Radiochimica Acta 70/71, 289 - 297 (1995)
© R. Oldenbourg Verlag, München 1995
Technetium in Nuclear Medicine
By A. G. Jones
Department of Radiology, Harvard Medical School, Boston,
(Received December 18, 1995)
Technetium-99m / Radiopharmaceuticals /Gammy ray imaging / Single photon emission
tomography / Nuclear medicine
Abstract
The introduction of the technetium generator and the development of the Anger camera in the
early 1960s formed the basis of modern clinical nuclear medicine. Chosen originally purely
for its physical decay characteristics, the radionuclide 99mTc has since become the backbone
of routine imaging. In the United States, for example, more than 85% of all studies involve
the use in one form or another of this short-lived gamma emitter. Since technetium is an
artificial element, which occurs on earth only by virtue of the fission process, this intense
medical use of the material seems an oddity. In fact, thanks to the work of a small number of
early pioneers, the choice turns out to be eminently logical. This short article outlines some of
the history associated with this radionuclide and its radiopharmaceuticals.
Discovery
The discovery of the element was made in Palermo by Segrè and Perrier in 1937 [1], and by
far the most complete account of this event is found in a talk given by Segrè in Italy in 1985
[2]. The discovery occurred as the result of a period during 1936 spent by Segrè at the
cyclotron of the University of California at Berkeley. He noted that parts of the interior of the
machine had been irradiated and replaced, in particular a strongly radioactive deflector lip
made of molybdenum that contained long-lived isotopes. Since the bombardments had been
made with deuterons, he surmised that there might exist isotopes of the then unknown
element 43 in the deflector. Returning to Italy with scraps of the deflector, he worked with
Perrier to develop a chemical separation for the new element and to acquire subsequently
some knowledge of its chemistry. Although the work announcing the discovery was
published in 1937, it would be eleven years before the new element was finally named, by
Segrè with the help of a colleague who was a Greek scholar.
In order to study short-lived radionuclides of the element, Segrè returned to Berkeley in
1938 and began working with an instructor in chemistry named Seaborg. The discovery of
the radioactivity with a half-life of six hours followed [3], though publication of this finding
was delayed because the concept of isomeric states was somewhat controversial at the time.
In fact, publication was held up until a paper appeared, authored by Pontecorvo, concerning
an isomeric state in rhodium [4]. Subsequent work by others in detecting conversion electrons
from the radionuclide confirmed that the activity indeed belonged to element 43 and the
discovery of the element itself was corroborated much later when it was isolated on a
macroscopic scale from fission products.
Nuclear medicine
Several other isotopes that would become important in nuclear medicine were also discovered
at Berkeley during the late 1930s, including 131I [5]. Though this nuclide would be used
medically almost immediately, it would be almost twenty years before the potential of 90mTc
was realized. Several things converged to make this possible. The first radionuclide generator
system in a convenient form was the 132Te-132I couple developed at Brookhaven National
Laboratory in the mid 1950s [6]. This system was loaded with 132Te derived from fission
products, and efforts to improve the purity of the eluted iodine led to the detection of a
contaminating activity that was determined to be 99mTc [7]. Subsequent work showed that the
molybdenum parent was following the tellurium through the separation process. The
technetium generator that resulted was first reported in 1958 [8]. The history of the generator
itself has been recounted by Richards who was primarily responsible for promoting the
medical applications of the isomeric state during the late 1950s and early 1960s [9, 10].
Another aspect of this period was the early effort by Harper and his colleagues at the
University of Chicago to further develop imaging techniques. Based upon estimates by Beck
that the optimum detection energy of the sodium iodide crystals being used in scanners lay
around 150 keV [11], Harper’s interest turned to 99mTc [12]. Eventually this gave rise to the
shipment of a series of technetium generators from Brookhaven to Chicago and to the
demonstration of the effectiveness of 99mTc in imaging the liver, brain, and thyroid [13]. The
early generators were eluted with dilute acids: nitric acid originally and then hydrochloric
acid in order to be more physiologically compatible. In early 1964 Maynard at the
Radiochemical Center (now Amersham International Plc) in England discovered that
equivalent yields of pertechnetate could be achieved with physiologic saline rather than acid
[14]. At this point the stage was set for establishing commercial generators that gave a sterile,
pyrogen-free source of pertechnetate. This was achieved in 1966 when a further convenience
was introduced with the evacuated vial technique of elution, which both limited the exposure
of the column to water and its radiolysis products and also ensured a fresh supply of sterile
eluate on each occasion. While each of these steps individually seems small, taken as a whole
they form the essential framework by which a short-lived isotope could be available as
required at any site any-where in the world on a timely basis. This was no small achievement.
