Continuing Nuclear Data Research for Production of Accelerator-Based Novel Radionuclides for Medical Use: A Mini-Review

Nuclear data are important for production and medical application of a radionuclide. This brief review concentrates on nuclear reaction cross-section data. The availability of standardized nuclear data for accelerator-based production of medical radionuclides is outlined. Some new directions in radionuclide applications, for example, theranostic approach, bimodal imaging, and radionuclide targeted therapy, are considered and the status of relevant nuclear data is discussed. The current trends in nuclear data research using accelerators are elaborated. The increasing significance of intermediate energy accelerators in production of therapeutic radionuclides is emphasized.

Introduction

Radionuclides find application in medicine, both in diagnosis and internal radiotherapy. Diagnostic investigations are carried out using short-lived radionuclides which emit either a single or major γ-ray of energy between 100 and 250 keV or a positron, the former in single photon emission computed tomography (SPECT) and latter in positron emission tomography (PET). In internal radionuclide therapy, on the other hand, radionuclides emitting low-range highly ionizing radiation, that is, α- or β^–-particles, conversion, and/or Auger electrons are used. A detailed knowledge of decay properties of a radionuclide is, therefore, essential to decide about its application. Furthermore, the radionuclidic purity and specific activity (defined as the radioactivity per unit mass of the material) play an important role in its medical application. Radionuclidic purity reduces the radiation dose due to impurities and higher specific activity ensures that the biological equilibrium is not disturbed and imaging is carried out at real molecular level. Those two parameters are controlled by knowledge of nuclear reaction cross sections, especially in production of radionuclides via charged particle-induced reactions [1, 2]. The level and type of radionuclidic impurity varies with the chosen reaction route and the projectile energy range effective in the target.

The positron emitters are generally produced at small-sized cyclotrons, the number of which worldwide is now increasing to about 1200 [3]. Attempts are presently also underway to produce several therapeutic radionuclides at cyclotrons/accelerators, using either the charged particle beam or secondary radiation, that is, neutrons and photons, generated at accelerators (for recent reviews, cf [4, 5]). Nuclear data play a continuing role in the development of radionuclides for applications. In this brief review, the availability of standardized data for production of medical radionuclides using accelerators is outlined, some new directions in radionuclide applications are discussed, and the current trends in nuclear data research are described.

Availability and Status of Standardized Data

Experimental data are compiled in the international file EXFOR, managed by the IAEA. Radionuclides to be used for a suitable modality of the medical procedure demand well-established data. The decay data of medical radionuclides are compiled and constantly updated in the MIRD file of the Society of Nuclear Medicine (SNM) of United States. Decay data of all radionuclides are available in the Evaluated Nuclear Structure and Decay Data File (ENSDF) and neutron-induced reaction cross-section data in the Evaluated Nuclear Data File (ENDF/B-VIII.0). In contrast, the evaluation methodology for charged particle-induced reaction cross sections started developing only about 2 decades ago [2] under the umbrella of IAEA in the form of coordinated research projects (CRPs), with major contributions from Jülich, Debrecen, Brussels, and Obninsk. To date three CRPs have been completed. The first two were related to radionuclides commonly used in diagnosis (IAEA-TECDOC-1211, 2001) and internal therapy (IAEA-Technical Report-473, 2011). In the third CRP, some updates were done but also the production data of some novel radionuclides were standardized [6–8]. The initial work was rather empirical. Later, however, strong application of nuclear models was built in. All modern calculation codes are based on the statistical model, taking into account angular momentum, nuclear structure, and level density effects, and also incorporate pre-compound emission contributions. Each code reproduces the experimental data to a certain degree of success. The nuclear model calculations performed using the codes EMPIRE 3.2 and TALYS 1.95 are generally very successful in reproducing the experimental data up to about 50 MeV, if only a few nucleons are emitted. Deviations are observed when emission of many nucleons and complex particles is involved. The adjustable parameters of the nuclear model codes are fitted within their prescribed limits to reproduce the experimental data in the process of validation and evaluation. All evaluated data are available on the website of the IAEA [9]. Using theory-aided evaluation, some work has been also carried out outside the abovementioned CRPs (see for example [10–14]). The evaluation efforts have provided reliable standardized data for accelerator-based radionuclides routinely used in patient care (PET/SPECT imaging and internal radiotherapy), produced either directly or obtained through positron-emitting generator systems ⁶⁸Ge/⁶⁸Ga and ⁸²Sr/⁸²Rb. Furthermore, data for a few novel and less commonly used radionuclides, for example, ⁶⁴Cu, ⁸⁹Zr, ¹²⁴I, ¹⁰³Pd, and ²¹¹At, have also been standardized. Standardized data are also available for the ¹⁰⁰Mo(p,2n)^99mTc reaction [10]. This is a very promising route for accelerator-based production of the most commonly used SPECT radionuclide ^99mTc, which is generally available via the fission-produced ⁹⁹Mo/^99mTc generator system. However, further extensive work is needed to settle the question of impurities in cyclotron production of this radionuclide. Similarly, for emerging radionuclides more experimental and evaluation work is necessary (see below).

