Radiopharmaceuticals for Bone Metastases

  • Benedetta Pagano
  • Sergio Baldari


Bone-seeking radiopharmaceuticals play a significant role in the treatment of metastatic pain as an alternative, or in addition, to classic palliative treatment.

Until a few years ago, radionuclides for the management of prostate cancer consisted of several beta-emitting agents, such as strontium (89Sr), phosphorus (32P) and samarium (153Sm) as well as rhenium (186Re and 188Re), which only exhibit a palliative effect in patients with extensive skeletal disease.

Radium (223Ra) dichloride represents a new generation of radiopharmaceuticals, being the first targeted alpha-emitting agent approved, which improves overall survival, postpones skeletal-related events (SREs) and controls bone pain.

Conjugates of bisphosphonates (BP) with macrocyclic chelators open new possibilities in bone-targeted radionuclide imaging and therapy, when labelled with positron and beta-emitting radiometals. [68Ga/177Lu]DOTAZOL appears to be the best leading compound showing fast blood clearance, low uptake in soft tissue and high accumulation in the skeleton.

Prostate-specific membrane antigen (PSMA) is an attractive target for diagnosis and therapy of prostate cancer. 177Lu-PSMA-617 is a new treatment option, which is not solely directed to bone metastases, but also demonstrates “antitumour” activity with limited and well-tolerated side effects.

26.1 Introduction

Bone pain due to skeletal metastases is one of the complications experienced by the majority of patients suffering from prostate cancer. These patients receive palliative care to improve quality of life. Bone-seeking radiopharmaceuticals play a significant role in the treatment of metastatic pain as an alternative, or in addition, to classic palliative treatment.

The choice of the radiopharmaceutical is based on the physical properties of the radionuclide, in relation to the extent of metastatic disease and bone marrow reserve and on availability in individual countries. Ionizing radiation can be selectively delivered to areas of increased osteoblastic activity, allowing the targeting of multiple metastases simultaneously, including both symptomatic and asymptomatic lesions. The goal of such irradiation is to kill tumour cells in the bone while sparing normal bone marrow, the site of haematopoiesis.

Until a few years ago, radionuclides for the management of prostate cancer consisted of several beta-emitting agents, such as strontium (89Sr), phosphorus (32P) and samarium (153Sm) as well as rhenium (186Re and 188Re), which only exhibit a palliative effect in patients with extensive skeletal disease. Radium (223Ra) dichloride represents a new generation of radiopharmaceuticals and a fundamental advance for nuclear medicine application, being the first targeted alpha-emitting agent approved, which improves overall survival, postpones skeletal-related events (SREs) and controls bone pain.

The insertion of radium in the armamentarium for the therapy of bone metastases has created enthusiasm regarding the contribution of nuclear medicine for improved management of prostate cancer patients. The great effort of chemists, pharmacists, biologists, physicists and physicians is the key to progress in bone therapy benefitting from an increased understanding of both physiological and pathological molecular processes. Among the more recent and developing applications, the theranostic approach covers a major role, where therapy is closely supported by imaging.

Conjugates of bisphosphonates (BP) with macrocyclic chelators represent an excellent example, opening new possibilities in bone-targeted radionuclide imaging and therapy, when labelled with positron and beta-emitting radiometals. Lutetium (177Lu) complexes of macrocyclic BPs might become options for therapy of skeletal metastases in the near future (such as 1,4,7,10-tetraazacyclododecane-1,4,7,10 tetracetic acid (DOTA)-based zoledronate), showing fast blood clearance, low uptake in soft tissue and a high accumulation in the skeleton.

Furthermore, thanks to recent developments in radiopharmaceutical chemistry, prostate-specific membrane antigen (PSMA) targeting has arisen as a key strategy for the development of several selective molecular agents. PSMA is highly and specifically expressed on the surface of prostate tumour cells and represents a promising theranostic target for radioligand imaging and therapy beyond metastatic bone disease. 177Lu-PSMA-617 is a new treatment option for metastatic castrate-resistant prostate cancer (mCRPC), which is not solely directed to bone metastases, but also demonstrates “antitumour” activity with limited and well-tolerated side effects.

26.2 Evolving Role of Targeted Radionuclide Therapy in Bone Metastases

Radionuclide therapy is indicated for the treatment of bone pain due to skeletal metastases associated with an osteoblastic response on bone scintigraphy; it is also indicated for the treatment of painful skeletal metastases, inadequately treated by analgesics, intolerant to analgesics and hormone resistant (metastatic castrate-resistant prostate cancer, mCRPC) [1].

The treatment of patients with bone metastases has dramatically changed over the last few years, due to new therapeutic approaches addressed to obtaining pain control, reducing skeletal morbidity and, most importantly, increasing survival rate. A possible therapy can be based on the use of radiopharmaceuticals systemically administered to slow or reverse bone metastatic progression. Bone-homing radiopharmaceuticals are taken up in areas of high bone turnover, including areas with high osteoblastic activity [2].

Although a large number of such radiotracers have been developed and have undergone preliminary biological investigations, only few radiopharmaceuticals have been administered in human patients and find regular use in clinics. The reasons rely probably on the competition with application of “classic” medical approaches and the lack of general consensus on the use of radioactive compounds. Furthermore, most radiopharmaceuticals show only partial benefits over the disease while requiring specific handling procedures, thus restricting application to nuclear medicine departments. Last but not least, regulatory and clinical development aspects should be considered for introductions into clinical practice, together with economic interests from the major pharmaceutical companies [3].

Radiopharmaceuticals for the treatment of bone metastases are particular with respect to standard therapies regarding mechanism of action. Treatment success depends on matching the pathophysiologic characteristics of the target tissue to a specific radiopharmaceutical. Once the chemical structure of a potential new radiotracer has been identified for a specific biological target, the next step is to synthesize the desired compound by coupling an emitting nuclide suitable for therapy.

For calcium mimetic and phosphate agents, it is the radionuclide itself which delivers the therapeutic emission on bone lesion, which shows elevated uptake because of altered matrix turnover.

This is the case of the first use of systemic radionuclide therapy, with the advent of strontium (89Sr) in the 1940s, which was quickly followed by the discovery of phosphorus (32P) as a potential radiotherapeutic agent for metastatic bone cancers. However, the use of 32P-phosphate became increasingly unpopular due to its high bone marrow toxicity, whereas 89Sr was approved in Europe in 1992 for treatment of painful bone metastases [4, 5, 6].

