Review
`
`pubs.acs.org/CR
`
`Lutetium-177 Therapeutic Radiopharmaceuticals: Linking Chemistry,
`Radiochemistry, and Practical Applications
`Sharmila Banerjee
`
`Radiopharmaceuticals Chemistry Section, Bhabha Atomic Research Centre (BARC), Mumbai 400 085, India
`
`M. R. A. Pillai*
`
`Molecular Group of Companies, Puthuvype, Ernakulam, Kerala 682 508, India
`
`F. F. (Russ) Knapp
`
`Medical Radioisotope Program, Oak Ridge National Laboratory (ORNL), P.O. Box 2008, 1 Bethel Valley Road, Oak Ridge,
`Tennessee 37830-6229, United States
`
`6.2.1. Indirect Route for Production of 177Lu
`6.2.2. Direct Route for Production of 177Lu
`6.2.3. Coproduction of 177mLu as Radionuclidic
`Impurity
`6.3. Logistical Advantages in Distribution of 177Lu
`and Cost Factors
`7. Review of 177Lu-Labeled Molecular Carriers as
`Potential Radiopharmaceuticals
`7.1. Monoclonal Antibodies
`7.1.1. Anti CD-20
`7.1.2. Anti-L1-CAM
`7.1.3. ch81C6
`7.1.4. Anti-VEGF
`7.1.5. CC-49
`7.1.6. Cetuximab
`7.1.7. cG250
`7.1.8. 7E11
`7.1.9. hLL2 (Epratuzumab)
`7.1.10. huA33
`7.1.11. Hu3S193
`7.1.12. J-591
`7.1.13. MOv18
`7.1.14. Pertuzumab
`7.1.15. RS7
`7.1.16. Trastuzumab
`7.1.17. U36
`7.2. Peptides
`7.2.1. Somatostatin Analogues
`7.2.2. Bombesin Analogues
`7.2.3. RGD Analogues
`7.2.4. Substance P
`7.2.5. Other Peptides Studied with 177Lu
`7.3. Bone Pain Palliation Agents
`7.4. Particulates for Targeted Therapy of Hep-
`atocellular Carcinoma
`7.4.1. 177Lu-Labeled Hydroxyapatite
`7.4.2. 177Lu Oxine in Lipiodol
`
`Received: March 27, 2014
`Published: April 13, 2015
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`DOI: 10.1021/cr500171e
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`CONTENTS
`
`1. Introduction
`1.1. Radiopharmaceutical Overview
`1.2. Role of Molecular Nuclear Medicine
`2. Targeted Therapy
`2.1. Therapeutic Radionuclides
`2.2. Theranostics: Use of Diagnostic/Therapeutic
`Radionuclide Pairs
`3. Evolution of 177Lu Radiopharmaceuticals
`4. Lutetium Chemistry
`4.1. Inorganic Chemistry of Lu
`4.2. Isotopes of Lutetium
`4.3. Bifunctional Chelating Agents (BFCAs) for Lu
`Complexation
`4.4. Radiolabeling of Bifunctional Chelators with
`177Lu
`5. Lutetium-177 Radionuclide
`5.1. Radionuclidic Characteristics of 177Lu
`5.2. Feasibility of Production of 177Lu in Ther-
`apeutic Quantities
`5.3. Theranostic Potential of 177Lu
`5.4. Lutetium-177 as a Replacement of 131I for
`Nonthyroid Applications
`6. Production of 177Lu
`6.1. Cyclotron Production of 177Lu
`6.2. Reactor Production of 177Lu
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`© 2015 American Chemical Society
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`Chemical Reviews
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`7.5. Particulates for Use in Radiation Synovec-
`tomy (RSV)
`7.6. Steroids
`7.7. Porphyrins
`7.8. Nitroimidazoles
`7.9. Human E. coli Heat-Stable Enterotoxin
`7.10. Fullerenes
`7.11. 177Lu-Labeled Nanoparticles for Targeted
`Therapy
`8. 177Lu Radiopharmaceuticals in Clinical Use
`8.1. 177Lu−CC49 Monoclonal Antibodies for Ad-
`enocarcinoma
`8.2. 177Lu−J591 Monoclonal Antibodies for Pros-
`tate Cancer
`8.3. 177Lu−Anti CD-20 Monoclonal Antibody for
`Non-Hodgkin’s Lymphoma
`8.4. Combination Therapy
`8.5. 177Lu−DOTATATE for Neuroendocrine Tu-
`mors
`8.6. 177Lu−EDTMP for Bone Pain Palliation
`9. Clinical Studies Demonstrate the Theranostic
`Potential of 177Lu
`9.1. Lutrin
`10. Summary
`Author Information
`Corresponding Author
`Notes
`Biographies
`Acknowledgments
`References
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`1. INTRODUCTION
`Interest in the use of radionuclides for treatment of various
`diseases has a long history and parallels the isolation of radium by
`Marie and Pierre Curie in the early part of the 20th Century. The
`availability of radium generated widespread enthusiasm and was
`considered as a potential medicine for many incurable diseases.