It might be interesting at this point to interject a quote from a talk given by Charlton to the
Pharmaceutical Society in April 1965 [15] to the effect that the 1963 British Pharmacopeia,
together with the 1964 Addendum, listed the following radioactive preparations:
cyanocobalamin (57Co), cyanocobalamin (58Co), ferric citrate (59Fe), gold (198Au) injection,
iodinated (131I) human serum albumin injection, sodium chromate (51Cr) solution, sodium
iodide (131I) solution, sodium phosphate (32P) injection. One year later the abstracts of papers
at a meeting of the British Institute of Radiology reflected a sea change in emphasis toward
low-energy gamma emitters and technetium [16]. Technetium agents available from Harper’s
research at this juncture included pertechnetate, sulfur colloid, DTPA iron ascorbate complex,
labeled human serum albumin and thiocyanate [17].
The next major contribution to modern nuclear medicine came again from Brookhaven in
1971 with the publication by Atkins et al. of a paper describing 99mTc-DTPA complexes
prepared by three different methods [18]. This was the first report of what has since become
known as an “instant kit” preparation, using stannous ion as a reducing agent for the pertechnetate precursor [19]. Though the basic chemistry was still poorly understood at this stage,
sufficient was known about soft donor ligands and their ability to coordinate the metal to
design such kits. Eventually this became a standard model for on-site synthesis of imaging
agents, for example, methylene diphosphonate (MDP), pyrophosphate (PYP), glucoheptonate
(GH), disofenin and mebrofenin. In each of these instances, the stannous ion serves to reduce
the metal prior to complexation and to maintain reducing conditions for a practical portion of
the clinical day, usually six hours. The ligand in turn can be seen to perform up to four
functions: complexing the technetium present, targeting the product, complexing the tin present in order to avoid the formation of colloidal material, and (certainly in the case of
glucoheptonate) helping to maintain the integrity of the complex by mass action.
Lyophilization of the vial contents in the presence of an expander such as a sugar allows for
long-term storage and instant reconstitution and reaction when the pertechnetate is added.
This concept was not only convenient but also introduced simplicity and reliability to the
preparation of radiopharmaceuticals as they were needed. These attributes thus brought a
range of technetium imaging agents into the mainstream of medicine in the 1970s through
approval by governmental regulatory agencies such as the Food and Drug Administration
(FDA) in the United States.
For the technetium generator the next major milestone came in 1974 when the first of the
fission product columns became routinely available. A carrier-free molybdenum parent
allowed the use of a much smaller column, with smaller elution volumes in turn producing a
much higher specific activity product. In concert with the standard kit design this also
contributed to the routine on-site preparation of radiopharmaceuticals. Molinski has outlined
the many difficulties presented in the design of these generator systems [20], not the least of
which was the separation of 99Mo from fission products in sufficient purity so that it could be
used safely to produce an injectable product. Nevertheless, the radiopharmaceutical industry
overcame these problems and the product is now extremely reliable.
Development of new imaging agents
The first phase
Research into the development of new agents over the past twenty-five years can be roughly
divided into three different, albeit overlapping, phases. During the first phase in the early
1970s the agents used in the clinic were relatively simple in nature, targeting basic
physiologic function, and were essentially commercialized versions of products devised by
Harper and other pioneers in the 1960s. The nuclear medicine clinic thus employed colloids
and particles to take advantage of capillary blockade in the lungs or the natural function of
the liver and spleen in removing debris from the circulation. Labeled albumen served for
blood pool scanning and the complex formed with DTPA for glomerular filtration studies of
renal function. Figure 1 compares a liver scan made on an early rectilinear scanner with 198Au
colloid with a similar study made on a modern Anger camera with 99mTc-sulfur colloid. This
clearly demonstrates the importance of advances in instrumentation as a second key factor in
the establishment of modern nuclear medicine.