In a poor therapeutic context, several agents have been designed and developed during the last two decades, such as rhenium phosphonate complexes ( 186 Re and 188 Re) that show similar indications but also shorter half-lives. However, despite the fact that a considerable number of radiolabelled molecules have been introduced into clinical trials, only a few have reached clinical approval in nuclear medicine. The late 1990s saw the authorization of samarium ( 153 Sm) in an attempt to utilize several advantages over the radioisotopes mentioned above, culminating in the evolution of novel α-emitting radium ( 223 Ra) as the radiopharmaceutical of great potential. 223 RaCl2 is the first radiopharmaceutical drug to demonstrate a prolongation of overall survival of patients with prostate cancer [7, 8].

26.2.1 The Ideal Radiopharmaceutical for Bone Pain Palliation

The success of a radiopharmaceutical being used for bone pain palliation depends on several factors, such as feasibility of production or sourcing of the radioisotope, nuclear decay characteristics, molecular structure and feasibility of formulation of the radiopharmaceutical, pharmacokinetic behaviour in vivo, logistics of distribution and cost-effectiveness [9].

When designing therapeutic radiotracers, the following key factors are taken into account: choice of the target indicative or representative of the pathology, identification of the lead compound/structure with specificity for the target, selection of the radionuclide and labelling strategy to synthesize the desired chemical structure. In addition, to allow the radioactivity to distribute into bone lesions, radiotracers should ideally exhibit rapid and quantitative absorption to bone matrix, high affinity and selectivity for the target, in vivo stability and absence of radioactive metabolites and favourable pharmacokinetic and pharmacodynamic properties in relation to radionuclide half-life [10].

The half-life of the radionuclide in a radiotracer should correlate with the kinetic of the process to investigate. In other words, the radiotracer, after injection, should reach the bone matrix and interact quantitatively with the target, in a time frame that must be consistent with the radionuclide half-life to avoid an unnecessary radiation burden on patients [11, 12].

However, most radiotracers are significantly metabolized in vivo. The nature and degree of the metabolism (biological half-life) of a radiolabelled compound depend on its molecular structure, and this can have a significant influence on radioactive distribution and, eventually, on the reliability of the therapeutic effects [13].

Typically, radiopharmaceuticals must meet several specifications in order to fulfil clinical requirements, including high specific activity, high radiochemical and radionuclide purity and high radiochemical yield. No-carrier-added (NCA) radionuclides are ideal to obtain high specific activity radiotracer. This will ensure that radioactive carrier molecules are delivered to the tumour, thus improving the delivery of radiation absorbed dose per unit of injected activity [14].

Specific activity is an important parameter to assess during radiotracer development, and it is defined as the amount of radioactivity per unit mass of a radiolabelled compound. This mass includes the mass of the radioactive product and the mass of its nonradioactive counterpart. Every radioactive molecule is characterized by a specific activity; however, its evaluation may not be critical for all application with radiotracers. On the other hand, specific activity becomes crucial when the radioactive and nonradioactive molecules contained in the radiotracer batch may produce undesired pharmacodynamics-toxicological effects as well as target occupancy [15].

Trabecular bone is considered a large capacity site and does not require a radionuclide with very high specific activity. For this reason, the need of a radionuclide with high specific activity for treatment of bone metastases is less pressing than other targeted therapies. Under this premise, medium-low specific activity radionuclide can generally be used for palliative treatment of bone metastases [16].

Several factors, regarding pharmaceutical requirements for human use, are also imposed by drug regulatory authorities. Current radiopharmaceutical development shares much with standard drug discovery and development practices, and although therapeutic radiopharmaceuticals are generally administered only a few times in a patient’s lifetime and adverse reactions are extremely rare, the safety profile of a new radiotracer has to be demonstrated and validated. This assessment includes the evaluation of pharmacological and toxicological activity of the therapeutic preparation (including any component other than the labelled tracer) and the estimation of the absorbed radiation activity to prove a favourable risk-to-benefit ratio [12].

Ideally, the emission characteristics of a therapeutic radionuclide should match the lesion size/volume to be treated to focus energy within the tumour rather than in the tissue surrounding the lesion.

Although beta-emitting radiopharmaceuticals used for the treatment of painful bone metastases differ in physical and biochemical characteristics, several studies reported differences in onset and duration of response, but did not report significant differences in response rate or bone marrow toxicity. The onset of response is rapid after treatment with short-lived isotopes (153Sm-EDTMP, 186Re-HEDP and 188Re-HEDP) and prolonged for a few weeks after treatment with long-lived isotopes (89Sr, 32P). The duration of response is longer for long-lived radioisotopes than for short-lived isotopes. Therefore, patients with progressive disease and pain, for whom rapid relief is required, are best treated with short-lived isotopes with acceptable toxicity and easy repeatability, while patients with better prognosis and better clinical condition may be treated with long-lived isotope [16].

26.2.2 Classification and Mechanism of Action of Bone-Seeking Radiopharmaceuticals

Therapeutic bone-seeking agents can be divided into two principal chemical classes:
  • Calcium mimetics and phosphate

  • Phosphonate chelating agent or non-calcium analogues (bone seekers with different mechanism of uptake into the bone)

The mechanism of uptake varies depending on the chemical behaviour of the radiopharmaceutical. The first class behaves like Ca2+ analogues (223RaCl2 and 89SrCl2) or phosphate anion (Na32PO4). These species target the bone because of their periodic similarity to natural constituents. They do not need a non-radioactive substance as a carrier to reach the target, and accumulate at high concentrations at sites of active bone remodelling, where osteoblastic activity is increased.

On the other hand, non-calcium analogues show no natural affinity for bone and thus need to be complexed with a chelator (organic phosphates and diphosphonate) to which the radioisotopes are chemically attached, in order to be chemisorbed in bone hydroxyapatite crystals Ca5(PO4)3(OH) by forming hydroxide bridges. The carriers are hydroxyethylidene diphosphonate (HEDP) or etidronate for 186Re and 188Re and ethylenediamine tetramethylene phosphonate (EDTMP) or lexidronam for 153Sm [17, 18, 19, 20].

A further evolution to this second approach is represented by the use of novel bisphosphonates chelated at 1,4,7,10-tetraazacyclododecane-1,4,7,10 tetracetic acid (DOTA), which is opening new possibilities in the theranostic field, as they can be used as both imaging and therapy agents depending on the radionuclide employed when labelled. Following positron emission tomography (PET) examinations utilizing 68Ga-labelled analogues, radioligand therapy with lutetium (177Lu)-labelled macrocyclic bisphosphonates may have great potential in the treatment of painful skeletal metastases [21, 22].