`Success evaded such attempts until radioactive phosphorus (32P)
`prepared at the University of California Berkeley cyclotron was
`found to be effective for treating polycythemia rubra vera, a
`myeloproliferative disease characterized by overproduction of
`red blood cells. The introduction of iodine-131 (131I) as a
`radioactive medicine for treatment of thyroid cancer in 1946 saw
`the successful application of radionuclides in medicine. The
`clinical use of radioiodine (131I) therapy is a key example of
`molecular nuclear medicine, and this therapeutic radionuclide
`continues to be used in many technologies focused on cancer
`treatment where no competing replacement is envisaged in the
`near future.
`Several radionuclides which decay by emission of beta particles
`(β−), alpha particles (α), or Auger (AE) and conversion electrons
`(CE) are under both radiopharmaceutical development and
`clinical evaluation as potential therapeutic radionuclides. Among
`the radionuclides suggested for targeted therapy, research with
`177Lu-based radiopharmaceuticals has demonstrated spectacular
`growth in recent years. Less than 10 papers were published on
`the development of lutetium-177 (177Lu)-labeled radiopharma-
`ceuticals in the last century, whereas more than 500 publications
`have appeared in the last 14 years, demonstrating the increasing
`interest in the use of this therapeutic radionuclide. Monoclonal
`antibodies, peptides, phosphonate ligands, particulates, steroids,
`and other small molecules have been radiolabeled with 177Lu for
`
`Review
`
`the development of a wide variety of therapeutic radiopharma-
`ceuticals. The success of
`treating patients suffering from
`neuroendocrine tumors with 177Lu-labeled DOTA-Tyr3-octreo-
`tate (DOTA-TATE), a somatostatin analogue peptide, is the
`single most important example that has contributed to the
`worldwide interest and growth of 177Lu as a therapeutic
`radionuclide.1
`Although decay properties are an important consideration for
`selection of a therapeutic radionuclide, the success of using any
`radioisotope as an integral part of a radiopharmaceutical depends
`on the feasibility for production in high activity levels with
`acceptable quality and the ability for transportation to nuclear
`medicine facilities, which are generally distant from production
`centers. As discussed later in this review, 177Lu has many
`advantages compared to other therapeutic radionuclides for the
`potential treatment of several types of cancers. Radionuclidic
`characteristics of 177Lu such as the energies and abundance of the
`emitted β− particles and gamma photons and its half-life make it
`suitable for use as a therapeutic radionuclide for targeting small
`primary tumors and metastatic sites.
`Although the clinical efficacy of several 177Lu radiopharma-
`ceuticals has been demonstrated using “in-house” formulations,
`at present there are no 177Lu-labeled radiopharmaceuticals with
`regulatory approval for routine clinical use. A number of clinical
`trials using 177Lu radiopharmaceuticals are also in progress in
`many countries; however, it is expected that approved 177Lu
`radiopharmaceuticals will be commercially available in the near
`future.
`This paper is the first published review on 177Lu radiophar-
`maceuticals and summarizes the developments in this emerging
`important field. This comprehensive review on 177Lu radiophar-
`maceuticals covers research from 1960 and begins with an
`introduction on radiopharmaceuticals used in nuclear medicine
`with a goal to orient the reader to the importance of this field.
