of CNS receptor ligands. Conceptually, the ligand molecule can be assembled by three building blocks: a small neutral chelate unit, an organic linker that may also serve as a pharmacological modifier and a receptor-binding region derived from selective receptor antagonists. The recent introduction of novel technetium chelate units, particularly mixed-ligand complexes and low-valency organometallic compounds of technetium, provides an impetus for the further development of CNS receptor ligands. Moreover, progress in receptor pharmacology and the experience gained with positron emission tomography radiotracers have facilitated the design of numerous 99mTc-based CNS receptor ligands. The formidable challenge of developing 99mTc probes as single-photon emission tomography imaging agents targeting CNS receptors can be viewed with optimism given the successful development of [99mTc]TRODAT-1 as a 99mTc complex for imaging dopamine transporters in the brain, although there are a number of receptor-specific imaging agents that have so far resisted all efforts to develop them. This review presents recent advances and discusses the remaining hurdles in the design of 99mTc-based CNS receptor imaging agents.     

Newer methods of labeling diagnostic agents with Tc-99m

The past several years have seen marked advances in technetium/rhenium chemistry applicable to the preparation of new 99mTc-labeled radiopharmaceuticals. This article focuses on recent developments in technetium chemistry, including the preparation of "3 + 1" complexes, the preparation and use of (99mTc[CO]3)+ complexes for labeling biomolecules, the preparation of rhenium steroid inclusion complexes, improvements in both hydrazinonicotinamide labeling chemistry and in the preformed 99mTc complex method of labeling biomolecules, and new solid-phase separation techniques that may allow the isolation of high specific-activity radiopharmaceuticals in a clinical setting.     

Technetium-99m radiopharmaceutical preparation by surface adsorbed stannous ions

A method of producing technetium-99m (99mTc) radiopharmaceuticals is described, where reduction of pertechnetate occurs through stannous ions adsorbed on the surface of an infusion catheter. This leads to radiopharmaceuticals containing microgram quantities of stannous ions and that, therefore, results in minimal blood-pool labeling and essentially the elimination of tin colloids. Other advantages of the method include a reduction in quantities of ligand required and the possibility to mass produce the "tinned" catheters as technetium "reduction" kits. A wide variety of 99mTc radiopharmaceuticals have been prepared in high yield. Excellent biodistribution in several of these is demonstrated.     

Microautoradiographic study of technetium-99m colloid uptake by the rat liver

A new microautoradiographic technique was developed to study the distribution of 99mTc-labeled radiopharmaceuticals. Using a thick emulsion, it is possible to get microscopically visible tracks of internal conversion and Auger electrons. The liver uptake of microscopic particles has been thought to occur in Kupffer cells but no direct evidence has been provided for technetium colloids. Using this method, 99mTc-labeled colloids were clearly identified in Kupffer cells in the sinusoidal areas of liver. "Track" microautoradiography using a thick emulsion layer may be used on any frozen tissue sections and may provide an important tool to assess the biodistribution of 99mTc radiopharmaceuticals.     

Detection of endotoxins in radiopharmaceutical preparations--III. Limulus test assessment using radiopharmaceutical preparations; correlation with the rabbit pyrogen test

Experiments using 17 radiopharmaceuticals containing known amounts of added endotoxin show that none of them inhibits the pyrogenic reaction of the rabbit. Gelation of the Limulus amoebocyte lysate (LAL) is inhibited by 4 of them: colloidal erbium 169Er citrate, colloidal rhenium 186Re sulfide, colloidal technetium 99mTc (Re) sulfide for liver scintigraphy and the colloidal technetium 99mTc (Re) sulfide for lymphography. This inhibition is cancelled, either by dilution or after neutral pH adjustment. Both controls were performed on 313 batches of various radiopharmaceuticals, 95% of results were identical (93% negative, 2% positive). The remaining 5% correspond to positive LAL tests vs negative rabbit tests on the same batches. No negative LAL test vs positive rabbit test was observed.     