Other than the fact that the mechanism of most radiopharmaceuticals is based on the well-known matrix turnover, the exact therapeutic effect of bone-seeking radiopharmaceuticals is not fully understood. A possible explanation is that radiation-induced tumour necrosis decreases the number of cells involved in inflammatory and immunological reactions, consequently reducing chemical mediators such as growth factors and cytokines that increase pain perception [23, 24, 25]. Therefore, in many patients, the use of opiates and other analgesics is considerably reduced.

26.2.3 The Choice of a Radionuclide with Appropriate Emission Properties

The first radiopharmaceuticals were formulated containing beta-emitting radionuclides, while during the last decade, alpha emitters have become important for the design of new agents for therapy. The differences between alpha and beta particles are energy, tissue range, linear energy transfer (LET) and number of DNA hits needed for cell killing. In general, for therapeutic purposes, alpha particles are preferred to beta particles. They are characterized by higher energy, higher LET and a short range in tissues, resulting in a dense deposition of energy very close to the origin of decay [3, 26, 27, 28].

However, the relative radiosensitivity of tumour cells can depend on several factors, including the local environment (e.g. state of oxygenation) and the quality of the radiation to which they are exposed. This fact is particularly relevant considering that bone is a hypoxic tissue. It would appear that, at the same dose, high LET radiation is more destructive, as energy is transferred to a small region of the cell. Therefore, it impacts on the DNA damage which, being concentrated, is more difficult to repair than diffused DNA damage.

Radiobiology demonstrates that cytotoxicity due to the effect of alpha particles is more effective than beta particles, leading to cell death in fewer interactions. The short range of tissue penetration of alpha particles has another important consequence: lower irradiation of neighbouring areas. In the case of bone metastases treatment, this implies lower myelotoxicity [11, 29].

26.2.4 Development of New Molecular Targets with Application Both in Imaging and Therapy

For a long time, radiopharmaceuticals for prostate cancer therapy were limited to bone lesions because of the specificity to the matrix. The latest application has been developed in order to overcome this limitation providing widespread therapeutic action similar to those of the classic pharmaceuticals.

The development of new therapeutic agents for prostate cancer follows a modern approach based on two main steps: first, the identification of the biological process indicative of the pathology and second, the identification of the molecular target best representing the process. This target will virtually represent the chemist’s workbench for the design of the proper chemical structures.

Prostate-specific membrane antigen (PSMA) is an attractive target for diagnosis and therapy of prostate cancer since expression levels are directly correlated to metastatic and hormone-refractory cancers. PSMA is a transmembrane protein, also known as glutamate carboxypeptidase (GCPII), which is anchored in the cell membrane of prostate epithelial cells and overexpressed at all tumour stages on the surface of prostate tumour cells in comparison to benign prostatic tissue. Radiolabelling of small molecular weight PSMA inhibitors with 177Lu has been obtained (such as 177Lu-PSMA-617), and results of several clinical studies have been published [30, 31].

26.3 Radiopharmaceuticals for Bone Metastases

26.3.1 Calcium Mimetics and Phosphate Strontium [ 89 Sr] Dichloride

Strontium (89Sr) dichloride (89SrCl2, commercial name Metastron®) is used for providing palliative care to patients suffering from bone pain due to skeletal metastasis. It was the first radiopharmaceutical to be approved in the European Union in 1992 (GE Healthcare, United Kingdom) and is indicated for men with hormone-relapsed prostate cancer and painful bone metastases, especially in those who are unlikely to receive myelosuppressive chemotherapy (Clinical guideline [CG175] January 2014) [32, 33].

89Sr has a long physical half-life of 50.7 days and decays to stable yttrium (89Y) by emitting beta particles with maximum energy E(max) = 1.492 MeV, mean energy E(mean) = 0.58 MeV and only 0.01% gamma emission, with energy of 909 keV. The therapeutic effects derive from beta particles, which have maximum tissue penetration range of approximately 7 mm [10, 34, 35, 36, 37].

Physical characteristics of bone-seeking radionuclides are shown in Table 26.1.
Table 26.1

Physical characteristics of bone-seeking radionuclides


Half-life (days)

Particle emission E(max) (MeV)

Energy gamma (γ) particles (MeV)

Maximum tissue penetration (mm)

Beta emitter



β 1.492 (99.99%)

0.910 (0.01%)




β 1.710 (100%)




β 0.807 (21%)

0.103 (28%)




β 1.077 (72%)

0.137 (9%)




β 2.118 (72%)

0.155 (15%)




β 0.497 (78.7%)

0.208 (11%)




β 2.284 (100%)


Alpha emitter



7.39 (95.3%)

0.82 (1.1%)


The standard recommended activity is 1.48 MBq/Kg for all patients, where administration of larger activities of this radiopharmaceutical results in higher myelosuppression. Toxicity is generally limited to a temporary reduction in leucocyte and platelet counts [3, 19].

Strontium is one of the alkaline earth metals and a member of family IIA in the periodic table, as is calcium. It acts as a calcium mimic and accumulates at sites of high osteoblastic activity through incorporation into mineralizing collagen during new bone formation. The sites of osteoblastic bone metastases show higher accumulation and longer retention compared to areas of normal bone in the same patient. Symptomatic improvement usually occurs within 6 weeks after i.v. injection, with a mean duration of relief of 3–6 months in approximately 50–60% of patients [8, 38, 39]. Retreatment for responders is possible at intervals of not less than 3 months. The success of 89Sr in providing this benefit probably relates to the long effective half-life of this radiopharmaceutical in the bone. After intravenous injection, 89SrCl2 is excreted by both the genitourinary (80%) and gastrointestinal (20%) systems. Urinary excretion is greater in the first 2 days following injection, and approximately 30–35% of the radiopharmaceutical remains in the bone after 90 days [20, 36].

Table 26.2 shows summary of the key clinical outcomes of different radiopharmaceuticals.
Table 26.2

Summary of the key clinical outcomes of different radiopharmaceuticals


Pain response to therapy (%)

Duration of therapeutic response (months)

Recommended therapeutic activity

Main elimination route




1.48 MBq/kg





0.055 MBq/kg





370–444 MBq





37 MBq/kg





1295 MBq





2960–3300 MBq


89Sr is usually produced via 88Sr(n, γ)89Sr reaction, but the need for highly enriched target material to avoid formation of concomitant radionuclidic impurities makes this radioisotope quite expensive.

It can also be produced using the 89Y(n, p)89Sr route. This nuclear reaction suffers from very low cross-section, thus making the agent expensive and thereby unaffordable for the majority of patients. In fact, the production of 89Sr with reasonable yield and specific activity suitable for therapeutic applications is difficult in reactors [14, 18].

