⁶⁷Cu (t_1/2: 2.6 days) emits beta particles with maximum energies of 577, 484, and 395 keV (mean 141 keV), which is similar to the mean β energy of ¹³¹I (180 keV). These therapeutic β-emissions, with a mean tissue penetration depth of 0.2 mm, are suitable for treating small tumors of up to 5 mm in diameter. ⁶⁷Cu also emits γ-radiation in the range 91–184 keV (49 % abundance), which is particularly suitable for diagnostic imaging with a gamma camera (Novak-Hofer and Schubiger 2002). ⁶⁷Cu can be produced by bombarding ⁶⁷Zn with neutrons in high flux reactors (Mausner et al. 1998), or in cyclotrons by irradiating ^natZn or enriched ⁶⁸Zn with protons (Schwarzbach et al. 1995; Dasgupta et al. 1991).

⁶⁷Cu has a formal charge of +2 in its complexed form, and the ionic radius of ⁶⁷Cu²⁺ is 71 pm, and is commonly complexed with a macrocyclic BCA, such as TETA (Fig. 2) (Meares et al. 1984; Moi et al. 1985). ⁶⁷Cu(II) can form stable octahedral complexes of coordination number 6 with DOTA and TETA. However, despite the high stability of the TETA-Cu complex, transchelation of Cu from the complex in liver has been observed in an in vivo experiment using a ⁶⁷Cu-TETA-antibody (Mirick et al. 1999). Recently, cross-bridged tetraamine macrocyclic (cyclam) ligands with nonadjacent nitrogens connected by an ethylene bridge were synthesized. These ligands increase the reduction potential of Cu(II), and thus, retard its electrochemical reduction to Cu(I), which is believed to facilitate copper dissociation from these complexes (Boswell et al. 2004). However, the complexation of Cu(II) with TETA derivatives requires an additional linkage site to maintain bifunctionality, because TETA has 6 binding sites, which are used for coordination with Cu(II). Moreover, the chelation reaction requires an elevated temperature (75 °C) which is not optimal for the post-conjugation labeling of proteins (Novak-Hofer and Schubiger 2002).

⁶⁷Cu is usually chelated by incubating it with BCA-conjugated peptides or proteins for 20–30 min at ambient temperature and pH ~5; excess and nonspecifically bound Cu(II) is sequestered with EDTA (Mirick et al. 1999).

⁶⁷Cu has been used for radioimmunotherapy by conjugating it to monoclonal antibodies (mAbs) or antibody fragments, which bind to tumor-specific antigens expressed by a large number of tumors (Postema et al. 2001; Smith et al. 1993; Hughes et al. 1997; O’Donnell et al. 1999). ⁶⁷Cu labeled receptor-specific peptide is also suitable for peptide receptor radionuclide therapy (PRRT). For example, ⁹⁰Y- and ¹⁷⁷Lu-octreotide derivatives have been used for treatment of neuroendocrine tumors. However, to date, radioactive copper-labeled peptides have only been used for ⁶⁴Cu imaging studies (Anderson et al. 2001; Lewis et al. 1999; Prasanphanich et al. 2007).

⁹⁰Y (β^–, E_max = 2.3 MeV, t_1/2 = 64 h) is of particular interest due to its high-energy pure β-particle emission with a 2.8 mm mean tissue penetrating depth. ⁹⁰Y can be produced from a generator by the decay of ⁹⁰Sr, and decays to stable ⁹⁰Zr. ⁹⁰Y has a half-life of 2.7 days, which is short enough to achieve a critical dosing rate and at the same time is long enough to allow the radiopharmaceutical to be manufactured and delivered for clinical use (Liu 2004). ⁹⁰Y has a charge of +3 when complexed, and an ionic radius of 104 pm. The BCAs commonly used to complex ⁹⁰Y are DTPA and DOTA derivatives (Brechbiel 2008).

The in vivo dissociation and transchelation reactions of ⁹⁰Y are the main sources of its toxicity. For example, reactions between ⁹⁰Y chelates and biologically important metal ions, such as Ca²⁺ and Fe³⁺, produce free ⁹⁰Y, which concentrates in bone and causes bone marrow toxicity. Competition between BCA and native chelators, such as amino acids and transferrin, may also result in the early release of ⁹⁰Y from ⁹⁰Y-labeled BCA-bioactive molecule (BM) conjugates (Liu 2004). To resolve these problems, DOTA derivatives, which form highly stable complexes, are better choices for ⁹⁰Y than DTPA derivatives (Carrasquillo et al. 1999; Eisenwiener et al. 2000).

To determine the biodistribution and radiation dosimetry of ⁹⁰Y, ¹¹¹In(III) is often used as a surrogate, because ⁹⁰Y does not emit γ-ray which is required for scintigraphic imaging in humans. The chelation chemistry of ¹¹¹In with polyaminocarboxylate ligands is similar to that of ⁹⁰Y (Wilder et al. 1996; Gordon et al. 2002).

⁹⁰Y is one of the most frequently used radioactive metals in clinical practice, due to its high-energy pure β emission and availability as a sterile pyrogen-free product with high specific activity. Radioimmunotherapy, which was initiated using ¹³¹I labeled monoclonal antibodies more than 30 years ago, provides a typical example of ⁹⁰Y radionuclide therapy. After much research and several clinical trials, ⁹⁰Y/anti-CD20 monoclonal antibody-based radioimmunotherapy was recently approved by the US Food and Drug Administration (FDA) as a therapeutic modality for B cell non-Hodgkin’s lymphoma (⁹⁰Y-ibritumomab tiuxetan; Zevalin; IDEC Pharmaceuticals, San Diego, CA).