New Directions in Radionuclide Applications and Relevant Nuclear Data

For investigating slow metabolic processes, about 25 longer lived metallic positron emitters, termed as “nonstandard” positron emitters, have been developed [15]. Similarly, several metallic radionuclides emitting low-energy corpuscular radiation are in development for internal therapy (cf [1, 16]). In parallel, considerable chemical research has led to enhanced possibilities of labeling monoclonal antibodies (mAbs) and other versatile organo-metallic chemical complexes with radionuclides for targeted therapy (for reviews cf [17, 18]). Based on those advances, applications of radionuclides are enhancing today in the following directions:

i) Radiolabeled monoclonal antibodies

ii) Peptide receptor radiotherapy

iii) Small molecules

iv) Theranostic approach

v) Bimodal imaging

vi) Radioactive nanoparticles

Radiolabeled monoclonal antibodies: Monoclonal antibodies (mAbs) labeled with radionuclides are used in diagnosis and therapy of tumors. The application of mAbs labeled with positron emitters is called immunoPET (cf. [19]). To date, the most widely used radionuclide for this purpose is ⁸⁹Zr, but also ⁶⁴Cu has found application in preclinical studies. For immunotherapy, ⁹⁰Y, ¹¹¹In, and ²²⁵Ac are potential candidates, for example, [⁹⁰Y]ibritumomab tiuxetan (Zevalin).

Peptide receptor radiotherapy (PRRT) makes use of peptide-based radiopharmaceuticals which can target different receptor systems like somatostatin receptors (SSTR), integrins, chemokine receptors, or the prostate-specific membrane antigen (PSMA). The most common approach uses octreotide derivatives labeled with ⁹⁰Y or ¹⁷⁷Lu to treat neuroendocrine tumors effectively, that is, [⁹⁰Y]Y-DOTATOC and [¹⁷⁷Lu]Lu-DOTATATE. Also [²²⁵Ac]Ac-DOTATATE is under study. A further important molecular target is the chemokine receptor-4 CXCR-4. This can be targeted with Pentixafor and studies with ¹⁷⁷Lu-labeled Pentixafor in cancer patients are underway.

Small molecules: Besides radioiodinated pharmaceuticals, different radiometal-labeled small molecules have been developed to treat oncological diseases, for example, PSMA-617, a urea-based derivative with excellent affinity to PSMA overexpressing prostate cancer tumor cells. After binding to the target, the molecule is internalized and facilitates eradication of the tumor cells. Therefore [²²⁵Ac]Ac-PSMA-617 and [¹⁷⁷Lu]Lu-PSMA-617 are under different clinical trials.