In this period insufficient basic chemistry was known, but nevertheless some ingenious
ideas emerged for new agents. One of the first objectives was to improve upon the ability to
monitor the skeletal system and to move away from scanning with 85Sr or, where it might be
available, 18F as fluoride ion. Ligands were chosen that had both an avidity for calcium and
oxygen donor atoms to bind technetium. Further, the typical aim was that these relatively
simple ligands even when complexed would guide the radiolabel to the intended target after
Fig. 1 Comparison of a liver scan made on a rectilinear scanner with 198Au colloid (left) and one made with
Tc-sulfur colloid using an Anger camera (right). Note the absence of splenic uptake in the 198Au scan. (Image
courtesy of S. Treves. M.D., The children´s Hospital, Boston).
99m
injection. Subramanian suggested polyphosphates of particular chain length [21]. Next,
technetium pyrophosphate (which later proved to be the active impurity in the particular
samples studied by Subramanian) was proposed [22]. Finally came the organic phosphonates,
put forward because they would be more stable than the inorganic phosphates against in-vivo
metabolism [23, 24]. One of these (again suggested by Subramanian), 99mTc-methylene
diphosphonate is still the imaging agent of choice and an essential part of routine clinical
nuclear medicine practice [25]. Figure 2 shows a comparison of bone scans performed with
sodium 18F-fluoride and with 99mTc-MDP. Though both agents are effective in targeting the
tissue of interest, the convenience of the generator-kit system outweighed the logistics of
production and the expense of distributing 18F to the point where the latter was eclipsed. For
example, the fluorine dose depicted here was generated in Chicago and imaged in Boston.
While technetium images such as these are routine fare for those familiar with nuclear
medicine, it is still a marvel to this author that the information is being provided by a
vanishingly small amount of a coordination complex of an element that does not occur
naturally on earth. Furthermore, unlike other modalities the image provides not a still picture
but a dynamic one of the state of the bone structure:
the density reflects accurately the turnover proceeding in normal areas of bone and the
increased reactivity in other areas due to the presence of pathology or trauma.
One of the more entertaining aspects of nuclear medicine is the frequency with which
alternative uses - beyond the one originally intended - are found for an agent. 99mTcpyrophosphate is a case in point in that it was also used to obtain positive images of the site
of myocardial infarction, targeting the crystallites of hydroxyapatite that eventually form after
such an event. An accidental observation made early in 1975 by Uren and colleagues in
Australia [26] and by others showed that injection of pertechnetate for brain imaging in a
patient who had previously had a bone scan with 99mTc-pyrophosphate led to the labeling of
red blood cells. These observations formed the basis
Fig. 2. Anterior views of the skeleton using 18F-sodium fluoride (left) and 99mTc-MDP (right). Both reflect the
dynamic state of bony tissue. Note the increased activity in joints and load bearring reagions. (Image courtesy of
S. Traves, M.D., The children´s Hospital, Boston)
for a standard protocol for performing radioventriculograms - functional studies of the left
ventricle - using two sequential injections of, respectively, the contents of a pyrophosphate
kit and half an hour later a dose of 99mTcO4-. This obviated the need for retrieving a sample of
the patient’s blood for labeling in vitro prior to reinjection. From the standpoint of a chemist
there remain questions about this process of adding the reactants together in a different
sequence. With this technique roughly half of the radioactivity resided on the erythrocytes
while the remainder cleared through the kidneys without targeting bone. This complex has
never been studied or compared with the bone-seeking pyrophosphate complex.
