Radiometals in Diagnosis and Therapy

Radiometals are the mainstay of both diagnostic and therapeutic nuclear medicine because the choice of radionuclide is primarily dictated by nuclear decay characteristics rather than chemistry. 99mTc is the most frequently used diagnostic radionuclide and requires coordination in a diversity of chemical disguises to permit imaging of a variety of tissues and disease states. Therapeutic nuclear medicine is less advanced but can provide significant benefits provided the radionuclide is accurately targetted.


Introduction
Radiopharmaceuticals are radioactive drugs which can have either diagnostic or therapeutic applications. In diagnostic nuclear medicine, the radionuclide is used as a tracer to provide functional information about the tissue under investigation. The very short-lived positron-emitting radionuc|ides such as IC, 3N, 150 and are used for diagnosis in hospitals with access to highly specialised and expensive positron emission tomography (PET) facilities. However, most hospital nuclear medicine departments are not equipped for such work and need to use radionuclides suitable for single photon emission tomography (SPET). The nuclear properties required for such radionuclides are: 1. A half-life long enough both to make it readily available in the hospital and to allow it to be distributed in vivo according to the physiological function being investigated, but not so long as to give the patient more radiation dose than is justified by the requirements of the study. These needs frequently dictate a half-life of2-3 days. 2. A decay which gives rise to penetrating y-emissions to allow the distribution of the radionuclide to be measured, but is not accompanied by damaging, non-penetrating particulate radiations such as cor particles.
In contrast, therapeutic radionuclides should have particulate radiations with an in vivo range sufficient to destroy the target tissue but not so long as to cause collateral damage and have little or no accompanying ,emissions which could cause unnecessary radiation exposure to both the patient and hospital staff. Again, the half-life needs to be sufficiently long to allow availability to the hospital and in vivo distribution but is otherwise dictated by whether the radiation dose is to be delivered at a high dose rate over a short time or at a lower dose rate over an extended period. The use of radionuclides in therapy is less advanced than in diagnosis because destructive doses require much more accurate targeting than tracer doses. The nuclear requirements for either diagnosis or therapy are seldom met by the radionuclides of the biologically ubiquitous elements such as C, H, N, O etc. but oblige the use of biologically unimportant or irrelevant elements, almost all of which are metallic. Although some radiometals will target a particular tissue when administered as a simple metal salt, it is frequently the case that the radiopharmaceutical chemist is required to coordinate the metal in a chemical Trojan Horse to cause it to be delivered to its biological target. The role of coordination chemistry in nuclear: medicine has been reviewed by Jurisson et af. This paper will illustrate the use of radiometals in nuclear medicine by discussing the use of the 99mTC coordination compounds 99mTc-HM-PAO for imaging cerebral blood flow and 99mTc-HL91 under development for imaging hypoxic tissue and the application of89Sr as the chloride salt for the treatment of metastatic bone pain.