Theranostic approach entails a combination of diagnosis (molecular imaging) and internal radionuclide therapy (molecular targeted treatment). It makes use of two radionuclides of the same element in the same chemical form, a positron emitter which allows quantitative diagnosis via PET and a therapeutic nuclide. Originally, the pair ⁸⁶Y/⁹⁰Y was developed (cf. [20]), but today several other theranostic pairs are also known, for example, ^44gSc/⁴⁷Sc, ⁶⁴Cu/⁶⁷Cu, ¹²⁴I/¹³¹I, and ¹⁵²Tb/¹⁶¹Tb (for review cf [4]). Two other concepts also exist: 1) use of an analog pair of trivalent metallic radionuclides, that is, a positron emitter (^44gSc or ⁶⁸Ga) and a β⁻- (¹⁷⁷Lu) or an α-emitter (²²⁵Ac). 2) use of a single radionuclide, emitting a β⁻- or α-particle as well as a low-energy γ-ray, which could be utilized for SPECT measurement to deliver data for dosimetry. Examples are ⁴⁷Sc, ⁶⁷Cu, ¹⁷⁷Lu, and ¹⁸⁶Re for β⁻-therapy and ²¹¹At, ²²³Ra, ²²⁵Ac, ²¹³Bi, ²¹²Pb/²¹²Bi generator, and ¹⁴⁹Tb for targeted alpha therapy (TAT). Several other alpha-particle emitters are also under consideration (cf [21]).

Bimodal imaging involves a combination of two organ-imaging techniques, for example, PET and magnetic resonance imaging (MRI) (for review cf [22]). From the viewpoint of PET, the major focus is on the elements Mn and Gd which are important contrast agents in MRI. The positron-emitting radionuclide ^52gMn is of great current interest (cf [23, 24]). For Gd, no positron-emitting radionuclide is available and the use of ⁶⁸Ga-labeled Gd(III) complexes has been proposed.

Radioactive nanoparticles in medicine constitute a long-term perspective, provided the stability and toxicity problems are overcome. In animal and preclinical studies, considerable success has been reported (for review cf [25, 26]) but application in humans has yet to be demonstrated. The radionuclides ⁶⁴Cu and ⁶⁸Ga are widely used positron emitters for surface labeling of nanoparticles. The longer lived ^52gMn and ⁸⁹Zr are also of great interest. For therapy, ¹⁸⁶Re and ²²⁵Ac are considered to be very useful.

In the abovementioned new applications seven positron emitters, namely ^44gSc (T_1/2 = 3.9 h), ^52gMn (T_1/2 = 5.6 d), ⁶⁴Cu (T_1/2 = 12.7 h), ⁶⁸Ga (T_1/2 = 1.13 h), ⁸⁶Y (T_1/2 = 14.7 h), ⁸⁹Zr (T_1/2 = 78.4 h), and ¹²⁴I (T_1/2 = 4.18 d) are in great demand. Similarly, eight therapeutic radionuclides, namely ⁴⁷Sc (T_1/2 = 3.35 d), ⁶⁷Cu (T_1/2 = 2.58 d), ⁹⁰Y (T_1/2 = 2.7 d), ^117mSn (T_1/2 = 13.6 d), ¹⁷⁷Lu (T_1/2 = 6.65 d), ¹⁸⁶Re (T_1/2 = 3.78 d), ²²³Ra (T_1/2 = 11.4 d), and ²²⁵Ac (T_1/2 = 10.0 d) are of great interest. For each radionuclide, the stringent criteria of purity and specific activity must be met.

The production of the listed positron emitters is generally carried out via the low-energy (p,n) reaction on a highly enriched solid target isotope. In the case of ⁶⁸Ga, the generator route is more commonly used. The status of the available cross-section data of the abovementioned positron emitters was reviewed and found to be generally good (cf. [1, 15]), except for ⁸⁶Y where considerable discrepancy existed.

In contrast to positron emitters, the therapeutic radionuclides ⁹⁰Y and ¹⁷⁷Lu are routinely produced using nuclear reactors. For the six other therapeutic radionuclides, it was shown (cf. [8, 16]) that the reactor production methods are not sufficient. For ⁴⁷Sc and ⁶⁷Cu, the required radionuclidic and chemical purity is not achieved and for ¹⁸⁶Re and ^117mSn, the specific activity is too low. The supply of ²²⁵Ac and ²²³Ra via reactor route is limited. Efforts are therefore underway to produce those radionuclides at accelerators, ¹⁸⁶Re at a small cyclotron and others at intermediate energy accelerators.

Current Nuclear Data Activities

Nuclear modeling and theory-aided evaluations are continuing. The emphasis is, however, on new experimental studies; some of the most recent examples are given below.

