Substituted phosphonate (Fig. 12.1) complexes represent attractive carrier molecules for targeting therapeutic radioisotopes to skeletal regions of increased osteolytic metabolism. Rhenium is a Group VIIb transition metal, and the ¹⁸⁶Re hydroxyethylidene diphosphonate (HEDP) complex, as an example, was developed in the 1980s for bone pain palliation and, in contrast to the traditional use of ⁸⁹Sr, had the added advantage of gamma photon emission (Table 12.1) which permits evaluation of localization with gamma camera imaging. It was expected that clinical use of this agent would rapidly progress but only became available locally on a physician prescription basis in Europe and was never approved for broad routine use because of apparent regulatory issue.

Although preparation of ¹⁸⁶Re-HEDP had been well established, the relatively low specific activity of reactor-produced ¹⁸⁶Re was a key requirement for preparation of the HEDP complex which was not initially realized. This was later established where only soft tissue uptake rather than skeletal localization was detected during evaluation of ¹⁸⁸Re HEDP prepared using very high specific activity no-carrier-added generator-produced ¹⁸⁸Re (Dash and Knapp 2015). In contrast, when carrier rhenium is added to similar levels encountered during the use of low specific activity ¹⁸⁶Re, the expected targeted skeletal localization is realized (Lam et al. 2008). In studies reported by Edler et al., the apparent reason for these observations is the unknown chemical structure of the Re(V)-HEDP species, which apparently consists of Re-Re bonds and is formulated as an oligomer (Elder et al. 1997). The authors used extended X-ray absorption fins structure (EXAFS) analysis to evaluate the species formed using nonradioactive rhenium and have formulated that the species formed in the presence of high levels of the stannous ion reductant probably represents a tetramer of rhenium atoms which are bridged by the HEDP ligands. This structure evidently also binds an equivalent number of tin atoms as well as additional HEDP ligands. Based on the levels of the stannous ion-reducing agent used, different species are apparently formed. When an excess of the stannous ion-reducing agent is used, the species formed appears to have the composition Li(x)Re₄(OH)₂Sn₄HEDP₁₂. Thus, ¹⁸⁶Re-HEDP and ¹⁸⁸Re HEDP described below are examples of agents which show specific targeted uptake but which have unknown chemical structures.

Samarium-153 is reactor-produced by the neutron irradiation of enriched ¹⁵²Sm targets (Sartor 2004) and is incorporated into the phosphonate entity, referred to as lexidronam (Fig. 12.2). With the emission of a moderate energy beta particle and an excellent half-life for outpatient applications, ¹⁵³Sm was evaluated as an alternative to ⁸⁹Sr for bone pain palliation (Bauman et al. 2005; Finlay et al. 2005; Silberstein 2005). Another advantage—which probably has not been fully appreciated until in more recent times—is the emission of a gamma photon, which permits the use of ¹⁵³Sm to monitor uptake/targeting, biokinetics, and evaluation of dose delivery in relation to therapeutic response. In the current developing era of “personalized medicine,” the use of dual beta-/gamma-emitting radioisotopes for these and other therapeutic applications thus offers several advantages.

Since both strontium and calcium are members of Group IIA the use of ⁸⁹Sr as a surrogate of calcium was an early strategy which had been explored and ⁸⁹Sr is still used for bone pain palliation. The evaluation of ⁸⁹Sr as a targeted agent for bone pain palliation was initially reported in Germany in 1946. This agent was later approved in the US by the Food and Drug Administration (FDA) as “Metastron®” in 1993 and has since that time been a widely used agent for bone pain palliation.

Another diphosphonate option for bone pain palliation utilized ¹³¹I, which is a readily available and well-established therapeutic radioisotope. Preparation and studies in a rat model were initially reported with the ¹³¹I-labeled α-amino-(4-hydroxybenzylidene)-diphosphonate (BPB3) agent (Fig. 12.3) (Eisenhut 1984). Iodine-131 radiolabeling was performed in about 95 % yield with a BPB3 specific activity of about 50 mCi/mg by electrophilic aromatic substitution using the iodate anion in 1 N HCl. The biokinetics, dosimetry data, and pain response were reported in initial studies in 18 patients with skeletal metastases from prostate, breast, and other primary carcinomas receiving doses from 6–48 mCi of ¹³¹I-BPB3 (Eisenhut et al. 1986a). In further studies, these authors then pursued evaluation of several structurally related radioiodinated benzylidenediphosphonates (BDP) with alpha and para position substitutions including -H, −OH, and -NH₂ (Eisenhut et al. 1987). The 4-methoxy- and 4-nitro-substituted diphosphonates were prepared by phosphorous acid treatment of the respective benzonitriles in the presence of phosphorus bromide (PBr₃). The 4-hydroxy and 4-nitro derivatives were then prepared by hydrolytic HBr cleavage and subsequent catalytic hydrogenation. Transformation of the 2-amino to the 2-hydroxy derivative was accomplished by treatment with sodium nitrate in HCl. The proposed structures of these derivatives were confirmed by chromatography, spectroscopy, and elemental analysis and were then radiolabeled with ¹³¹I. Further studies of these BDP analogs were focused on the comparative biokinetics and bone uptake values in Sprague Dawley rats. Total-body retention measurements of α-amino-(3-[¹³¹I]iodo-4-hydroxybenzylidene)diphosphonate analog revealed an effective half-life of the activity of 169 h. LD₅₀ measurements in rats amounted to 64 mg/kg. In addition, autoradiographic analyses were performed in bone samples obtained from osteosarcomic SD rats following intravenous administration (Eisenhut et al. 1986b). Apparently, these agents have not been evaluated further and subsequent patient trials have not been reported.