The Role of 99mTC in Diagnostic Nuclear Medicine Tc is a second row transition metal which did not occur on Earth before its artefactualproduction, mainly as a product of 235U fission. 99mTC has nuclear decay characteristics which make it the most frequently used diagnostic radionuclide. It decays with a 6.02 hour half-life by isomeric transition to 99Tc. The decay is accompanied by the emission of a 140 keV y-ray (89%)which is near-ideal for imaging with a modem ycamera. Although 99Tc is itself radio9a9mCtive (decaying by [3-emission with a half-lifeof 2.1x10 years), the quantities produced by the decay of Tc radiopharmaceuticals are not usually considered hazardous the ratio of 99Tc radioactivity to originating 99mTc radioactivity is the ratio of the half-lives,-1 to 3 108. The short half-life of 99mTc is long enough to be suitable for most nuclear medicine procedures but usually precludes convenient distribution from manufacturer to hospital radiopharmacy. However, 99mTC is produced by the decay of 66-hour half-life99Mo. Distribution is achieved by the supply of commercially produced 99"Mo/99mTC generators. These contain an alumina chromatography column on which 99M0 has been adsorbed from acidified molybdate solution. The 99mTc is extracted as 9mTcO4" by elution with 0.9% NaC1 to produce a sterile solution which is isotonic with blood and ready for injection. The chromatography column is "99 surrounded by a lead or depleted uranium shield. As the 99mTC is continuously produced by the Mo decay, the generator can be eluted one or more times a day. The decay and regrowth characteristics are illustrated in Figure for a variety of elution times. The calculation of these curves is described in most radiochemistry or nuclear chemistry textbooks (e.g. reference 2). It is seen that the generator system allows preparation of WcO4 once or twice a day p" efficiency of 99mTC use. Although 99mTcO4" has nuclear medicine uses in its own right, such as thyroid imaging, the majority of applications for 99mTC require it to be in other chemical forms. Tc exhibits a range of oxidation states from-1 to +7. The Tc in 99mTco4" is in oxidation state +7 and requires reduction and coordination with a suitable ligand system to provide an appropriately targeted radiopharmaceutical. Most 99m 99n Tc radopharmaceutcals are produced from TcO4 with the aid of commercially produced kits, either in the hospital or at a centralised radiopharmacysupplying many hospitals in a region. The simplest and most convenient technetium kits consist of a sterile vial containing a freeze-driedmixture of a reducing agent (usually a salt of Sn(II)), a complexing agent and perhaps some excioients such as a filler or a buffer. On addition of generator eluate and any required 0.9% NaC1 diluent, the 99tnTcO4" reacts with the kit ingredients to produce a finished radiopharmaceutical in just a few minutes.
The Use of 99mT-HM-PAO for Imaging Brain Blood Flow Imaging of brain blood flow is used for the diagnosis and management of patients with a wide variety of neurological and psychiatric conditions such as stroke, epilepsy, trauma, depression and dementias of various 99m origins. In the 1980 s, the discovery of Tc-based agents for imaging brain blood flow was an important goal for radiopharmaceutical research. The need for the molecule to cross the intact blood-brain barrier (BBB) < dctated that t should be electrically neutral, of low molecular mass 500 daltons) and lpophlc. Several 99m 99m TM Tc complexes were identified as potential brain blood flow agents but only Tc-HM-PAO (Ceretec 99m 99m Amersham International) and Tc-ECD have progressed to routine clinical use. The development of Tc-HM-PAO stemmed from the discovery that the 99mTC complex of PnAO ( Figure 2)6 possesses the properties required to cross the BBB and shows transient flow-related brain uptake in humans. It is formed by reacting 99mTcO4" with Sn(II) and PnAO to cause reduction of the Tc from oxidation state +7 to +5 and complexation by the PnAO ligand to give a lipophilic neutral molecule. The Tc-PnAO did not persist in the brain for long enough to permit imagine using conventional SPET equipment. Synthesis of a range of PnAO derivatives led to the discovery of 99nTc-HM-PAO3. This molecule is unstable in aqueous solution, reacting to produce 99m a poorly characterised hydrophilic Tc complex. Its in vivo behaviour appears to be similar except that the intracellularrate ofconversion to a hydrophilic complex is sufficiently fast to cause -50% of the 99mTC that enters brain to be trapped7. The greatly enhanced rate of conversion in vivo appears to be due to reaction with intracellular glutathione. The trapping arises because the conversion product is too hydrophilic to cross the BBB and so is unable to diffuse out of the brain. The resultant distribution of 99mTC within the brain gives a snapshot of blood flow at the time of injection. Figure 3 illustrates this with planar (as opposed to tomographically reconstructed SPET) scans of normal and brain-dead subjects the radioactivity is only deposited in viable tissue. Figure 4 shows SPET images of a trauma patient 2 weeks after injury and following recovery. The scans give detailed information about the progression of brain function.  Tc-HM-PAO brain scans of normal and brain-dead subjects. The dense radioactivity distribution in the normal subject is consistent with the regional distribution of brain blood flow. In the brain-dead subject, radioactivity is concentrated in the catheter used for administering the injection but is absent from the brain. 99mTc-HM-PAO is normally administered by intravenous injection in the arm. (Images reproduced courtesy of Dr D. C. Costa8, University College London Medical School, London, UK).