Although 89SrCl2 has been proven to be efficacious in retarding, as well as controlling bone pain, haematological toxicity becomes a relevant impediment to the widespread use of this radiopharmaceutical. Several observations suggest higher and often delayed myelotoxicity for 89Sr. However, as widely confirmed in literature data, the percentage of early haematological complications is accounting for approximately 25% of cases. The degree of bone marrow suppression appears associated with the proportion of 89Sr accumulated and retained in the bone. The risk of such complications increases proportionally to not only every administered dose of radioisotope but also is a result of prior or concurrent treatment with other anticancer modalities such as radiotherapy, chemotherapy, hormonotherapy or symptomatic pain treatment, etc. Unfortunately, each of these combinations is related to an increase in probability of side effects [38]. Radium [223Ra] Dichloride

Radium (223Ra) dichloride (223RaCl2, Alpharadin) represents a new generation of bone-targeting agents to significantly improve patient overall survival while reducing pain and symptomatic skeletal events (SSEs).

On 13 November 2013, the European Union approved the use of 223RaCl2 (with the brand name Xofigo®, Bayer Pharma AG, Germany) for the treatment of patients with mCRPC, symptomatic bone metastases and unknown visceral metastatic disease, on the basis of the results of the ALpharadin in SYMPtomatic Prostate CAncer (ALSYMPCA) trial [40, 41, 42].

223Ra is widely used, as its decay chain and half-life (T1/2 = 11.4 days) have good characteristics for biomedical application. The alpha particle range is less than 100 μm (less than 10 cell diameters) which minimizes damage to the surrounding normal tissue [10, 43] (Table 26.1).

223Ra decays via a chain of short-lived daughter radionuclides to stable lead (207Pb), producing four alpha particles for each atom with high energy deposition (each composed of two protons and two neutrons) and two beta particles with a total decay energy of 28 MeV: 95.3% of the energy is due to alpha emissions (energy range of 5.0–7.5 MeV). The fraction emitted as beta particles is 3.6% and only 1.1% of the energy emitted is gamma rays. The first three alpha emissions occur within 5 s: in this period, significant translocation between organs does not happen. However, it is likely to occur during the last alpha decay (211Pb decay to 211Bi with a t1/2 of 36 min) [12, 44, 45, 46].

Table 26.3 shows decay of radium-223 dichloride.
Table 26.3

Decay of radium-223 dichloride (223RaCl2)


Alpha energy

Beta energy

T 1/2


5.64 MeV

11.4 day


6.75 MeV

4.0 s


7.39 MeV

1.8 ms


0.45 MeV

36.1 min


6.55 MeV

2.17 min


0.49 MeV

4.8 min

Pb-207 stable


223Ra is administered intravenously in its cationic form (223Ra++) bound to dichloride (2Cl) forming the radiopharmaceutical 223RaCl2, soluble in water. The use of 223RaCl2 is simple and easy, it does not require lengthy preparation and handling (ready-to-use), and it can be administered in a hospital outpatient setting. 223RaCl2 is a sterile solution, which is supplied in single-dose vials. The recommended dosing schedule is one intravenous injection every 4 weeks for 6 months (for a total of six injections), with an activity per injection of 55 kBq/kg body weight. The volume of the administered agent to achieve the required dose must be calculated using a combination of patient body weight (kg), radioactive concentration of the product (1100 kBq/mL) at reference date (given on the vial) and decay correction factor to correct for physical decay of 223Ra [47, 48].

223Ra is a therapeutic alpha particle-emitting pharmaceutical that acts as a calcium mimetic by forming complexes with the bone mineral hydroxyapatite in areas of high bone turnover, thereby directly targeting the areas of bone metastases. Alpha particles induce a highly localized biological effect, producing non-repairable double-stranded DNA breaks and subsequent cell killing, while limiting damage to the surrounding normal tissue; undesired off-target effects in the bone environment, especially on bone marrow cells, are minimized. It appears that alpha particles are more cytotoxic than beta particles, especially under hypoxic conditions, and because of their higher biological efficacy, the required activity is lower than that of beta particles. The high linear energy transfer of alpha emitters is 80 keV/μm [43, 49, 50, 51].

Repeated administration of 223RaCl2 results in pain responses of 50–60%. In general, 223Ra is well tolerated, and myelosuppression is one of the most significant adverse events [52, 53]. The total skeletal uptake of 223Ra in patients with osteoblastic bone lesions is estimated to range between 40 and 60% of the administered dose, and 223Ra uptake in bone increased up to 24 h without significant redistribution of daughter nuclides from bone (2% at 6 h and <1% at 3 days) [28, 54].

223Ra is an isotope that decays and is not metabolized. After intravenous injection, it is rapidly cleared from the blood (10 min). It is taken up primarily into the bone or is excreted by the intestine (without significant uptake in nontarget organs such as the heart, liver and spleen); less than 1% of the activity can be found in the blood at 24 h. Approximately 63–76% of injected radioactivity is eliminated from the body within 7 days. The principal route of excretion is through the gastrointestinal tract (about 51% at 24 h), while urinary excretion is negligible (approximately 5%) [55, 56, 57, 58] (Table 26.2).

223Ra is produced relatively inexpensively, readily and in large amounts from the decay of actinium-227 (227Ac) (half-life 21.7 years) using a long-term 227Ac-based generator system (227Ac is produced by neutron irradiation of the available 227Ra). The comparatively longer half-life of 223Ra provides sufficient time for the preparation of the agent, its distribution to distant places and administration to patients [2].

The use of 223RaCl2 in different clinical conditions needs to be thoroughly evaluated to maximize the advantages of each available treatment in a multidisciplinary, individualized approach to the patient. In other words, a deeper insight into the mechanism of action on the tumour microenvironment may provide the rationale for an association of 223RaCl2 with other drugs and their sequential use in clinical practice [49, 59, 60, 61, 62]. Sodium Phosphate [32P]

Phosphorus (32P) was introduced for treatment of metastatic bone pain in 1942 and was the most widely used radiotracer until the 1980s.

32P is a beta emitter radiopharmaceutical with physical half-life of 14.3 days, E(max) = 1.71 MeV, E(mean) = 0.696 MeV and the maximum tissue penetration range of approximately 8.5 mm [10, 34] (Table 26.1).

32P is absorbed in the particles of hydroxyapatite, one of the major constituents of bone matrix, and causes cell death when it decays to stable sulphur (32S). The radiopharmaceutical is usually administered either through an intravenous pathway (such as sodium orthophosphate, Na32PO4) or by oral route. The monograph “sodium phosphate (32P) injection” is reported in both the European and US Pharmacopeia [63, 64].