The second phase
The second phase of research into new agents was a direct result of the ever increasing
amount of fission products being generated by power reactors, and hence of the long-lived
nuclide 99Tc. The availability of this isotope in weighable quantities began to make possible
conventional studies of technetium chemistry, applying the usual spectroscopic and analytical
methodologies of the inorganic chemist. This phase began in the early 1970s and is still
continuing. The usual procedure has been to generate new classes of technetium coordination
complexes containing 99Tc, to characterize these fully by a variety of means, and then to
study the pharmacokinetics of the corresponding 99mTc material in animal models or in vitro
using cellular or tissue preparations. Though there may be an element of serendipity to this
approach it has in fact led to significant advances in the design of both radioactive and
nonradioactive contrast agents, as well as to the introduction of new tests in routine nuclear
medicine.
Much of the original effort was directed toward new complexes that could be formed in
high yield in aqueous media, because the starting material in practice is pertechnetate ion in
isotonic saline. The first major new class to be discovered was the oxotechnetium complexes
in the +5 oxidation state. The first of these was a bis ligand complex with the bidentate
mercaptothioacetic acid [27]. This was noteworthy not merely because it was new but also
because the technetium selected specifically a ligand that was an impurity in the sample of
the intended ligand (thioglycolic acid). This was the first indication of the affinity of Tc(V)
for sulfur as a donor and also of the dangers in assuming that at trace levels the chemistry is
totally predictable. The second complex containing the TcVO3+ core found by Smith [28]
underscored this avidity and also confirmed the fact that these materials can be formed
readily and in high yield, an important factor in practice. A study of the relative affinities of
different donor sets followed and led to the design of a bisamide-bisthiol (N2S2, or DADS)
chelate under the assumption that greater in-vivo stability would be gained from the chelate
effect than from complexes formed with bidentate ligands [29]. Initially proposed as a renal
imaging agent, this system was developed further by Fritzberg into an N3S chelate [30] that is
now commercially available under the name Technescan MAG3TM. During these early
studies of oxotechnetium complexes the use of mass spectrometry for the identification of
coordination compounds was first proposed [31]. This technique has proved so effective for
this purpose that it is now a standard method for characterizing metal compounds, not only in
radiopharmaceutical chemistry but also in inorganic chemistry as a whole.
An analogous N2S2, chelate system containing a bisamine bisthiol (DADT or BAT) was
devised by Burns et al. [32, 33]. Whereas the amides formed anionic products, this system
was chosen to form a neutral species when complexed with the metal, with the objective of
penetrating the blood-brain barrier and providing a means of imaging the brain. This class has
subsequently been extensively studied by Lever [34] and by Kung [35] for this and a variety
of other purposes. For nuclear medicine, the most important result stemming from this work
is a brain perfusion agent that is comprised of the bis ester of the original Burns ligand,
available in the United States since 1994 and marketed under the name NeuroliteTM. This
material is neutral upon injection, but when it crosses into the brain one only of the two ester
moieties becomes hydrolyzed by an enzyme in tissue, thus rendering the overall charge
negative and effectively blocking its egress from the cells. This is a symmetrical molecule
containing two chiral centers, and only one isomer is active and then only in certain species,
including the higher primates and man [36].
At this stage at least seven of the routinely available radiopharmaceuticals are in fact
relatively simple oxotechnetium(V) species, including four approved or near approval in the
United States over the past ten years. Two of these, complexes formed with glucoheptonic
acid and with dimercaptosuccinic acid (DMSA), stem from the era before extensive structural
studies were required by the regulatory agencies. Some work has been done on the DMSA
system that indicates it is a technetium(V) complex and that isomerism occurs. Not yet
explained, however, is the product of an alternative formulation used in Japan for detecting
thyroid tumors [37]. Figure 3 shows 99mTc—DMSA in its more usual role for assessing renal
function. This should be compared with the left hand panel which is an image obtained on a
rectilinear scanner in the 1960s with 203Hg-chlormerodrin, then commonly used for renal
scanning.