`Lutetium is the last member of the lanthanide family, and its
`chemistry plays an important role in the preparation of
`radiopharmaceuticals that are stable in vivo. Various bifunctional
`chelating agents (BFCA) that are used for tagging 177Lu with
`carrier vectors are discussed. The review also covers the
`production aspects of 177Lu in detail and its different production
`methods. The comparative advantages and disadvantages of the
`two major reactor production routes are elaborated. Research
`which led to the development of different 177Lu radiotracers is
`provided, and this review also describes the results of promising
`clinical studies that have been conducted with 177Lu radiophar-
`maceuticals.
`1.1. Radiopharmaceutical Overview
`Radioactive drugs (radiopharmaceuticals) used in nuclear
`medicine, oncology,
`interventional radiology/cardiology, and
`related specialties involve the use of unsealed radioactive
`sourcesas opposed to the use of sealed radioactive sources in
`radiation oncology. Radiopharmaceuticals are radiolabeled
`molecules designed to target tissues and processes in vivo and
`are used in either diagnostic or therapeutic applications. Unlike
`the well-established applications of nonradioactive drugs,
`diagnostic radiopharmaceuticals contain very small doses of the
`active ingredients and are not pharmacologically active. On the
`other hand, therapeutic radiopharmaceuticals generally possess a
`significant concentration of active ingredient which can induce
`pharmacological changes. Radiopharmaceuticals are designed to
`measure a physiological event (imaging) or for the treatment of a
`malady (therapy). In the case of therapeutic applications, such as
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`the use of 177Lu-labeled pharmaceuticals discussed in this review,
`the therapeutic effects results from the radiotoxicity induced by
`the emission of particulate radiations. Radiopharmaceuticals are
`manufactured under current Good Manufacturing Practices
`(cGMP) with specific regulations and must be of adequate purity
`for human administration.
`The major tools employed for diagnosis are imaging
`modalities, which include both planar and tomographic imaging
`technologies such as single-photon emission computed tomog-
`raphy (SPECT) and positron emission tomography (PET).
`Radionuclides that primarily emit gamma photons or positrons
`that can have a high abundance of photon emissions are used in
`diagnostic nuclear medicine. Radiopharmaceuticals used for
`therapeutic applications, in contrast, contain radionuclides that
`decay by particulate emission (alpha, beta, or Auger electrons),
`and the decay energy is deposited at the target sites to kill
`cancerous or other diseased cells.2,3 The design of radiophar-
`maceuticals involves radionuclide attachment to the targeting
`molecule either directly or via the use of a bifunctional chelating
`agent (BFCA). An example of a direct radiolabeling is the
`radioiodination of the phenolic group of the amino acid tyrosine
`in a biological vector. In the case of radiolabeling through a
`chelator, a radionuclide is complexed with the donor atoms of a
`BFCA. These targeting molecules are often peptides, antibodies,
`antibody fragments, or small molecules that are receptor specific
`and peptidomimetics or nonpeptide receptor ligands. Often a
`proven conventional drug is selected as a lead molecule to be
`developed into a radiopharmaceutical by incorporating an
`appropriate radionuclide useful for diagnosis or therapy. An
`important challenge is to maintain the molecular targeting
`characteristics of the modified molecule, since even subtle
`structural changes in molecules that act as the vector can often
`result
`in loss of
`targeting properties. The design of a
`radiopharmaceutical for a specific application therefore must
`take into consideration the properties of both the targeting
`carrier molecule as well as the radionuclide.
`1.2. Role of Molecular Nuclear Medicine
`The distinct advantage of nuclear medicine is its application
`using novel biomarkers for the study of biochemical processes at
`the cellular level. These techniques can delineate changes in
`cellular function at a stage much earlier than the manifestation of
`anatomical changes or the onset of clinical symptoms. This
`unique and important strength is referred to as molecular nuclear
`medicine.4 Many nuclear medicine imaging techniques measure
`flow, but localization of the radiopharmaceutical can also provide
`information to visualize and map the biological processes, such as
`cell growth or cell destruction leading to biochemical changes
`occurring in living systems. An example is the widespread use of
`18F-labeled fluorodeoxyglucose ([18F]FDG or simply FDG)
`where a glucose analogue radiolabeled with 18F, a positron-
`emitting radionuclide,
`is injected into a patient followed by
`imaging with positron emission tomography (PET) instrumen-
`tation. The images obtained permit the visualization of abnormal
`cellular metabolism and proliferation as glucose, and thereby
`FDG is taken up by diseased cells more than in normal cells. The
`clinical introduction of dual imaging modalities such as PET/CT
`(computed tomography) and more recently PET/MRI (mag-
`netic resonance imaging) permits simultaneous measurement of
`both cellular metabolic processes as well as anatomical details.
