The element technetium (Z = 43), which is derived from the Greek word ' techni-kos' meaning artificial, is located in a central position in the periodic table and possesses 25 known isotopes ranging from 86 to 118 atomic mass units. All of the isotopes of technetium are radioactive having a wide range of different half-lives. These include short-lived isotopes such as 86mTc (t1/2 = 1.11 ms), 93mTc (t1/2 = 43.5 min) and 94Tc (t1/2 = 53min) and those with half-lives surpassing thousands of years like 97Tc (t1/2 = 2.6 x 106y), 98Tc (t1/2 = 4.2 x 106y) and 99Tc (t 1/2 = 2.1 x 105y).
The existence of technetium was predicted by Mendeleev in 1869 on the basis of trends in the periodic table. Mendeleev reported that the unknown element should be similar to manganese and gave it the name 'ekamanganese'. In 1925, an erroneous claim of the discovery of element 43, which was named masurium, was published.1 The actual discovery was published in 1937, when Perrier and Segre reported the isolation of element 43 from a sample of molybdenum that was bombarded with deuterons from the Berkeley cyclotron.2 The official naming of element 43 as technetium occurred just after the end of World War II.3
The discovery of this 'artificial' element prompted a search for natural sources of technetium. In 1956, Merrill showed that 99Tc existed in stellar matter prompting new theories into the production of heavy elements in stars.4 Later, in 1961, a terrestrial source of 99Tc was isolated in minute quantities from African pitchblende (a uranium-rich ore) by Kenna and Kuroda.5 The low natural occurrence of technetium impeded investigation of its chemistry because long-lived isotopes were only available at an exorbitant cost. Currently 99Tc, which is isolated in kilogram quantities as a by-product of 235U fission, is available at a cost of less than $100 (US) per gram.
The first report of nuclear isomerism by element-43 was by Segre and Seaborg in 1938.6 That isotope, 99mTc (t1/2 = 6.02 h, Eg = 141 keV), possesses ideal properties for medical radioimaging because the 7 emission is sufficiently energetic to allow for visualization of sites deep within the human body by scintillation cameras without exposing patients to high levels of ionizing radiation. The daughter of 99mTc, the long-lived emitter 99Tc (Emax = 293.6 keV), also does not contribute significantly to the overall radiation dose. A further attraction to 99mTc is the half-life of 6 h, which provides sufficient time for labeling, administration and biodistribution without having to use excessive amounts of radioactivity to compensate for losses due to radioactive decay. The long half-life also provides the opportunity to perform protracted imaging studies, which can take up to several hours, without having to significantly increase the injected dose.
An important invention that made 99mTc widely available to all hospitals is the 99Mo/99mTc generator, which was developed at the Brookhaven National
Laboratory in the late 1950s.7 99Mo/99mTc generators are based on the decay of the parent 99Mo to 99mTc which occurs with 87.5% efficiency,8 the other principal pathway being direct decay to the isomer, 99Tc. 99Mo/99mTc generators contain high specific activity 99Mo (E^ — max = 1.36 MeV, t1/2 = 66.0 h), which is adsorbed onto an alumina (Al2O3) column as molybdate (MoO|—). Flushing the column with a 0.9% saline (0.15 M NaCl) solution results in the selective elution of 99mTc as 99mTcO—. The parent 99MoO2— remains bound to the column. The attractiveness of the generator lies in the fact that it provides a closed, self-shielded system for the production of sterile, non-pyrogenic and isotonic solutions of 99mTcO—. Generators are routinely shipped, typically on a weekly basis, to nuclear medicine departments around the world.
Over the useful lifetime of a generator (typically 1-2 weeks), the amount of 99mTc that can be eluted is affected by several factors including column elution efficiency, the initial activity of the 99Mo, and the elapsed time between elu-tions. After one half-life of 99mTc, approximately 47% of the maximum amount of technetium that is available can be eluted from a generator while after four half-lives (approximately 24 h), 88% of the available activity can be obtained. It is therefore convenient to 'milk' generators on a daily basis.
The first clinical use of 99mTc was reported by Harper in 1964 at the University of Chicago.9 99mTcO— eluted from a generator was used to probe the anatomical definition of various organs including the brain, the liver and the thyroid gland. These seminal studies led to the premise that 99mTc complexes of alternative chemical forms could enable imaging of different sites and/ or biological processes because different 99mTc complexes would be expected to exhibit unique distributions in vivo.
In order to prepare complexes of 99mTc, TcO— is reacted with a ligand in the presence of a reducing agent. A wide range of different reducing agents have been investigated with SnCl2 being the most widely employed for preparing complexes of Tc(V) and Tc(I) while boron hydrides are used to prepare organo-metallic Tc(I) complexes (discussed later). The reduction potential of TcO— to TcO2 in acidic aqueous solutions is +0.738 V, which is comparable to the standard reduction potential for Fe3+/Fe2+ (+0.771 V).10
The development of technetium 'instant kits' in 1968 was another important discovery that further propelled the clinical use of 99mTc.11 A kit consists of a pre-mixed formulation of reducing agent and metal-complexing agent in a sterile vial to which generator eluent containing 99mTcO— is added. The desired product is then formed, usually after the application of heat, in high radio-chemical yield and purity without having to perform complex synthetic or purification procedures.
An interesting aspect of the early development of 99mTc radiopharmaceu-ticals is that the structures of compounds produced at the tracer level were often not well understood. Determining the structures of 99mTc complexes unambiguously is complicated by the miniscule amounts of the isotope that is present at the tracer level (10—7-10—10 M), which is below the detection limits of standard structural characterization techniques. This problem is overcome by using the long-lived isotope 99Tc, which can be handled safely in large quantities (typically 10-250 mg per reaction) with only nominal shielding. Reactions with 99Tc provide sufficient material to characterize new Tc complexes, which in turn serve as reference standards for those compounds produced at the tracer level. In the absence of a license to handle the long-lived 99Tc isotope, which is considered a disposal problem, researchers can use rhenium (Re) to prepare well-characterized reference standards. This latter approach must be done cautiously because there are numerous examples of where the chemistry of the two congeners differs significantly.
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