Fig.3. Comparison of a kidney scan performed with 203Hg-chlormerodrin (left) with a modern example done
using 99mTc-DMSA complex (right) The 99mTC scan shows a damaged though still partially functioningright
kidney (Image courtesy of S. Treves, M. D., The Children´s Hospital, Boston)
A product of the post characterization era among oxotechnetium(V) complexes was first
marketed in 1988 in the United States (earlier in Europe) under the name Ceretec TM. This
complex contains an N4 or four nitrogen donor set [38] and is designed to assess cerebral
blood flow. A typical use for this agent is shown in Figure 4 where several modalities come
together, specifically magnetic resonance imaging (MRI) and scanning with two different
radiopharmaceuticals, CeretecTM to monitor blood flow and 201Tl-thallous chloride to
delineate a brain tumor. The ligand/complex system on which CeretecTM is based is another
example of isomer formation, with different forms showing different in-vivo properties. This
issue of isomerism in technetium complexes and its influence on drug design is a fascinating
topic, and the best and most comprehensive account to date has been published recently by
Nowotnik [39].
Fig. 4. Images taken of a brain tumor. Top panel: left, 201Tl-thallous chloride scan; center, magnetic resonance
imaging (MRI) of tumor bed; right, superpositioning of the nuclear medicine image on the MRI. Bottom Panel:
left, blood perfusion scan with 99mTc-CeretecTM; center, co-registration of perfusion and MRI scan; right
superimposed 201Tl and 99mTc scans. Both agents target the same volume of tumor but the mass is more
extensive by MRI.(Image courtesy of B. Leonard Holman, M.D., Brigham and Women´s Hospital, Boston.)
This second phase in radiopharmaceutical development of essentially inorganic
complexes also yielded a body of research on myocardial perfusion agents. The first materials
to show avidity for cardiac tissue in vivo were cationic phosphine complexes of Tc(III) and
Tc(I) [40, 41]. When tested in humans, however, an unexpected species difference emerged
that slowed their development as clinical agents until the recent development of tetrofosmin
[42] and Q12 [43]. In late 1981, however, a second class of complexes, the hexakis isonitriles
of technetium(I), was discovered to have an avidity for cardiac tissue, and three examples of
this potentially large group of molecules were successfully tested in man [44 - 46]. The third
of these, 99mTc-metboxyisobutylisonitrile (MIBI), has been available for clinical use under
the name CardioliteTM in parts of Europe since as early as 1987 and in the United States since
1991. Although designed originally as a myocardial perfusion agent, anecdotal observations
by Muller published in 1987 [47] prompted research into the possible use of isonitriles as
tumor-seeking agents [48, 49]. Such studies parallel those going on in photoaffinity therapy
in which other positively charged lipophilic species with a generally spherical form such as
organic dyes are being investigated for ablation of tumor with lasers. During this same period
Piwnica-Worms et al. discovered the dependence of uptake upon membrane potential, not
only that of the plasma membrane but also that of the mitochondrial membrane [50].
Reduction of the membrane potential results in clearance of the technetium complex from the
cell. The existence of 99Tc-MIBI in mitochondria of exposed cells has been demonstrated by
physical means [51]. Perhaps even more interesting is the recent finding, again by PiwnicaWorms, that the uptake of 99mTc-MIBI in tumor cells is markedly affected by the presence of
P-glycoprotein, a molecule that is expressed on the surface of cells showing one of several
forms of multidrug resistance [52]. It is intriguing to note that these properties are no doubt
shared by other classes of materials not yet studied in this manner. In keeping with the
experience in nuclear medicine with new classes of agents, CardioliteTM recently underwent
clinical trials to assess its usefulness for detection of breast cancer in certain patient populations. Similar results have been reported for 99mTc-tetrofosmin [53], an agent currently
approved for myocardial perfusion studies in Europe and nearing approval in the United
States that is another example of an oxotechnetium(V) species.
The third phase
The third phase of radiopharmaceutical development overlaps considerably with the second,
briefly outlined above, and represents attempts to capitalize upon known technetium
chemistry to link the radionuclide to molecules of biologic interest. It also may reflect the
sense that it is difficult or perhaps impossible to adequately screen each and every new class
of technetium complex for relevant biologic activity. In the 1990s, therefore, there is an
increasing emphasis on modification of molecules, or portions thereof, that may help to
detect a particular disease process. There is thus a real dependence upon discoveries made in
other fields of research. For example, although N2S2 and N3S chelates have been used for the
conjugation and subsequent metallation of monoclonal and polyclonal antibodies for over ten
years [54], there is now a concerted effort to investigate the usefulness of technetium-labeled
peptides. Instances include the work designed to develop a means of imaging thrombi, using
labeled platelet GPIIb/IIIa antagonists, now at or near the stage of clinical testing [55, 56].