`The increasing availability of these technologies has led to a new
`era of accurate mapping of cellular processes occurring in cancer
`and other diseases, which range from detection, staging,
`
`Review
`
`treatment planning, and finally disease management. These
`studies not only aid in assessing treatment response for the use of
`chemotherapeutic agents but also help in distinguishing cells
`which are proliferating owing to angiogenesis from normal cells.
`Molecular nuclear medicine has thus attained the present
`status due to a gradual evolutionary process which includes the
`unique capability for noninvasive assessment of physiological
`processes occurring in vivo by following radiopharmaceutical
`metabolism. The advances in imaging techniques have expanded
`opportunities, paving the way for nuclear medicine investigators
`to obtain two-dimensional
`images of
`the whole body.
`Subsequent improvements brought about by the introduction
`of new and improved radiotracers as well as new imaging
`techniques have enabled the acquisition of tomographic (i.e.,
`three-dimensional) images of coronary blood flow and related
`tissue function.
`Understanding changes at the molecular and cellular level
`provides vital clues for evaluating the effectiveness of a clinical
`treatment strategy. This information, in turn, has a major impact
`on understanding disease and its detection and progression,
`deciding individualized treatment, and consequently developing
`suitable drugs. The concept of molecular nuclear medicine
`provides a “window” to visualize the biochemical processes
`occurring in vivo.5 Functional radionuclide imaging helps in
`following the pathology in individual patients and provides a
`means to tailor clinical management, contributing to the
`conceptualization of the new era of “personalized medicine”.
`The relatively well-established, unique advantages of molecular
`nuclear medicine over conventional techniques such as ultra-
`sound (US), CT, and MRI are the opportunities to provide
`unique physiological and molecular information in the fields of
`oncology, cardiology, and neurology.
`
`2. TARGETED THERAPY
`In contrast to the use of diagnostic applications in nuclear
`medicine, radiopharmaceuticals designed for therapy are agents
`which deliver therapeutic doses of particulate and ionizing
`radiation to the diseased sites.2,3,6 As the term implies, targeted
`therapy is a treatment modality using agents which act as
`molecular vectors for transporting/targeting radionuclides to
`specific biological sites. Agents intended for use in targeted
`therapy are endowed with target specificity due to the presence of
`the carrier molecule with specific affinity for targeted sites.
`Examples include monoclonal antibodies which target specific
`antigens or peptides which target specific receptors that are
`overexpressed on cancerous tissues. Therapeutic efficacy is
`accomplished by inducing cytotoxicity to the tumor cells to arrest
`further proliferation. The most desirable features of a therapeutic
`radiopharmaceutical are the ability to deliver sufficient radiation
`dose to the target, to retain the radiopharmaceutical or the
`metabolite carrying the radionuclide at the site of interest, and to
`ensure rapid clearance of radioactivity from nontargeted tissues
`and organs. Target specificity is ensured by identifying a suitable
`target-seeking molecule and radiolabeling it with the radio-
`nuclide without compromising biological targeting.
`There are several challenges involved in the development of
`therapeutic radiopharmaceuticals which arise from the required
`balance between specific in vivo targeting properties to the sites
`of interest with simultaneously less accumulation and more rapid
`clearance of radioactivity from nontarget sites. The possibilities
`of designing new radiopharmaceuticals arise from the evaluation
`of a large number of therapeutic radionuclides with widely
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`different radionuclidic characteristics and also the availability of a
`large library of molecular targeting vectors.