Nitroimidazole radiopharmaceuticals in bioimaging: part I: synthesis and imaging applications

The paper is review on synthesis of nitroimidazole radiosensitizers useful in imaging of tumor cells. Nitroimidazole compounds are radiolabeled probes for specific use in imaging such as 18F for positron emission tomography; 99mTc for single photon emission computed tomography; 123I, or 131I for computer assisted tomography and 19F for magnetic resonance imaging. In synthesis of radiopharmaceutical compounds, parent nitroimidazole is modified to thiopyranosyl nucleosides, neuraminic acid derivatives followed by nitro group deprotection-substitution and radiolabeling by specific isotopes. Commercial attempts have been made to radiolabel the nitroimidazole by [18F]fluorine, [131I or 123I]iodine, [99mTc]technicium and [64Cu]copper on modified side chain of nitroimidazole compounds to design multimodal and multifunctional imaging techniques to detect and monitor the tumor hypoxia by measuring distribution of radiatiolabel or radiation. Nitroimidazole initially showed poor diffusion and poor stability in tissues with neurotoxicity concern limited its use as radiosensitizer. In last decade, several nitroimidazole derivatives were developed as potent less toxic and highly stable radiopharmaceuticals with optimized radiolabel concentration with high detectability of tumor oxygen or hypoxia. Currently, nitroimidazole based radiopharmaceuticals have emerged as multimodal and multifunctional hypoxia reporters with antitumor, anti-ischemic, anti-inflammatory and tumor targeting properties. In conclusion, nitroimidazole based radiopharmaceuticals are a new generation hypoxia biosensors for localized theradiagnostic utility in clinical medicine.     

Evaluation of formamidine sulfinic acid and other reducing agents for use in the preparation of Tc-99m labeled radiopharmaceuticals.

Various reducing agents have been evaluated for their potential usefulness in the preparation of 99mTc labeled radiopharmaceuticals for use in nuclear medicine. Adequate labeling of various radiopharmaceuticals was accomplished using formamidine sulfinic acid. Nitrogen-purging of solutions is not required, which is an advantage for in-house preparation. Tagging requires heating, however, so heat-labile material cannot be used. Various compounds that could not be labeled when stannous chloride was used, could be tagged with 99mTc when formanidine sulfinic acid was used as the reducing agent.     

[<Superscript>99m</Superscript>Tc]Demotate,a new <Superscript>99m</Superscript>Tc-based [Tyr<Superscript>3</Superscript>]octreotate analogue for the detection of somatostatin receptor-positive tumours: synthesis and preclinical results

Demotate is a new tetraamine-functionalised [Tyr3]octreotate derivative that binds technetium-99m with a high efficiency under mild conditions. The resulting radioligand, [99mTc]Demotate, forms in a high purity and is stable for at least 6 h after labelling. The affinity of the unlabelled peptide for somatostatin receptors is high (IC(50)=0.13 n M) and comparable to that of [Tyr3]octreotate or [Tyr3]octreotide, as demonstrated by competition binding experiments in rat brain cortex or AR42J cell membrane preparations. An equally very high affinity ( K(d)=0.07 n M) was exhibited by [99mTc/99gTc]Demotate during saturation binding experiments using rat brain cortex membrane homogenates. The radioligand resisted hydrolytic degradation in mouse plasma and was excreted intact in mouse urine. In vivo, [99mTc]Demotate cleared very rapidly from non-target tissues into the bladder via the kidneys, while radioactivity uptake in target organs was very high. In mice bearing the experimental AR42J tumour, [99mTc]Demotate demonstrated a very high tumour uptake at 1 h p.i. (25%ID/g) that remained high (20%ID/g) at 4 h p.i. This uptake could be effectively blocked by co-injection of a high dose of [Tyr3]octreotate together with the radioligand. High-quality planar and single-photon emission tomographic images were acquired 1 h after injection of [99mTc]Demotate in tumour-bearing mice, illustrating the excellent properties of this agent for somatostatin receptor tumour imaging.     

An evaluation of six kits of technetium 99m human serum albumin injection for cardiac blood pool imaging.