A number of ⁹⁰Y-labeled peptides have been reported for PRRT, and ⁹⁰Y labeled octreotide derivatives (targeting somatostatin (SST) receptor) are being extensively used for neuroendocrine tumor therapy (Bodei et al. 2004).

⁹⁰Y labeled microspheres also are used for radioembolization purposes to treat hepatic cancer (Sangro et al. 2009). Microspheres having diameters larger than 10 μm accumulate in hepatic cancer after administration via the hepatic artery, the major supplier of blood to liver cancers, whereas the portal vein supplies most blood to normal liver tissue.

¹⁷⁷Lu is a relatively low-energy β-emitter that emits β-particles in three different maximum energy peaks (12 % 0.176 MeV, 9 % 0.384 MeV, and 79 % 0.497 MeV). It has a half-life of 6.75 days and a mean tissue penetrating depth of 0.28 mm. In addition, it emits γ-radiations of 113 keV (6.4 %) and 208 keV (11 %), which are useful for scintigraphic imaging. ¹⁷⁷Lu is a reactor-produced radionuclide and is produced by irradiating enriched ¹⁷⁶Lu in a reactor. ¹⁷⁷Lu can be prepared in high yields at medium to high specific activity comparatively cheaply (Liu 2004). Until recently, ¹⁷⁷Lu was only available from a reactor with a radioactive abundance of approximately 25 %. However, higher purity ¹⁷⁷Lu (approximately 50 % pure) is now available, and anticipated improvements in the production and purification of ¹⁷⁷Lu will allow further investigations to be conducted on its potential clinical utility (Michel et al. 2005a).

¹⁷⁷Lu has a formal charge of +3 when complexed. The ionic radius of ¹⁷⁷Lu (III) is 100.1 pm, and it is commonly complexed using DTPA and DOTA derivatives, such as ⁹⁰Y, because ¹⁷⁷Lu and lanthanide nuclides have chemical properties that resemble those of ⁹⁰Y. In particular, lanthanides and ¹⁷⁷Lu produce more stable complexes with DOTA than DTPA (Cacheris et al. 1987).

In terms of ¹⁷⁷Lu applications, the focus of research has been on PRRT, and to date, several types of tumor-specific peptides, such as octreotide derivatives for SST receptor, Arg-Gly-Asp (RGD) peptide derivatives for α_vβ₃ integrin, and bombesin (BBN) analogs for gastrin-releasing peptide (GPR) receptor, have been reported (de Jong et al. 2001; Yoshimoto et al. 2008; Thomas et al. 2009).

The performances of ¹⁷⁷Lu-based radioimmunotherapies have been compared with those based on ⁹⁰Y (Vallabhajosula et al. 2005; Fortin et al. 2007). In a recent study, it was demonstrated that ¹⁷⁷Lu-antibodies showed less non-specific cell killing than analogous antibodies labeled with ⁹⁰Y in Raji B lymphoma cells. This result was attributed to the much higher energy of the ⁹⁰Y β-particle (2.4 MeV) (Michel et al. 2005a).

¹⁷⁷Lu has also been examined as a palliative radiotherapy for cancer bone metastasis. In a comparative study of ¹⁷⁷Lu-EDTMP and ¹⁷⁷Lu-DOTMP, ¹⁷⁷Lu-EDTMP was found to accumulate in skeletal bone more so than ¹⁷⁷Lu-DOTMP, whereas ¹⁷⁷Lu-DOTMP was found to show lower retention in liver and kidneys and slightly greater blood clearance in animal models (Chakraborty et al. 2008).

Rhenium has two candidate therapeutic radioisotopes (¹⁸⁶Re and ¹⁸⁸Re). ¹⁸⁶Re emits β-radiation (E_max = 1.07 MeV, 91 %) and has a half-life of 3.68 days and a mean tissue penetration depth of 0.92 mm, and a γ-radiation (E = 137 keV, 9 %), which allows imaging during treatment. ¹⁸⁶Re is produced in a reactor by irradiating ¹⁸⁵Re with neutrons (¹⁸⁵Re(n, γ)¹⁸⁶Re). ¹⁸⁶Re is not available with high specific activity, which limits its usefulness.

¹⁸⁸Re was introduced relatively recently, and has excellent physical and chemical properties (Jeong and Chung 2003). ¹⁸⁸Re emits high-energy β-radiation (E_max = 2.12 MeV, 85 %) with a half-life of 16.98 h and has a mean tissue penetration depth of 2.43 mm. In addition, it emits γ-radiation (155 keV, 15 %) which allows imaging during therapy, and it produces better image qualities than ¹⁸⁶Re. ¹⁸⁸Re can be prepared either by nuclear reaction (¹⁸⁷Re(n, γ)¹⁸⁸Re) or using a ¹⁸⁸W–¹⁸⁸Re generator. Generator-produced ¹⁸⁸Re is carrier-free and has high specific activity. The major advantages of using ¹⁸⁸Re in therapeutic nuclear medicine are that it is readily available and inexpensive, because it is produced using ¹⁸⁸W–¹⁸⁸Re generator which has a long shelf-life (longer than 4 months) due to the long half-life (69 days) of the ¹⁸⁸W.

Rhenium and technetium are members of Group 7 of the periodic table, and therefore, have similar chemical properties. Accordingly, chelating agents suitable for technetium are also usually suitable for rhenium. However, the labeling conditions required, such as reaction temperatures, pH levels, and the amount of reducing agent, are often quite different. In general, rhenium requires higher reaction temperatures, lower pH levels, and higher concentrations of the stannous ion for reducing perrhenate than technetium.