`2.1. Therapeutic Radionuclides
`for a particular
`While designing a radiopharmaceutical
`therapeutic application, the choice of the appropriate radio-
`nuclide constitutes a prime determinant.2,3,7−9 The major criteria
`for choice of a radionuclide for therapeutic use include the
`radionuclidic half-life, the type, energy, and branching ratio of
`particulate radiation, as well as photon abundance and energies.
`It is important to match the physical half-life of the radionuclide
`with the biological half-life of the carrier molecule used. Other
`important considerations include the availability of convenient
`and high-yield chemical strategies for stable attachment of the
`radionuclide to the carrier molecule, specific activity (activity/
`mass), radionuclidic and chemical purity, production feasibility,
`and cost. There are a large number of radionuclides which show
`potential use for the development of therapeutic radiopharma-
`ceuticals. While it is difficult to select any one radionuclide as
`ideal or the best suited for therapy, a few will have more desirable
`properties than others for a desired application. A summary of
`key radionuclides which exhibit nuclear decay characteristics of
`interest for various in vivo therapeutic applications is given in
`Table 1.10
`the emitted radiation,
`the nature of
`On the basis of
`radionuclides can be classified as α-particle emitters, β−-particle
`emitters, conversion electron (CE) emitters, or Auger electron
`emitters (AE). Auger electrons are emitted by radionuclides that
`decay by electron capture (EC) or internal conversion (IC). The
`decay creates a vacancy in an inner atomic shell which is filled by
`electrons cascading down from higher shells leading to a cascade
`of electron transitions with the emission of characteristic X-ray
`photons or Auger, Coster−Kronig, or super Coster−Kronig
`monoenergetic electrons. These electrons are distinguished on
`the basis of the shells involved with the transition and are often
`collectively referred to as Auger electrons.
`Many of the radionuclides also emit γ rays after emission of
`either α or β− particles, and some metastable radionuclides emit
`only γ photons. Each type of particle emission used for targeted
`therapy with unsealed sources has different linear energy transfer
`(LET) values and different ranges in soft tissue (Figure 1). LET is
`the measure of the energy transferred to the medium as an
`ionizing radiation passes through it and is used to quantify the
`effect of ionizing radiation on the medium such as a biological
`specimen. The LET values depend on both the nature of the
`radiation as well as on the material through which the particulate
`radiation passes. Particulate emissions such as α and β− particles
`have high LET, whereas gamma and X-rays have low LET. High
`LET results in higher radiation damage to the biological systems
`and is quantified by the term “relative biological effect” (RBE).
`The RBE is the ratio of biological effectiveness of one type of
`ionizing radiation relative to another, given the same amount of
`absorbed energy. Among nuclear radiation, the RBE of alpha
`particles is the highest, followed by β− particles and γ rays. The
`higher the RBE, the more damaging the radiation for the same
`absorbed energy. Radiations having higher LET, and hence high
`RBE, are necessary for inducing therapeutic effects. Pure gamma
`emitters are hence not useful for therapeutic applications in
`nuclear medicine, whereas high intensity γ radiation is used in
`sealed sources. Among the three other particulate emissions, α
`particles have the highest LET and are hence capable of
`producing the maximum RBE.11 Radionuclides which emit α
`particles are effective where it is advantageous to use particulate
`
`Table 1. Summary of Key Therapeutic Radionuclides of
`Current Interest10
`
`Review
`
`particulate
`energy in keV
`
`principal γ energy in keV (%
`abundance)
`
`half-life
`radionuclide
`β−-particle emitters
`111Ag
`7.450 days
`77As
`38.83 h
`198Au
`2.695 days
`199Au
`3.139 days
`67Cu
`61.83 h
`165Dy
`2.33 h
`169Er
`9.400 days
`159Gd
`18.48 h
`166Ho
`26.83 h
`131I
`8.020 days
`177Lu
`6.734 days
`32P
`14.26 days
`109Pd
`13.70 h
`149Pm
`53.08 h
`142Pr
`19.13 h
`186Re
`90.64 h
`188Re
`16.98 h
`105Rh
`35.36 h
`47Sc
`3.345 days
`153Sm
`46.27 h
`89Sr
`50.53 days
`161Tb
`6.88 days
`90Y
`64.10 h
`175Yb
`4.185 days
`α-particle emitters
`225Ac
`10.0 days
`211At
`7.21 h
`212Bi
`60.55 min
`213Bi
`45.59 min
`Auger electron emitters
`125I
`59.40 days
`111In
`2.80 days
`67Ga
`3.26 days
`conversion electron emitter
`117Sn
`13.6 days
`127, 129
`159 (86)
`aFor β− particles the maximum β− energy is mentioned. Auger
`electron energy is the average kinetic energy of Auger and Coster−
`Kronig electrons emitted per decay.