We have investigated the suitability of five different commercially available kits which provide human serum albumin (HSA) labelled with technetium 99m (99mTc) for cardiac blood pool imaging. Four of these products were one-step processes using stannous chloride as the reducing agent; the fifth was based on an electrolytic reduction. In addition, we also assessed our own modification of the electrolytic method. We measured the radiochemical purity by precipitation with trichloroacetic acid and by gel filtration on a Biogel P4 column. In addition, we measured the clearance of radioactivity from the blood at frequent time intervals after intravenous injection. Each product was assessed in separate groups of six patients. The labelling efficiency of the one-step kits varied between 73 and 93% compared with 94 and 98% for the electrolytically labelled albumin. The blood clearance for all one-step kits was significantly faster than that obtained for the radiopharmaceuticals prepared by the electrolytic method. We conclude that HSA labelled with 99mTc by the electrolytic method is to be preferred.     

Utility of<Superscript>99m</Superscript>Tc dextran scintigraphy in diabetic patients with suspected osteomyelitis of the foot

PURPOSE: Osteomyelitis of the foot is a frequent complication of diabetes mellitus and its diagnosis is often difficult. The goal of this study was to demonstrate the utility of 99mTc dextran scintigraphy in suspected diabetic foot infections. MATERIALS AND METHODS: Twenty-six patients (20 males, 6 females, age range 18-80 years) with diabetes mellitus who had a total of 36 foot ulcers or necrosis were studied. All the patients underwent both three phase bone scan and 99mTc dextran scintigraphy. Final diagnosis was based upon either pathologic examination or clinical follow-up at least four months. RESULTS: On bone scan increased uptake was seen in 55 sites, and among these there were 11 lesions of proven osteomyelitis. There were 11 true-positive, 0 false negative, 0 true negative and 44 false positive results for bone scan. The sensitivity, specificity and accuracy of bone scan were 100%, 0% and 20%, respectively. With regard to 99mTc dextran scan, nine lesions produced true-positive results with two lesions indicating false negatives resulting in a sensitivity of 82%. Thirty-six true negative and eight false positive results produced a specificity of 82%, and an accuracy 82% from 99mTc dextran studies was obtained. Eight false-positive results were possibly due to neuroarthropathy, pressure points and deep penetrating ulcers. A patient with one false-negative result had angiopathy while other had neither neuropathy nor angiopathy. CONCLUSIONS: According to these results, 99mTc dextran scintigraphy seems to be a sensitive and specific diagnostic method, and because of its advantages over other radiopharmaceuticals (shorter preparation time, highly stability in vivo/in vitro, early diagnostic imaging and low cost), it may be a radiopharmaceutical of choice for diagnosing in diabetic foot infections.     

Excretion of technetium 99m hexakismethoxyisobutylisonitrile in milk

The amount of radioactivity excreted in breast milk following the administration of technetium 99m hexakismethoxyisobutylisonitrile (99mTc-MIBI) to a patient referred for cold spot myocardial scintigraphy was determined. During the first 24 h after administration, only 41.2 kBq 99mTc (0.0084% of the injected dose) was excreted in 448 ml milk with the highest concentration of 0.49 kBq/ml in the first sample. The images obtained show a high concentration of 99mTc-MIBI in the lactating breasts contrary to the very small percentage excreted in the milk. Comparison with various recommendations regarding nursing after administration of radiopharmaceuticals seems to indicate that the administration of 99mTc-MIBI does not necessitate an interruption of breast-feeding.     

The use of the effective dose equivalent, HE, for 99mTc labelled radiopharmaceuticals

Using the concept of effective dose equivalent, HE, it is shown that a knowledge of the detailed biodistribution data in most organs and tissues taking up 99mTc labelled radiopharmaceuticals is unnecessary for the calculation of radiation risk. Reasonably precise dosimetry (+/- 25%) can be obtained from urine excretion data alone providing there is no significant uptake within the gonads or the thyroid. Special attention should only be paid to absorbed dose measurements in red bone marrow, skin, lungs, gonads and thyroid, with the greatest attention directed toward the retention and dosimetric aspects of radioactivity in the latter two organs. An example HE calculation for 99mTc labelled d,1-HMPAO is presented to illustrate the importance of these specific five organs to radiation risk.     