The Development of 99mTc--HL91 for Imaging Hypoxic Tissue The imaging of hypoxic (under-oxygenated)tissue is of potential importance because it may allow the identification and management of tumours resistant to radiotherapy or of at risk myocardium (hea muscle) in heart patients. A possible targeting mechanism is the intracellular reduction of nitroimidazoles ( Figure 5). The in vivo reduction of nitroimidazoles is mediated by cytosolic or mitochondrial enzymes but, in normoxic (normally oxygenated)cells, the first step is reversed due to reaction with oxygen (the "futile cycle"). In hypoxic cells, this reversal does not take place and products which may be unable to diffuse out of the cell occur.
The first 99mTC agent to employ this trapping mechanism was BMS-181321 ( Figure 6). Inspection of Figure 2 shows this is formed from a nitroimidazole derivative of PnAO. While BMS-181321 exhibits uptake and retention in hypoxic tissue, its very high lipophilicity results in poor clearance from background tissue, especially the liver . A Tc complex of HLgl (also known as Bn(AO)z)has been described by showed, the. analogous14 99mTc complex of the underivatised HLgl ligand gave more selective retention" m" hypoxc tssue The complex has subsequently been shown to be reducible under conditions similar to those required to reduce nitroimidazoles r3. 99Tc-HLgl is still undergoing development as a hypoxia imaging agent. Figure 7 shows scans of a head tumour comparing a PET metabolism image deoxyglucose, SFDG)with a 99mTc-HLgl SPET image-this is one of the first patient studies with 99mTC-HL91. Prostate cancer is the second most common male cancer in many Westem countries. Most cases are detected too late for curative treatment. Metastases (secondary cancers)usually appear in bone. Bone pain is a 1"5 n common problem which is often difficult to control effectively .Management of bone pa'n ofte progresses through the following stages: hormone treatment; chemotherapy and/or local radiotherapy and/or analgesics; hemibody radiotherapy; narcotics. Once these measures have failed as the disease progresses, the quality of life of such patients is frequently poor. At this stage, the use of a therapeutic radiopharmaceutical that concentrates at the sites of lesions to provide in situ radiotherapy can be an attractive option.   Sr 2+ can behave as an analogue of Ca 2+ both metals are in group IIA of the periodic table; the ionic radii (2+) are 11.3 nm and 9.9 nm respectively). Sr decays by emission of a 1.49 MeV (maximum energy) 13-particle with a half-life of 50.5 days. The -emission has a range in bone of 3.5 mm. There are no accompanying 'emissions. Tracer studies with the y-emitting nuclide'SSSr show Sr administered intravenously as a solution 16 85 of SrCI2 is taken up in bone, concentrating at sites of high bone turnover The Sr washed out of normal 85 bone but was retained at metastatic sites. Sr not incorporated in bone was excreted in the urine. Whole body retention of 85Sr at 3 months following injection varied from 88% in a patient with complete skeletal involvement to 11% in light disease. Consequently, 89SrC12 (MetastronTM, Amersham International) may be administered by intravenous injection and concentrate in fast-growing regions of bone, such as metastases, destroying the metastatic tissue and causing reliefof pain. Studies to establish the optimum dosage were conducted in 112 patients7. There was a positive dose-pain relief response relationship which rose to a plateau at 1.5 MBq/kg. The major side-effects were depression of platelets and leukocytes. At a dose of 150 MBq (-2.15 MBq/kg), the three-month post treatment levels had dropped-30% for platelets and -20% for leukocytes. This was adopted as the standard dose to allow for patient variation, whilst ensuring side-effects were kept below unacceptable levels. A double-blind study was conducted to compare patient response to 12 10 ::::::::::::::::::::::: ::::::'::::,':..: .

Conclusions
Radiometals are the mainstay of both diagnostic and therapeutic nuclear medicine because the choice of radionuclide is primarily dictated by nuclear decay characteristics rather than chemistry. Although some metals are usefully targeted as simple salts, most uses require the application of carefully researched coordination chemistry to ensure delivery of the radionuclide to the target tissue.