The administered therapeutic activity generally varies between 185 and 370 MBq when injected intravenously and between 370 and 444 MBq when delivered through oral route. Following administration, 85% of the activity is incorporated into the bone matrix with pain palliation in 50–70% of patients and a mean response duration of 2–4 months, but it is also associated with a 20–30% incidence of significant bone marrow toxicity [35, 36] (Table 26.2).

This radionuclide can be prepared by neutron activation of natural phosphorus 31P(n,γ)32P (100% abundance) or sulphur 32S(n,p)32P (95.02%). The nuclear reactor using (n,p) reaction employing 32S as the target material yields 32P in no-carrier-added form; however, several hundred grams of sulphur target are required in order to produce GBq quantities of 32P. Furthermore, specific activity can be considerably reduced by the introduction of 31P impurities during the radiochemical processing. Due to the low production cross-section and the large irradiation volumes required, the cost of 32P is considerably high.

32P can also be produced by direct neutron capture using elemental phosphorous as the target, which is a simpler and more cost-effective method. This production involves comparatively simple radiochemical processing, thereby reducing the processing time and radiation exposure. However, 32P produced via this route is of very low specific activity and hence not suitable for many applications [36, 65].

The long half-life of 32P displays favourable nuclear properties for the supply of this radiopharmaceutical to nuclear medicines far from its production site without much loss of activity due to radioactive decay. However, unfortunately, despite its efficacious nature, as well as economic availability, the use of the agent steadily declined due to the high tissue penetration range of the emitted radioactive particles, which causes severe bone marrow toxicity including myelosuppression and pancytopenia [37].

26.3.2 Phosphonate Chelating Agents or Non-calcium Analogues Samarium [153Sm] Lexidronam Pentasodium

Samarium (153Sm) is a member of the lanthanide series labelled EDTMP (ethylene diamine tetramethylene phosphonic acid, lexidronam), commonly known by the trade name Quadramet®. It is a beta-emitting radiopharmaceutical that was approved by the European Union in 1998 (CIS Bio International, France) for alleviating bone pain in cancer patients suffering from skeletal metastases [66].

153Sm emits beta particles with a half-life of 1.95 days, E(max) = 0.807 MeV and E(mean) = 0.23 MeV; the maximum tissue penetration range of the beta particles is approximately 4 mm [16, 34]. It is also a gamma emitter of 103 keV (28%) that allows correlation with conventional technetium-99 m (99mTc) bone scans (Table 26.1). Notably, the gamma emission from this agent enables localization of bone metastases through imaging, making this bone-seeking radioisotope useful for both diagnostic and therapeutic purposes [8, 35].

153Sm-EDTMP is administered intravenously as pentasodium salt with molecular mass of 696 g mol−1. EDTMP is a polydentate ligand that chelates 153SmCl2 (1:1) by forming four O-153Sm bonds and two N-153Sm bonds. It is bone-seeking as EDTMP contains four phosphonate moieties and is structurally similar to bisphosphonates. Figure 26.1 shows chemical structures of non-calcium analogues.
Fig. 26.1

Chemical structures of non-calcium analogues

The ability of bisphosphonates to target bone is due to their great affinity for inorganic hydroxyapatite in sites of accelerated bone turnover. It is proven that as 153Sm-EDTMP readily chelates calcium cations, the compound accumulates in the metastatic sites where metabolism, and thus calcium levels, is high. The cytotoxic irradiation delivered by the beta decay of 153Sm kills malignant cells in the bone and thus can relieve pain [18].

However, the chelating properties of EDTMP produce a reduction in blood calcium levels, and this led to the development of a 153Sm-Ca/Na-EDTMP complex which, due to the presence of added calcium in the formulation, prevents the decrease in plasma calcium levels and is now considered safer. The addition of calcium to the formulation reduces the potential toxicity without changing the biodistribution [67].

153Sm-EDTMP given at 37 MBq/kg leads to pain reduction in 62–84% of evaluated patients for as long as 2–4 months. The radiation dose to the red marrow from activity in the blood is assumed negligible [3, 36, 37, 38, 39].

The relatively shorter half-life of 153Sm (compared to 89Sr and 186Re) enables faster radiation delivery and rapid clearance from the body after intravenous injection, making it a suitable radionuclide for bone-targeted treatment. Approximately half of the injected dose is excreted into the urine after 6–7 h. The remaining dose (<45%) is deposited in bone with little accumulation in soft tissue, such as the liver. Metastatic lesions can accumulate about five times more 153Sm-EDTMP than healthy bone tissue. Less than 1% of the injected dose remains in the blood 5 h post injection [39, 66, 68] (Table 26.2).

153Sm can be produced from neutron capture of natural or isotopically enriched 153Sm (as Sm2O3) in a nuclear reactor. Due to the large thermal neutron capture cross-section of 152Sm(n,γ)153Sm reaction, 153Sm can be produced in large quantities and with high specific activity. The reaction is high yielding (>99%) and creates only trace amounts of by-products europium-152 (152Eu) and europium-154 (154Eu). Because Sm+3 metal has some distribution to the liver, lung and spleen, it is important that 153Sm-EDTMP preparations be of high quality, with little or no unchelated Sm+3 to avoid liver uptake and potential hepatotoxicity [2, 69].

The simple postirradiation radiochemical processing and easy formulation of the radiopharmaceutical, either by using a freeze-dried kit or in situ at the hospital radiopharmacy, make this agent attractive for large-scale commercial utilization. However, one of the major drawbacks associated with the agent comes from the comparatively shorter half-life of 153Sm which causes significant loss of activity due to radioactive decay. This in turn necessitates production and handling of a much higher quantity of radioactivity to deliver the desired dose to the end user [9]. Rhenium [186Re/188Re]etidronate

Rhenium-186 (186Re) and rhenium-188 (188Re) are two isotopes linked to hydroxyethylidene diphosphonate (HEDP, the generic name of this chelator is etidronate) and are bone-seeking radiopharmaceuticals used for radiometabolic treatment of painful bone metastases (Fig. 26.1).

These radiopharmaceuticals show no natural affinity to the bone and need to be complexed with a chelator (organic phosphates) to be chemisorbed into calcium atoms in bone hydroxyapatite crystals by forming hydroxide bridges in a hydrolysis reaction.

Interestingly, the chemical properties of rhenium are similar to technetium as both these elements exist in group VIIB of the periodic table and label the carrier molecule with either 186Re and 188Re for target radiotherapy or the most used imaging radionuclide, technetium-99 m (99mTc) [70].