Graphical analysis of<Superscript>99m</Superscript>Tc thyroid scintigraphy

A new non-invasive simple method for quantitative evaluation of thyroid was presented using graphical analysis of the transfer process of technetium-99m pertechnetate (99mTc) from the blood to thyroid. Thirty subjects were studied. After a bolus injection of 111 MBq of 99mTc, the data were recorded on a 128 x 128 matrix as 60 frames of 1.5-second duration. ROIs were placed over the aortic arch and bilateral thyroid lobes. The activity of the aorta was monitored instead of the arterial activity. Graphical analysis by plotting B(t)/A(t) versus integral(0)t A(tau)d tau/A(t) gave a straight line within the first 30 seconds in all subjects. The slope of the line was the unidirectional influx rate of 99mTc (k(u)). Thyroid perfusion index (TPI) was calculated to standardize where the ratio of ROI(thyroid) size to ROI(aorta) size was set as 10. K(u) and TPI showed good correlation with 99mTc thyroid uptake. Hyperthyroid patients showed high values of k(u) and TPI. Considering that these indices were determined at the first pass of 99mTc, this method may be helpful especially in the evaluation of thyroid perfusion.     

Cationic complexes of technetium for myocardial imaging

Over the past 15 years a major goal of research in cardiovascular nuclear medicine has been the development of 99mTc complexes that could replace 201Tl and thus enhance the utility of myocardial perfusion imaging. This paper presents an overview of the current state-of-art of the development of cationic 99mTc complexes for this purpose. Cationic 99mTc complexes that have been evaluated as myocardial perfusion imaging agents in human volunteers and/or animals are discussed and classified on the basis of the oxidation state of the technetium center.     

Technetium 99m sestamibi in the assessment of chronic coronary artery disease.

Extensive work has already been performed with regard to both planar and single photon emission computed (SPECT) technetium 99m sestamibi studies. Before widespread application of optimized acquisition and processing methods, clinical results between 99mTc sestamibi and thallium 201 were remarkably similar. It is anticipated that as techniques for 99mTc sestamibi planar and SPECT imaging become optimized, improvements in sensitivity and specificity for detection of coronary artery disease, over those observed with 201TI, might be forthcoming. This expectation is based on the improved image quality inherent in the use of the 99mTc agent with its higher count rate and higher energy. This improvement in image quality may be a principal reason for laboratories to switch from 201TI to 99mTc sestamibi imaging. It is anticipated that, with improved imaging characteristics, it will be easier for the average community hospital to obtain higher quality planar or SPECT imaging using 99mTc sestamibi rather than 201TI. In addition to improved image quality, the characteristics of 99mTc sestamibi allow gated planar or SPECT perfusion images to be obtained. It has been suggested that stress-gated SPECT sestamibi studies may provide all the information contained in a stress-rest nongated 99mTc sestamibi study, thereby potentially increasing patient throughput, a major concern with SPECT. Throughput can also be increased by using dual-isotope approaches with rest 201TI and stress technetium sestamibi acquisitions, employing either separate or simultaneous imaging with which the entire study can be accomplished in less than 2 hours. With simultaneous dual-isotope acquisition, camera time can be reduced by 50%. Finally, 99mTc sestamibi offers the advantage of the ability to perform first-pass exercise ventricular function and SPECT myocardial perfusion studies with a single injection of tracer. Regarding the assessment of myocardial viability, results to date suggest a very high degree of concordance between 201TI and 99mTc sestamibi studies using either planar or SPECT acquisition techniques. Correlative rest studies with both tracers will be of particular interest, as will preoperative and postoperative and position emission tomography correlation studies.     

Rapid determination of oxidation state of unbound 99mTc and labeling yield in 99mTc-labeled radiopharmaceuticals.