Low-energy charged particle beam: Low-energy medical cyclotrons (E_P ≤ 18 MeV; E_d ≤ 9 MeV) are mainly utilized for the production of the standard positron emitters (¹¹C, ¹³N, ¹⁵O, and ¹⁸F) using gas and liquid targets. Since solid targetry is not available, a new methodology for the production of some nonstandard positron emitters via the (p,n) reaction at those cyclotrons has emerged. It makes use of “solution targets”, especially for ^44gSc, ⁶⁴Cu, ⁶⁸Ga, ⁸⁶Y, ⁸⁹Zr, and ^94mTc (for review cf. [27]). The product yield is low but sufficient for local use. This approach has, however, put an extra demand on chemical purification of the product as well as on the accuracy of the cross-section data near the threshold of the reaction (cf. [28, 29]). To improve the cross-section data of the ⁸⁶Sr(p,n)⁸⁶Y reaction, an accurate measurement was very recently completed [30]. The new results agree with the TALYS calculation and the discrepancy has been solved.

Intermediate energy charged particle beam: In the energy range up to 30 MeV, several routinely used radionuclides are conveniently produced, especially the SPECT radionuclides ⁶⁷Ga, ¹¹¹In, ¹²³I, and ²⁰¹Tl. At a higher proton energy up to 100 MeV, several radionuclides could be produced via (p,x) reactions, where x stands for multiparticle emission. Such accelerator facilities are now available at several places, for example Nantes (France), Legnaro (Italy), Moscow (Russia), Cape Town (South Africa), Brookhaven (United States), and Los Alamos (United States). A recent example is the measurement of the excitation function of the ⁷⁵As (p,4n)⁷²Se reaction [31] for the production of ⁷²Se which is useful for preparing the β⁺-emitting generator system ⁷²Se/⁷²As.

The intermediate energy range, however, is now being utilized more extensively for the production of therapeutic radionuclides. A recent cross-section measurement on the reaction ⁷⁰Zn(p,α+2p2n)⁶⁷Cu [32] is very interesting. Although the experimental data are not reproduced by the model calculation (due to complexity of reaction and energy range), they are of great technical value. In Figure 1 the yields of ⁶⁷Cu are shown. They were calculated from the excitation functions of relevant charged-particle–induced reactions using the standard activation equation [1]. It is an updated version of the diagram given earlier [16]. In order to minimize the impurities of ⁶⁴Cu (radioactive) and ⁶⁵Cu (stable, decreasing the specific activity of ⁶⁷Cu), the energy range E_p = 80 → 30 MeV was found to be very suitable for the production of ⁶⁷Cu via the ⁶⁸Zn(p,2p) process. From the new results, it is concluded that protons of energy up to about 80 MeV are very suitable for the production of ⁶⁷Cu not only when isotopically enriched ⁶⁸Zn is used as target material [16, 33] but also if enriched ⁷⁰Zn would be the target, provided good radionuclidic purity is achieved. For production of the β⁻-emitter ⁴⁷Sc (for review see [4]), neither the intermediate energy reaction ⁴⁸Ti(p,2p)⁴⁷Sc investigated earlier nor the ⁵¹V(p,αp)⁴⁷Sc process studied recently [34] appears to be successful because of the high level of the radionuclidic impurity ⁴⁶Sc. With regard to the conversion electron emitter ^117mSn, the production route ¹¹⁶Cd(α,3n)^117mSn was established [11]. Yet, a new measurement suggests that the nuclear process ^natSb(p,xn)^117mSn over the proton energy range of 30–90 MeV could also be potentially useful [35]. Regarding the α-particle emitters ²²⁵Ac and ²²³Ra, the present emphasis is on their production through proton-induced reactions on ²³²Th, either directly or via the indirect routes ${}^{232}\mathrm{T}\mathrm{h}{\left(p,x\right)}^{225}\mathrm{Ra}{\stackrel{\beta -}{\to }}^{}{}^{225}\mathrm{A}\mathrm{c}$ and ${}^{232}\mathrm{T}\mathrm{h}{\left(p,x\right)}^{227}\mathrm{Th}{\stackrel{\alpha -}{\to }}^{}{}^{225}\mathrm{A}\mathrm{c}$, respectively, over the energy range up to 200 MeV. Several cross-section measurements exist (for review cf [8]) and studies on radionuclidic impurities, for example, about 0.3% ²²⁷Ac in ²²⁵Ac, as well as technical development are in progress. Besides its direct use, the radionuclide ²²⁵Ac also serves as the parent of the α-emitter ²¹³Bi.

