Introduction

Radiopharmaceutials are radiolabelled molecules that are used to achieve non-invasive imaging or to deliver a therapeutic dose of sterilizing radiation to specific disease sites. Following systemic administration, these molecular agents localize in specific areas as a consequence of a number of factors. In the case of the diagnostic imaging agents the goal is to use a radioisotope that emits radiation that can be readily detected as it leaves the body but has little effect on surrounding tissue. This is achieved with 7- or positron-emitting isotopes, the most commonly used isotope being 99mTc, which is used in over 85% of all diagnostic scans currently performed in hospital nuclear medicine departments.1

The treatment of cancers with conventional beam radiation is well established and plays an important role in modern oncology but it is not particularly appropriate for the treatment of metastatic sites or widely disseminated disease. Treatment of secondary tumours with a systemically administered radiophar-maceutical could be a useful supplement to conventional beam radiation treatments and surgery. Recent developments in targeting vectors such as receptor

Metallotherapeutic Drugs and Metal-Based Diagnostic Agents: The Use of Metals in Medicine Edited by Gielen and Tiekink © 2005 John Wiley & Sons, Ltd avid molecules, monoclonal antibodies, fragment antibodies and site-specific peptides have led to the possibility of selective in situ delivery of radioisotopes that can administer a sterilizing dose of ionizing radiation to cancer sites. This is best achieved with a- and ^-emitting (and Auger-electron emitting) isotopes. If the nuclide also emits 7-photons, they can be used to simultaneously image the distribution of the therapeutic agent, although such emissions should be of low abundance so they do not increase the dose to non-target tissue.2 The effects of ionizing radiation on cells stem from modification of cellular DNA and the prime target is therefore the cell nucleus. The eventual death of the cell via apoptosis is a result of a series of complex steps which follow the original interactions of the radiation with the cellular environment. Chemical reactions initiated by the radiation result in the formation of reactive species such as radicals which can alter certain cell components.3 Since the principal target is the cell nucleus, very low energy ^-emitters and Auger-emitters, which have a short path length in tissue, must be delivered directly into the nucleus. When higher energy ^-emitters which have a longer range in tissue are used, it is not necessary to deliver the radionuclide to the nucleus but the energy of the ^-emissions dictates the size of the tumour that can be treated. It is also essential to minimize irradiation of non-target tissue although 'cross-fire' can be of use in non-uniform large tumour masses.4

Ideally, therapeutic radiopharmaceuticals should locate specifically in the target area whilst causing minimum damage to normal tissues. If specific targeting molecules are used, it is essential that the radionuclide is attached in a way that the bioconjugate is sufficiently stable in vivo, the binding ability of the receptor molecule is not compromised and that the therapeutic agent localizes in the target tissue within a time frame that is appropriate for the half-life of the radioisotope. The development of effective radiotherapeutic agents is a complex problem which cannot be achieved by just adding a radio-nuclide to a targeting vector in an indiscriminate fashion. The choice of radio-nuclide depends on a number of factors including the nature of the emissions, half-life, ease of production, availability, the nature of the decay products, the size of the tumour and cost. Rhenium has two ^-emitting isotopes, 186Re and 188Re, that offer potential to be used as therapeutic radionuclides (Table 24.1). The superficial chemical similarity of rhenium to its group VII congener

Table 24.1 Radioactive isotopes of rhenium

Max. ^-energy

Range in

7-Energy

Method of

Isotope Half-life (h)

(MeV)

tissue (mm)

(MeV)

production

186Re 90

1.07 (71%)

5

137 (9%)

185Re + n (reactor)

188Re 17

2.1 (100%)

11

155 (15%)

188W decay generator

technetium means that at least some of the research and development into technetium imaging agents can be extrapolated to rhenium-based therapeutic agents.

Rhenium-186 can be produced by neutron irradiation of natural rhenium in a nuclear reactor. Natural rhenium consists of 37.4% 185Re and 62.6% 187Re, which leads to a considerable impurity of 188Re which can be removed by allowing it to decay but this also results in considerable loss in activity of the desired isotope. Higher specific activities can be obtained by using isotopically enriched 185Re which minimizes both 188Re contamination and the amount of residual non-radioactive 'carrier' rhenium. 186Re has medium energy ^-emissions (max. 1.08 MeV) with a range of about 5 mm in tissue which means it is suitable for use with small tumours. It has a long half-life of 3.7 days which makes it particularly useful in the labelling of large biomolecules that are not rapidly cleared from the blood stream.1,4

Rhenium-188 can be obtained as a solution of 188ReO4 in high specific activity from a 188W/188Re generator similar in design to the commonly used 99mTc generator.5 The generator design involves utilizing the 188Re which forms as a decay product from 188W, which has a half-life of 60 days. The generator has an alumina column to which 188W-tungstate has been chemisorbed and the decay product 188Re is then eluted with a saline solution as Na[188ReO4]. A single generator with 0.5 Ci of 188W can last between 2 and 6 months and in this time it has the potential to provide sufficient radioactive rhenium for the treatment of several hundred patients. 188Re is a high-energy ^-emitter (max. 2.1 MeV) with a range in tissue of about 11 mm and a half-life of 17 h. This makes it potentially useful for the treatment of large tumour masses but its relatively short half-life dictates that it must be used in conjunction with agents that are rapidly cleared from the blood into the target tissue.1,4

Both nuclides also emit 7-photons of energy in a diagnostically useful range in relatively low abundance which means that simultaneous therapy and imaging is a possibility without too much irradiation of non-target tissue. In addition both isotopes give rise to secondary electron emissions that add to the radiation dose delivered within a zone much less than one cell diameter.

As therapeutic radionuclides, both 188Re and 186Re have advantages over other ^-emitting nuclides such as 131I and 90Y. The isotope 131I, a ^-emitter, was the first isotope to be investigated for therapeutic applications. However, the success was limited due to relative ease of dehalogenation in vivo and subsequent accumulation in the thyroid and the abundance of high-energy 7-photons that can irradiate non-target tissue. Several other studies have focussed on the ^-emitter, 90Y; however, preliminary therapy trials in humans were plagued by accumulation of 90Y in bone following premature dissociation of the metal ion from the chelate. In contrast, the thermodynamically favoured fate of rhenium in vivo is [ReO4], which is rapidly excreted via the kidneys, and does not accumulate in the thyroid or in bone.1

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