`
`1036
`682
`1372
`452
`577
`1286
`351
`970
`1854
`970
`498
`1710
`1115
`1071
`2162
`1069
`2120
`567
`600
`808
`1496
`518
`2282
`470
`
`5935
`5982
`6207
`5982
`
`12.24
`6.75
`6.26
`
`342 (6.7)
`239 (1.6)
`411 (95.5)
`158 (36.9)
`184 (48.7)
`94 (3.6)
`nil
`58 (26.2)
`80 (6.2)
`364 (81.2)
`208 (11.0)
`nil
`88 (3.6)
`285 (2.8)
`nil
`137 (8.6)
`155 (14.9)
`318 (19.2)
`159 (68.0)
`103 (28.3)
`nil
`74 (10.2)
`nil
`396 (6.5)
`
`99 (3.5)
`687 (0.25)
`727 (11.8)
`439 (27.3)
`
`35 (6.68)
`245 (94)
`93 (39.21)
`
`radiation with a range of only a few cell diameters, such as the use
`of 213Bi for therapy of leukemia cancer cells in the vascular
`system.12 An emerging clinical application of an alpha emitter
`(223Ra), such as Alpharadin,
`is for the treatment of cancer
`metastases in the skeleton.13 Alpha particles deposit their energy
`over a short range (40−100 μm) and produce high-density
`ionizations along the tracks they traverse.14 As a result, α particles
`are capable of producing significant cellular damage by inducing
`double-stranded DNA breakage while delivering minimum
`radiation damage to nontargeted tissues. For oncologic
`applications, α-particle emitters are more compatible for use in
`the treatment by rapid localization in blood-borne cancers and
`tumors with small diameters and where their localization within
`the tumor is homogeneous and crossfire to surrounding cells is
`not an issue.15 One of the challenges for broader use of α-particle
`therapy is the lack of
`large-scale availability of suitable
`radionuclides. In addition, the short tissue range and short
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`Figure 1. Cartoon illustration showing the interaction of different types
`of particulate radiation with DNA. Path ranges in the figure are not
`drawn to scale.
`
`half-life generally require rapid targeting. The ranges of the
`different ionizing radiations along the tracks as they pass through
`the biological system are α = 50−100 μM, β− = 0.2−15 mm,
`Auger electrons = a few nanometers, γ = several centimeters. The
`ionization densities (mean energy deposition/path length (keV/
`μm) are α = 80−300, β− = 0.2, and AE = 4−26.3
`Radionuclides that decay by emission of β− particles and
`conversion electrons have been most extensively used for a broad
`series of radiotherapeutic applications because of their availability
`and suitability to treating large tumor volumes. These
`applications include cancer therapy, treatment of rheumatoid
`arthritis (synovectomy), arterial restenosis therapy, nonmelano-
`ma skin cancer, etc.2,3 β-Particle emitters produce a nearly
`homogeneous radiation dose distribution even though generally
`their deposition is heterogeneously distributed in target tissues.16
`As an example, most neoplasia consist of a heterogeneous
`distribution of stromal (structural), normal parenchymal (func-
`tional) cells, and tumor cells. Although the tumor cells may
`express a specific receptor, due to differential blood flow and
`other barriers, all cells will not be accessible by the targeting agent
`and hence will not receive the tracer. This makes the “cross-fire”
`effect particularly important for larger tumors.
`Auger electrons are monoenergetic,
`low-energy electrons
`emitted during the decay of certain radionuclides by internal
`conversion (IC) or electron capture (EC) processes. Auger
`electrons have very short range in soft tissues and deposit their
`energy over subcellular dimensions. If targeted to the cell
`nucleus, high radiotoxicity is exhibited in the immediate vicinity
`of the DNA decay site.17,18 Although Auger electrons actually
`have very low energy (20−500 eV), a high LET-like response is
`achieved due to their short range (1−10 nm).19 However, Auger
`electron emitters must generally be targeted into the cell nucleus.