More removed from the clinic and yet representative is the attempt by Katzenellenbogen et
al. to label progestins with 99mTc in order to develop an agent for assessing therapies in cases
of breast cancer [57]. This is a fine instance of a situation in which basic chemistry, in this
case the chelation chemistry of the element, is being developed further in order to meet
demands set by the required in-vivo properties of the final molecule, including attributes such
as lipophilicity, charge and shape.
Even further from routine clinical use is the effort by many groups to develop agents that
will target a variety of receptor types and hopefully thereby reflect various aspects of organ
activity. The most comprehensively studied technetium agent is 99mTc-galactosylneoglycoalbumin (NGA) targeted to a receptor in the liver [58], though this has seen only
investigational use in humans. Much of current research is directed to imaging receptors in
the brain, including work by Kung [59, 60], Spies [61], Jurisson [62] and Lever [63]. This is
a very difficult exercise for the bloodbrain barrier represents a formidable obstacle to the
entry of imaging agents. This may be particularly so for those that include a requirement to
firmly coordinate a metal radionuclide, i.e., a portion with an extra 300 daltons in weight and
the size of a tripeptide. Beyond this, it is necessary to prove that the molecule being studied is
indeed specific for one particular receptor type, that the variation in receptor density reflects a
given function, and that the progression of a disease state may be followed in a quantitative
manner or that the scan is effective in the management of the patient. Practicality also deems
that the disease being followed be present in a significant proportion of the patient
population; otherwise there will be insufficient incentive to invest the vast sums necessary to
bring a drug to the marketplace. These are major hurdles to overcome, but nevertheless it is
recognized that for the future of nuclear medicine new windows on the brain and its function
must be developed. Figure 4 shows the exquisite structural information that can be provided
by MRI. Within the next decade it is predicted that blood perfusion imaging in the heart and
the brain will be possible with this technique. Figure 4 also demonstrates, albeit with an agent
that shows low specificity for tumor, that the anatomical detail from MRI and the physiologic
information available from nuclear medicine could be a very powerful combination.
Summary
The story of 99mTc is remarkable in that this metastable isotope of an artificial element has
exhibited real staying power in a field of medicine. The reasons for this may be summarized
as follows.
The radionuclide has a single 140 keV photon and relatively little nonpenetrating
radiation, decaying to a long-lived ground state that is a low-energy beta emitter. These
properties ensure that the absorbed radiation dose to the patient is kept at acceptable levels, as
is proper for a diagnostic test, and the emitted energy meshes well with the efficiency of
sodium iodide detectors used in modern gamma cameras. The dosimetry allows the use of
higher doses, hence more photons, clearer pictures, and shorter imaging times.
The yield of the precursor nuclide 99Mo from uranium fission by thermal neutrons
exceeds 6 percent and the mass 99 decay chain is the only one in the region that results in a
radioactive isotope of molybdenum. This molybdenum can be isolated in high purity from
other fission products and thus provides a monoisotopic source (from the radioactive
standpoint) of the isotope to be administered into humans. This is also invaluable from the
standpoint of dosimetry and of imaging without, for example, interfering gamma rays from
contaminants.
The daughter isotope when needed can be isolated in high yield (about 80%) from an
alumina column with sterile, pyrogen-free physiologic saline at high specific activity. The six
hour half-life allows ample time for synthesis using convenient kit formulations and also for
quality control procedures. The half-life of the nuclide is reasonably compatible with the
duration of the average imaging procedure. The radiological problems associated with all
phases of its use are relatively minimal.
Finally, technetium is a second row transition metal with a very rich chemistry, much of
which has not yet been exploited. The extent of this chemistry and its applicability to the
design of imaging agents are evidenced by the steady flow of new radiopharmaceuticals into
the clinic and by the numerous new compounds being investigated in the research laboratory.
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