However, though technetium and rhenium possess a chemical analogy with each other, it is known that rhenium complexes are more difficult to prepare than technetium analogues. Rhenium complexes have a higher tendency to reoxidize back to perrhenate than the analogous technetium complexes. This reoxidation, and consequently, the presence of high radiochemical impurities in the final product, is one of the major hindrances in the development of rhenium radiopharmaceuticals [28].

Rhenium [ 186 Re]etidronate

In the late 1980s, 186Re-HEDP was identified as a potential agent for palliative treatment of bone metastases. 186Re is a beta emitter with E(max) = 1.077 MeV, E(mean) = 0.349 MeV and 137 keV (9%) gamma emission. Its short half-life (T1/2 = 3.8 days) and the maximum tissue penetration range of approximately 5 mm make it a potentially useful isotope in patients with poor bone marrow reserve (Table 26.1). The availability of suitable energy gamma photons helps in dosimetric and pharmacokinetic evaluation of the agent, without adding any significant additional radiation dose burden to the patient [10, 34].

The agent is administered intravenously with high dose ranging from 1.48 to 3.33 GBq (in the published European Association of Nuclear Medicine guidelines, the recommended dose of 186Re-HEDP is 1295 GBq) and has exhibited a response rate of 77–90% [18, 71].

The mean duration of pain relief is 2–4 months. It binds to plasma proteins in a time-dependent interaction and reaches peak skeletal uptake 3 h after intravenous administration. Following administration of 186Re-HEDP, around 70% of the radioactivity is excreted in the urine over 72 h. This radiopharmaceutical is retained longer in the reactive bone around the lesion than in normal bone. 186Re-HEDP has been reported to be characterized by less clinically significant haematological toxicity than 153Sm-EDTMP and by more suitable physical characteristics for imaging than 89Sr [8, 72] (Table 26.2).

186Re can be produced either in a nuclear reactor or in a particle accelerator (cyclotron). The former method utilizes neutron capture of enriched 185Re, 185Re(n,γ)186Re. In the latter method, 186Re is obtained mainly via proton bombardment of natural tungsten (186W) as a target [19, 73].

Rhenium [ 188 Re]etidronate

188Re-HEDP is currently considered a very attractive candidate for a wide variety of therapeutic applications. 188Re emits beta particles with E(max) = 2.118 MeV, E(mean) = 0.78 and 15% of gamma rays with energy of 155 keV which are adequate for therapy and imaging, respectively. Its physical half-life is 17 h (0.7 days), and the maximum tissue penetration range of the beta particles is approximately 10 mm [16, 34] (Table 26.1).

The higher beta energy of this isotope offers the potential for lethal insults to tumour cells in the region of decay, and emission of gamma photons is an added benefit that permits evaluation of biodistribution, pharmacokinetics and dosimetry [20].

As previously reported, it is necessary to add a carrier when preparing 188Re-HEDP to allow accumulation in bone. 188Re-HEDP is administered with a dose of 2.96–3.33 GBq through the intravenous route. Multiple administrations of the agent in patients, up to a maximum of eight times, have been performed with an interval of 8 weeks between two successive administrations, and this is reported to enhance pain palliation of patients with a response rate of 64–77% and a mean duration of 3–6 months. However, the high energy of beta particles of 188Re emission is reported to cause considerable bone marrow suppression [9, 35] (Table 26.2).

The production method of choice for 188Re is by the decay of the longer-lived tungsten-188 (188W) parent (T1/2 = 69.4 days), which is produced in a nuclear reactor by irradiation of tungsten oxide. The decay chain from a 100% pure target 186W according to neutron flux and irradiation time shows the origin of some of the radioactive contaminants present in the generator [70].

Preparation of 188Re from a 188W/188Re generator is interesting, as it provides a long-term source for NCA 188Re in nuclear medicine departments. 188Re is eluted with a saline solution in the form of sodium perrhenate (Na188ReO4), and the chromatographic generator with alumina is suitable for high specific activity 188W. The 24-h postgenerator 188Re elution ingrowth of 62% and high elution yields (75–85%) result in daily yields of about 50%, with consistently low 188W parent breakthrough (<10−6). Simple postelution concentration methods have been developed to provide very high radioactive concentration solutions of 188Re for radiolabelling. The radionuclidic and chemical properties of rhenium, and the possibility of obtaining 188Re in-house and on demand, make this generator system ideal for many applications [74].

The availability of the 188W/188Re generator is especially important for providing a reliable source of this versatile therapeutic radioisotope to remote sites, especially in developing regions, which involve long distances and expensive distribution costs. The development of new chemical strategies allows to obtain 188Re radiopharmaceutical in very high yields and in physiological conditions and gives a novel attractive prospective to the development of new radiopharmaceuticals for therapy [75, 76].

On the other hand, the limited availability of reactors in the world for the production of 188W, coupled with the long irradiation period required to produce the isotope in sufficient quantity, makes the 188W/188Re generator expensive, and this may consequently restrict the affordable availability of this useful radionuclide [14].

26.4 The Role of Bisphosphonates

Several bisphosphonates (BP) (formerly referred to as diphosphonates) are used for bone pain. A phosphonate is formed by a non-ionic bond between a carbon and a phosphorus atom. They inhibit osteoclast-induced resorption by binding to bone mineral through the phosphate moiety, interfere with osteoclast activation and also induce osteoclast apoptosis. Meanwhile, these bisphosphonates have been shown also to stimulate osteoblast differentiation and hence new bone formation.

Clinically bisphosphonates reduce the risk of developing skeletal complications of metastatic disease including hypercalcemia and pathologic fracture. They delay the progression of existing bone metastases and reduce the development of new lesions. Bisphosphonates appear to have a beneficial effect on bone pain [16, 40]. Taking into account the pharmaceutical class of bisphosphonates, it is thought to bind them to a chelator and label with radionuclides.

177Lu-EDTMP was one of the most common administered bone-targeting agents for palliative care. Although the results of using this complex in clinical studies indicated significant pain relief in metastatic patients, EDTMP complexes have shown low in vivo stability and thus dissociate which result in liver accumulation and high toxicity. As a consequence, new compounds with improved characteristics have been developed [77].

26.4.1 DOTA-Based Bisphosphonate for Bone Targeting

DOTA-bisphosphonates can be used as imaging and therapy agents, when labelled with positron and beta-emitting radiometals. Their theranostic potential has been explored using 177Lu for the treatment of widespread, progressive and painful skeletal metastases refractory to conventional treatment [32].

DOTA is an excellent lanthanide-chelating moiety, which has the specific advantages of binding trivalent (III) metal and allowing nearly quantitative radiolabelling yields of lanthanides under mild conditions with the formation of a stable Lu complex [12].