`The cytotoxicity, and hence the therapeutic efficacy, will be much
`less even when these radionuclides are present in the cytoplasm
`or on the surface of the target cells. Early studies have indicated
`that 111In−Octreotide, an Auger-electron-emitting radiopharma-
`ceutical, has low therapeutic efficacy where the tumor size
`becomes an important factor for the success of such therapy.20
`The disadvantage of the peptides radiolabeled with hard beta
`emitters such as 90Y is the dose-limiting toxicity to the kidneys.
`
`Review
`
`While efforts with promising Auger electron emitters are
`currently being focused on the design of therapeutic radiophar-
`maceuticals, the design of agents which demonstrate the high
`targeting required for effective in vivo therapy remains a
`challenge.
`2.2. Theranostics: Use of Diagnostic/Therapeutic
`Radionuclide Pairs
`The term “theranostics” was coined to describe the combined use
`of a diagnostic tool that assists in the selection of the most
`appropriate therapeutic tool
`for treatment of a specific
`disease.21,22 The concept of
`theranostics, also known as
`“theranosis”, is utilized to tailor the therapy in a specific patient
`following the complete diagnosis of the disease, thus introducing
`the concept of personalized medicine. Nuclear medicine offers an
`ideal opportunity for theranostics since the dose of a diagnostic
`agent can be augmented to obtain a therapeutic effect. The
`advantage of this modality is the ability to perform imaging using
`SPECT/CT or PET/CT to provide the necessary pretherapy
`information on biopharmacokinetics and to guide the dosimetry
`focused on limiting dose to a critical organ or tissue.23 The
`information thus obtained is used for defining the maximum
`tolerated dose (MTD). If the imaging results then warrant it, it is
`generally considered safe and appropriate to follow up with dose-
`ranging experiments to allow targeted molecular therapy using a
`higher dose of the same radiopharmaceutical. These factors are
`especially important for being able to perform individualized
`imaging as well as therapy with the same radiopharmaceutical, in
`the same patient.
`A typical example of a theranostic radionuclide which emits
`both gamma photons as well as particulate radiation is 131I, which
`has been used for many years in low doses for the diagnosis and
`staging of thyroid cancer using gamma imaging.24 Subsequently,
`large doses of 131I are administered for thyroid ablation therapy.
`Examples of radionuclides which have theranostic potential are
`given in Table 2.
`
`3. EVOLUTION OF 177Lu RADIOPHARMACEUTICALS
`The first clinical use of 177Lu was reported by Anderson et al. in
`1960 when three patients suffering from myelomatosis were
`treated by intravenous injection of 177Lu as lutetium chloride
`and/or citrate.25 Results of these clinical studies were not
`promising since the patients did not show long-term survival but
`reported mild pain relief. No subsequent publication on 177Lu
`appeared until Keeling et al. in 1988 reported a study on the
`uptake of 177Lu hydroxyapatite (HA) particles to investigate the
`mechanism of uptake on bone minerals by in vitro techniques.26
`Schlom et al. in 1991 reported 177Lu radiolabeling of the CC49
`murine monoclonal antibody that recognizes the tumor-
`associated glycoprotein 72 (TAG-72).27 Ando et al. reported
`the preparation and biological evaluation of 177Lu−EDTMP
`(EDTMP = ethylenediaminetetramethylene phosphonic acid) as
`a bone palliating agent which was followed by another
`independent report by Solla et al., who applied this agent in
`patients.28,29 The broader potential use of 177Lu as a therapeutic
`radionuclide was, however, established with the use of 177Lu−
`DOTATATE (DOTA = 1,4,7,10-tetraazacyclododecane-
`1,4,7,10-tetraacetic acid; TATE = tyrosine-3-octreotate), a
`radiopharmaceutical which targets neuroendocrine tumors.1,30
`Radiolabeling of several lead molecules has been more recently
`reported, and the potential application of 177Lu as a therapeutic
`radionuclide is expanding, as seen from the increase of
`publications since the beginning of the past decade (Figure 2).