The bone is constructed of a complex hydroxyapatite matrix in which phosphorus plays an integral role. The use of beta-emitting ³²P as the phosphate had thus been an obvious candidate to evaluate for bone pain palliation since it mimicked the natural cation and has been cost-effectively available on a broad scale. In an IAEA-coordinated multicenter study (Fettich et al. 2003) to evaluate safety and efficacy of ³²P for palliation of bone pain due to bony metastases by comparing it to ⁸⁹Sr, or bone pain palliation, 93 cancer patients with osteoblastic bony metastases were included into the study of which 48 were treated by ⁸⁹Sr (150 MBq) and 45 by ³²P (450 MBq). The results of this study suggested that ³²P is slightly but not significantly less effective than ⁸⁹Sr for palliation of bone pain due to bony metastases. Although ³²P appears to be more toxic it is important to note that no toxic effects requiring specific treatment were seen in either group. This study inferred that ³²P was as safe as ⁸⁹Sr using doses up to 450 MBq (Fettich et al. 2001). The results of this study are expected to shed further light on the perspectives of ³²P for patients with painful skeletal metastases. In light of the cost-effective availability, widespread use of ³²P should be encouraged to reduce cost of medical care of patients with intractable bone pain due to cancer metastases, but further widespread use of ³²P for bone pain palliation has not been reported.

Very early during the assessment of beta-emitting radioisotopes for bone pain palliation ⁹⁰Y had been evaluated as a high-energy beta particle-emitting radioisotope for this application as the citrate complex but had not been subsequently widely used. Renewed interest in the use of ⁹⁰Y, however, resulted in the commercial release of the Multibone® agent (EDTMP) in central Europe for radiolabeling with ¹⁵³Sm, ⁹⁰Y, ¹¹¹In, and¹⁸⁸Re (Mitterhauser et al. 2004a, b). In this case, the strategy was to make available a common kit which could be used for radiolabeling with a variety of radionuclides. In the case of bone pain palliation, the use of beta emitters with different beta energies would permit the tailoring of irradiation of diagnosed metastases to minimize damage to normal tissue (Bouchet et al. 2000; Lewington 2005). The commercially available multibone EDTMP kit agent consists of EDTMP, SnCl₂, ascorbic acid, and glucose (Mitterhauser et al. 2004a, b). The ⁹⁰Y-DOTA conjugated 4-amino-1-hydroxybutylidene-1,1-bisphosphonate (⁹⁰Y-DOTA-HBP) (Fig. 12.4) has also been prepared and biodistribution studies compared with ⁹⁰Y-citrate in mice (Ogawa et al. 2009). The HBP analogs demonstrated much faster blood and most soft tissue clearance and higher bone accumulation. The advantage of further studies and potential human use of the HBP analogs is the very stable Y⁺³-DOTA complex, which would not release free ⁹⁰Y⁺³ for targeting to normal bone.

Because of its availability from the ¹⁸⁸W/¹⁸⁸Re generator which has a useful shelf-life of several months (Dash and Knapp 2015), the use of ¹⁸⁸Re-HEDP offers many benefits. In addition to similarity to the established use of ¹⁸⁶Re-HEDP, the ¹⁸⁸Re-HEDP has been extensively evaluated on a clinical trial basis with extensive discussion in the literature. Within the basic science and clinical research communities, ¹⁸⁸Re-labeled bone pain palliation agents have by far seen the greatest progress.

More recently, several studies have described the use of ¹⁷⁷Lu-labeled phosphonate complexes for bone pain palliation. Lutetium-177 is a lanthanide (+3) therapeutic radioisotopes of great interest (Banerjee et al. 2015), since it can be reactor-produced even at moderate thermal neutron flux with very high specific activity (Dash et al. 2015). Ando et al. have reported for the first time the utility of ¹⁷⁷Lu-ethlyendiammine tetramethylene phosphonate (EDTMP; Fig. 12.9) (Ando et al. 1998). In one study, the International Atomic Energy Agency (IAEA) sponsored a multicenter trial evaluating the efficacy of ¹⁷⁷Lu-ethlyendiamminetetramethylenephosphonate (EDTMP) (Chopra 2011).

In addition, the ¹⁷⁷Lu-labeled (DOTMP) has also been evaluated. The ¹⁷⁷Lu-labeled (4-{[bis-(phosphonomethyl) carbamoyl} methyl}-7,10-bis (carboxymethyl)-1,4,7,10-tetraazacyclododec-1-yl)acetic acid (BPAMD; Fig. 12.10) has been developed as a new bone pain palliation agent (Fellner et al. 2010). The +3 DOTA is an excellent lanthanide-chelating moiety which has the specific advantages of very tightly binding +3 metal and allowing very facile nearly quantitative radiolabeling yields of lanthanides under mild conditions with the formation of a highly stable Lu complex. Initial human trials have demonstrated the excellent targeting of this agent in skeletal lesions (Fellner et al. 2010) and MIRD/OLINDA/EXM dosimetry estimates utilizing data from 8 patients with skeletal metastases from prostate cancer have also been recently reported (Schuchart et al. 2013; Yousefnia et al. 2015). These studies have demonstrated very rapid blood clearance whole-body biexponential clearance with a second half-life of 62 ± 19 h and a metastases site clearance of 57–162 h. In addition, the broad interest in the production and use of ¹⁷⁷Lu (Pillai and Knapp 2015)—currently focused on the use of therapeutic peptides such as ¹⁷⁷Lu-DOTATATE and DOTATOC—would suggest that the expected broad availability of pharmaceutical grade ¹⁷⁷Lu may catalyze further interest and broad use of ¹⁷⁷Lu-BPAMD.