New DOTA-based molecules have been successfully prepared, such as (4-{[bis-(phosphonomethyl))carbamoyl]methyl}-7,10-bis(carboxymethyl)-1,4,7,10-tetraazacyclododec-1-yl)acetic acid (BPAMD) [77].

BPAMD is a simple DOTA-α-H-bisphosphonate conjugate whose complexes have been proven to effectively seek bone tissue. In contrast to open-chain chelating agents such as HEDP and EDTMP, macrocyclic tetraaza ligands can complex the positron-emitting PET radionuclide 68Ga(III), as well as the therapeutic low-energy beta emitter 177Lu(III). 177Lu-BPAMD is now becoming more widely used, both in experimental preclinical work and in patients for treatment of bone metastases, and a kit for eventual regular production in hospitals has been developed [78].

177Lu is chosen for its physical properties, emitting a short-range (0.2–0.3 mm) beta particle E(max) = 0.49 MeV) with maximum tissue penetration range less than 2 mm, as well as gamma radiation, which allows the scintigraphic evaluation of biodistribution and dosimetry. Its half-life is 6.71 days, and it decays to stable hafnium (177Hf). The relatively low radiation energy results in less penetration into the marrow, hence less bone marrow toxicity, while a relatively short half-life offers a faster rate of dose delivery for therapeutic purposes [79, 80].

177Lu is produced by simple 176Lu(n,γ)177Lu reaction with high specific activity and excellent radionuclidic purity even using medium-high flux research reactors. On the other hand, 177Lu can be produced with high specific activity via the indirect method by neutron irradiation of 176Yb. Since 2016, it is available commercially as 177LuCl3 with marketing authorization [25, 34, 81].

However, 177Lu-BPAMD efficiency may be further improved as more than half of the injected dose is rapidly eliminated from the body. To evaluate the possibility to delay body clearance in bone-targeting radiotherapy, a new class of “DOTA-BP retard” tracers was synthesized and evaluated in vitro and in vivo. The new ligand 1,4,7,10-tetraazacyclododececane, 1-(glutaric acid)-4,7,10-triacetic acid (DOTAGA) is bound to an albumin-binding moiety and has a significant blood concentration and high affinity for hydroxyapatite [21, 82].

Recently, based on the established pharmaceuticals pamidronate (3-aminopropyl-1-hydroxy-1,1-bis[phosphonic acid]) and zoledronate ([1-hydroxy-2-(1H-imidazol-1-yl)-ethylidene]bisphosphonic acid), two new DOTA-α-OH-bisphosphonates (DOTAPAM and DOTAZOL) have been successfully synthesized and show significantly improved accumulation in the skeleton [83].

Chemical structures of DOTA-based bisphosphonates are shown in Fig. 26.2.
Fig. 26.2

Chemical structures of DOTA-based bisphosphonates

In particular, zoledronic acid containing an imidazole ring belongs to the class of bisphosphonates and acts primarily on bone mineral. It is an inhibitor of osteoclastic bone resorption, which alters the bone marrow microenvironment, making it less conducive to tumour cell growth, anti-angiogenic activity and anti-pain activity. In addition, zoledronic acid also possesses several antitumour properties that contribute to its overall efficacy in the treatment of metastatic bone disease [84].

Therefore, the compound DOTAZOL seems quite suitable for the use of the theranostic pair 68Ga/177Lu to both detect and treat bone diseases. The overall change of the Me(III)-DOTA-moiety results in two different complexes, the six-dentate 68Ga complex and the seven-dentate 177Lu complex, and contributes to the pharmacology of the whole molecule. In particular, [68Ga/177Lu]DOTAZOL appears to be the best leading compound showing fast blood clearance, low uptake in soft tissue and high accumulation in the skeleton [22]. This class of bisphosphonate enables an increased tumour to healthy bone ratio, which might end up in an improved therapeutic success [16, 40].

26.5 Beyond Bone Seekers: New Radiopharmaceuticals for Prostate Cancer

Because of high incidence, and the morbidity and mortality associated with prostate-derived cancer, the development of new technologies continues to be an important goal for the accurate detection and treatment of localized prostate cancer, lymphatic involvement and metastases.

Targeted therapy using bone-seeking agents such as 89SrCl2, 153Sm-EDTMP or 188Re-HEDP has been in use for over 30 years for palliative treatment of advanced prostate cancer patients. However, this class of tracers is not taken up by the primary or soft tissue lesions. The discovery and cloning of PSMA have opened the possibility of using it as the target for radiopharmaceuticals [85].

26.5.1 PSMA-Targeted Radionuclide Therapy of Prostate Cancer

PSMA (glycoprotein II or N-acetyl-l-aspartyl-l-glutamate peptidase) is expressed in high levels on prostate-derived cells and is an important target for visualization and treatment of prostate cancer: the ideal target is highly expressed on tumour cell surfaces and only lightly expressed (or not expressed) on normal tissues. Therefore, important clinical factors include the highest tumour radiation dose with concomitant low radiation dose to nontarget tissues, primarily including the kidneys, lachrymal gland and salivary glands [86].

Two distinct approaches have been used for targeting PSMA: the first approach takes advantage of the macromolecular protein structure of PSMA to provide specific monoclonal antibodies as targeting vectors, and the second approach takes advantage of the enzyme activity of PSMA and uses radiolabelled enzyme inhibitors or binding agents as target-seeking agents. However, the first approach is slowly becoming overshadowed by the second approach which utilizes radiolabelled small molecules targeting the enzyme activity of PSMA [87].

Among the different types of inhibitor molecules developed as part of drug discovery, the dipeptide Lys-urea-Glu appears to be the most successful to be used as the pharmacophore in radiopharmaceutical development. Therefore, the availability of these types of small molecular weight inhibitors exhibiting high uptake in prostate cancer has opened the possibility of radiolabelling them with therapeutic radionuclides. One essential requirement is that the radionuclide must be available either as no carrier added (NCA) or with high specific activity [2, 88].

Since 2013, commercial availability of PSMA-617 has helped in the use of [177Lu]PSMA-617 in multiple centres in different parts of the world. PSMA-617 consists of Glu-urea motif and chelator DOTA, separated by a lipophilic linker region. DOTA chelator can be labelled with radionuclides, for example, 68Ga and 177Lu, and used for both imaging and therapy. In order to prevent relevant kidney toxicity, the treatment regimen. The 177Lu-PSMA-617 treatment regimen is limited to four to six cycles of approximately 5.9 GBq (range 3–8 GBq), generally at a minimum 6-week intervals, in order to prevent relevant kidney toxicity. Dose calculations for individual patients have been determined from a combination of disease burden, patient weight and renal function which is based on initial dosimetric studies. Several publications reported PSA response rates of 70–80% in patients receiving up to three cycles of 177Lu-PSMA-617 [89, 90, 91, 92, 93].