`
`2938
`
`DOI: 10.1021/cr500171e
`Chem. Rev. 2015, 115, 2934−2974
`Evergeen Ex. 1016
`5 of 41
`
`

`

`Chemical Reviews
`
`Table 2. Key Examples of Theranostic Radionuclides Which
`Emit Both Gamma Photons as Well as Particulate Radiation10
`
`radionuclidea
`166Ho
`
`half-life
`26.83 h
`
`131I
`
`177Lu
`
`8.02 days
`
`6.73 days
`
`186Re
`
`90.64 h
`
`188Re
`
`105Rh
`
`16.98 h
`
`35.36 h
`
`153Sm
`
`46.27 h
`
`161Tb
`
`6.88 days
`
`Eγ in keV (%
`abundance)
`81 (6.2)
`
`364 (81.2)
`636 (7.27)
`208 (11.0)
`113 (6.4)
`
`137 (8.6)
`
`155 (14.9)
`
`306 (5.13)
`
`103 (28.3)
`70 (5.25)
`
`74 (9.8)
`49 (14.8)
`
`Eβmax in keV (%
`abundance)
`1854 (50.0)
`1774 (48.7)
`606 (89.9)
`333 (7.27)
`498 (78.6)
`385 (9.1)
`176 (12.2)
`1069 (80)
`932 (21.5)
`581 (5.78)
`2120 (71.1)
`1965 (25.6)
`567 (75)
`260 (5.2)
`247 (19.7)
`808 (17.5)
`705 (49.6)
`635 (32.2)
`593 (10.0)
`567 (10.0)
`518 (66.0)
`461 (26.0)
`968 (76)
`884 (24)
`
`170Tm
`
`128.4 days
`
`84 (3.2)
`52 (2.2)
`51 (1.3)
`59 (0.9)
`175Yb
`396 (6.5), 282 (3.1)
`470 (86.5), 73 (10.2)
`4.185 days
`aRadionuclides with beta and gamma emissions and suitable for
`therapy are listed.
`
`Figure 2. Number of publications with 177Lu related to nuclear medicine
`(data from Pubmed, Medline, and Scopus).
`
`in 177Lu as a therapeutic
`interest
`The rapid growth of
`radionuclide can be attributed to its favorable nuclear character-
`istics and amenable chemistry, leading to stable products that
`show good in vivo characteristics. However, the single most
`important factor which contributes to the increased interest and
`use of 177Lu in nuclear medicine is its ease of production in high
`activity levels with high specific activity in many existing nuclear
`reactors worldwide.31
`
`2939
`
`Review
`
`4. LUTETIUM CHEMISTRY
`
`4.1. Inorganic Chemistry of Lu
`Lutetium is the last member of the lanthanide series, with 71
`electrons arranged in the [Xe]4f145d16s2 configuration. During
`chemical reaction, Lu atoms lose the two outermost electrons as
`well as the only 5d electron, thereby generating a +3 metal
`cationic species. Chemically, lutetium is a typical lanthanide since
`its only common oxidation state is +3, observed in its oxide,
`halides, and other compounds. The Lu atom is the smallest
`lanthanide, due to the lanthanide contraction phenomenon,
`which explains several important properties of Lu, including the
`highest metallic hardness and density. Unlike other lanthanides
`which are categorized in the f block of the periodic table, Lu could
`also be considered as the first element of the d block in the sixth
`period because it has a completely filled 4f orbital containing 14
`electrons. In its most stable +3 oxidation state, Lu has empty s, p,
`and d orbitals and a closed shell of f orbitals. Electrons in f orbitals
`are incapable of bond formation since they are tightly bound due
`to high effective nuclear charge and are not influenced by ligands
`surrounding the metal ion. Thus, the hard Lewis acid chemistry
`of Lu3+ is mostly governed by the empty s, p, and d orbitals. Due
`to the completely filled f orbital, the ionic radius of Lu3+ is the
`smallest (86.1 pm) among the lanthanides, and as a consequence,
`the number of ligands that may be placed around Lu3+ are
`limited. The coordination number is mostly dictated by the
`reciprocal repulsions between the various ligands without any
`relevant influence attributable to t