Current techniques for determining the radiochemical purity of 99mTc-labeled radiopharmaceuticals are limited by the variety of compounds that can be tested or the length of time required to complete the test. A chromatographic method, based on the use of two solvents (0.9% saline and acetone) and a stationary phase made of silica-coated cellulose strips, solves these problems for water-soluble 99mTc-labeled radiopharmaceuticals. With this method, the oxidation state of unbound 99mTc and the labeling yield of 99mTc-labeled radiopharmaceuticals can be quickly determined: the whole procedure takes only a few minutes to run. This system compares favorably with lengthier procedures and with a commercially available kit.     

Current and future radiopharmaceuticals for brain imaging with single photon emission computed tomography

Development of radiopharmaceuticals for functional brain imaging has progressed rapidly in recent years. Measurement of regional cerebral blood flow in humans can be achieved by using [123I]-iodoamphetamine or [99mTc]-HMPAO. Several other lipid-soluble [99mTc]-technetium complexes are currently undergoing clinical trials. New 123I-labeled agents designed to measure central nervous system receptors, including D1 and D2 dopamine, serotonin, muscarinic, and benzodiazepine receptors, have been developed. In conjunction with single photon emission computed tomography, they may provide useful tools to evaluate brain function related to changes in receptor concentration.     

A neutral technetium-99m complex for myocardial imaging

Technetium-99m-CDO-MeB [Bis[1,2-cyclohexanedione-dioximato(1-)- O]-[1,2-cyclohexanedione dioximato(2-)-O]methyl-borato(2-)- N,N',N',N',N',N'')-chlorotechnetium) belongs to a family of compounds generally known as boronic acid adducts of technetium dioxime complexes (BATOs). It has an intrinsic affinity for the myocardium, with negligible lung activity and rapid blood clearance. The uptake of 3.44% ID in rat heart at 1 min postinjection for [99mTc]CDO-MeB versus 3.03% for 201TI indicates high extraction of [99mTc]CDO-MeB by the myocardium. In dogs an ischemic defect is clearly seen in SPECT images obtained 10 min after injection of [99mTc]CDO-MeB. Tissue distribution data in rats show that [99mTc]CDO-MeB is excreted primarily in the feces and to a lesser extent in the urine. Approximately 80% of the activity is excreted within 24 hr after injection.     

Use of myocardial imaging agents for tumour diagnosis--a success story?

The search for new radiopharmaceuticals for tumour diagnosis usually proceeds on the basis of rational concepts drawing on the latest advances in molecular biology. Using this approach, radioactive peptide hormones, antibodies and oligonucleotides have been developed that are used increasingly in nuclear medicine for diagnostic and therapeutic purposes. This article, however, focusses on a group of radiopharmaceuticals whose use in tumour diagnosis was not the outcome of a methodical development programme but rather the result of a chance discovery. These radiopharmaceuticals, thallium-201 and technetium-99m labelled 2-methoxyisobutylisonitrile (MIBI), tetrofosmin and furifosmin, were first developed through extensive research efforts for cardiac imaging, but during their worldwide application for myocardial scintigraphy they were accidentally found to accumulate in tumours. Intensive studies were then begun on cell cultures in an attempt to discover the cause of their uptake into tumours. The aim was to compare the effectiveness of the radiopharmaceuticals for tumour diagnosis in a range of indications and to investigate the various mechanisms by which they are taken up into tumours. While the more favourable radiophysical properties of 99mTc-MIBI render it superior to 201Tl for many diagnostic purposes, neither 99mTc-tetrofosmin nor 99mTc-furifosmin has yet proved suitable for clinical routine examinations, although the former has found limited application. In the case of 99mTc complexes, the breakthrough came with the experimental finding that these substances are substrates of P-glycoprotein, a product of the human multidrug resistance gene (MDR1). The concentration of 99mTc complexes in tumour cells is a function of a passive, membrane potential-dependent influx into and a P-glycoprotein-controlled efflux out of the tumour cell. Preliminary studies suggest that in vivo detection of MDR may even be possible. There is also evidence that the P-glycoprotein-mediated transport system can be blocked competitively. However, it will be some time before a system can be developed for detection of MDR on a routine basis.