Currently, a DOTA version (DOTAGA-(I-y)fk(Sub-KuE) of the same PSMA-617 has been synthesized and has shown promising properties when labelled with 177Lu, such as accumulation in prostate cancer lesions and low kidney retention. Clinical trials have demonstrated the beneficial effect of DOTAGA-for-DOTA substitution and of using a d-amino acid peptide linker on PSMA affinity and metabolic stability and thus uptake and clearance kinetics, respectively. Furthermore, the substitution of one of the d-phenylalanine residues in the peptidic linker by 3-iodo-d-tyrosine has improved the interaction of the tracer molecule with a remote binding site. The use of this compound is proposed for both imaging and therapeutic applications and thus designated PSMA I&T acronym (i.e. PSMA for Imaging & Therapy).

Chemical structures of small-molecule PSMA inhibitors are shown in Fig. 26.3.
Fig. 26.3

Chemical structures of small-molecule PSMA inhibitors

It allows fast and high-yield labelling with 68Ga(III) and 177Lu(III), high PSMA affinity and enhanced internalization into PSMA-expressing cells. With the possibility of 177Lu-based therapy, PSMA I&T opens new perspectives for theranostic approaches in the management of prostate cancer [94].

Thus far, 177Lu is emerging as the isotope for therapy of prostate cancer, as its radiochemistry is well understood, and 177Lu, having high specific activity, both NCA and carrier added (CA), is available from several sources [95].

In the future, 90Y (T1/2 = 2.7 days), the high-energy beta emitter (2.284 MeV), may also emerge as an alternative to 177Lu since many of the prostate metastases are bulk tumours and the beta particles emitted by 90Y have a range up to 11 mm in tissue. 90Y obtained from 90Sr/90Y generator is NCA and might be efficacious for therapy [31, 34].

Furthermore, interest is also emerging for the evaluation of PSMA targeting with ligands labelled with alpha-particle emitting radioisotopes, such as actinium (225Ac) and bismuth (213Bi). These studies are in progress and will be reported in the near future. However, the highly localized ionization of alpha particles would suggest that such PSMA-targeted agents will be more effective to treat micrometastases and will not have any “crossfire” radiation exposure, as seen with beta particle emitters such as 177Lu or 90Y for larger mass irradiation.

In conclusion, it can be foreseen that radiolabelled enzyme inhibitors and binding agents targeting PSMA are poised to have a significant role in the theranostic management of prostate cancer patients [29, 96, 97, 98]. Concluding Remarks and Prospects

Over the years, efforts have been undertaken to identify radionuclides with improved physical properties for use in palliative care of metastatic bone pain, as well as to develop better bone-seeking agents to be radiolabelled with promising radionuclides.

The management of refractory metastatic prostate cancer has recently seen impressive advances thanks to the development of novel radiopharmaceuticals both for diagnosis and therapy. It may be considered the new strategy for the treatment of painful bone metastases with high therapeutic efficacy and low complications and side effects. NCA radionuclides are ideal to obtain high specific activity radiopharmaceuticals, and this will ensure that radioactive carrier molecules are delivered to the tumour. Furthermore, targeted alpha particles have some theoretical advantages, given their small radius of damage and high linear energy transfer. Towards that end, 223RaCl2 is a step in the right direction, but there is much more to be done, given that 223Ra only targets osteoblastic bone lesions.

However, if nuclear medicine therapy is to sustain the expected growth rate, it is essential to ensure steady production and reliable supply of therapeutic radionuclides at affordable costs. To ensure wider distribution, the radionuclide should have a relatively longer half-life or be available from a radionuclide generator system having a parent with a relatively longer half-life.

Therefore, several aspects need to be considered when choosing the radiopharmaceutical to use for target tumour radiotherapy. This should go beyond the inevitable analysis of costs and logistics, and should include an analysis of the radionuclide’s physical properties, as well as the size of the lesions to be treated and the patient’s clinical condition and life expectancy, in order to optimize therapeutic efficacy.

In the future, personalized therapies are expected to guide the treatment for patients (especially targeted treatments) and to significantly improve healthcare delivery and reduce costs.

In particular, the increased awareness for the quality and safety of radiopharmaceuticals and the need for confirmation that the therapeutic agent has to provide clinically useful data contributed to making widespread use of new agents very challenging. In this scenario, academic investigators play a major role in the design and synthesis of therapeutic agents whose development must be in line with the emerging needs of the public health system, but which must also be economically sustainable for companies.

PSMA is a promising target for directing new therapies. Radioactive PSMA ligand, which is directly internalized into tumour cells, will be effective in delivering high doses for systemic radiotherapy. Thus, PSMA targeting is complementary to currently approved drugs and can be effective when targeting the androgen receptor axis fails.

Key Points

  • Bone-seeking radiopharmaceuticals play a significant role in the treatment of metastatic pain as an alternative, or in addition, to classic palliative treatment. Ionizing radiation can be selectively delivered to areas of increased osteoblastic activity, allowing the targeting of multiple metastases. The goal of such irradiation is to kill tumour cells in the bone while sparing normal bone marrow, the site of haematopoiesis.

  • Until a few years ago, radionuclides for the management of prostate cancer consisted of several beta-emitting agents, such as strontium (89Sr), phosphorus (32P) and samarium (153Sm) as well as rhenium (186Re and 188Re), which only exhibit a palliative effect in patients with extensive skeletal disease.

  • Radium (223Ra) dichloride represents a new generation of radiopharmaceuticals and a great advance for nuclear medicine application, being the first targeted alpha-emitting agent approved, which improves overall survival, postpones skeletal-related events (SREs) and controls bone pain.

  • Conjugates of bisphosphonates (BP) with macrocyclic chelators open new possibilities in bone-targeted radionuclide imaging and therapy, when labelled with positron and beta-emitting radiometals. [68Ga/177Lu]DOTAZOL appears to be the best leading compound showing fast blood clearance, low uptake in soft tissue and high accumulation in the skeleton.

  • Prostate-specific membrane antigen (PSMA) is an attractive target for diagnosis and therapy of prostate cancer since expression levels are directly correlated to metastatic and hormone-refractory cancers. 177Lu-PSMA-617 is a new treatment option, which is not solely directed to bone metastases but also demonstrates “antitumour” activity with limited and well-tolerated side effects.


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Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Nuclear Medicine UnitAOU Policlinico “G. Martino”MessinaItaly

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