FIGURE 1

FIGURE 1. Integral yield of ⁶⁷Cu, calculated from the excitation function of each reaction for an irradiation time of 1 h, shown as a function of incident particle energy. The dashed part of the curve for the ⁷⁰Zn(p,x)⁶⁷Cu process is an extrapolation because no data exist.

It should be mentioned that besides protons, intermediate energy deuterons and alpha-particles are also potentially useful for production of a few special radionuclides, for example, ¹⁰³Pd and ¹⁸⁶Re using deuterons and ²¹¹At using alpha-particles. Furthermore, in recent years it has been demonstrated that the high-spin isomers of a few radionuclides, for example, ^117mSn and ^193mPt, can be advantageously produced using alpha-particles [36]. They are useful in therapy because they emit low-energy conversion and Auger electrons. In general, however, the use of protons is preferred due to their easier availability and the resulting higher yields of the products.

High-energy charged-particle beam: The spallation process with high-energy protons (E_p > 500 MeV) combined with on-line mass separation was utilized at CERN in cooperation with the Paul Scherrer Institute (PSI) to produce some exotic radionuclides in the region of rare earths, especially ¹⁴⁹Tb (T_1/2 = 4.1 h) and ¹⁵²Tb (T_1/2 = 17.5 h). The former is a unique low-energy α-particle emitter suited for TAT. The latter is a theranostic PET partner. A new measurement gives cross sections for the formation of several terbium radioisotopes in the spallation of tantalum as a function of proton energy [37]. For more general use of the two radionuclides, however, development of alternative production methods, preferably using intermediate energy protons, are called for. Preliminary cross-section measurements on the reactions ¹⁵⁵Gd(p,4n)¹⁵²Tb and ¹⁵²Gd(p,4n)¹⁴⁹Tb are promising [38].

Use of photons and fast neutrons: The use of electron linear accelerator (LINAC) to deliver high-energy photons for the production of the therapeutic radionuclides ⁴⁷Sc and ⁶⁷Cu via the ⁴⁸Ti (γ,p)⁴⁷Sc and ⁶⁸Zn (γ,p)⁶⁷Cu reactions, respectively, is presently under investigation. The excitation functions are known (cf. IAEA-TECDOC-1178, 2000) but further improvement in the data is needed. The production for preclinical tests has been reported [39, 40]. In practice, however, GBq amounts of ⁶⁷Cu have been produced whereas the methodology for ⁴⁷Sc production is still developing. Some on-going nuclear data work deals with determination of spectrum-averaged cross sections and production yields [41, 42]. The production of ²²⁵Ac via the ${}^{226}\mathrm{R}\mathrm{a}{\left(\gamma ,n\right)}^{225}\mathrm{Ra}{\stackrel{\beta -}{\to }}^{}{}^{225}\mathrm{A}\mathrm{c}$ process is also being investigated. The estimated cross section is relatively high but the use of the radioactive target is a deterrent.

The use of accelerator-generated fast neutrons is also under investigation. In particular, a 30 or 40 MeVd(Be) or d(C) breakup neutron source is considered to be suitable for the production of a few radionuclides via the (n,p) or (n,np) reaction [43]. The estimated integral cross sections amount to a few mb [5]. The spallation neutrons also appear to be interesting for the formation of a few radionuclides [44]. However, extensive further nuclear data work is called for.

Concluding Remarks

Nuclear data play an important role in the production and medical application of accelerator-based radionuclides. The data for routine production of radionuclides for patient care have been standardized. For development of novel radionuclides, however, continuing data research is needed. The present thrust in medical application of radionuclides is directed toward PET studies using metallic positron emitters as well as toward targeted radionuclide therapy, preferably applying the theranostic approach. With tremendous developments in antibody labeling and organo-metallic complex formation chemistry, a big impetus has come to the field of theranostics. This is leading to an enhanced interest in accelerator-based production of radionuclides. The nonstandard positron emitters are produced at small-sized cyclotrons and now development of production methodologies of many therapeutic radionuclides is shifting from nuclear reactors to intermediate energy accelerators. Another strategy is to utilize hard photons from powerful LINACs or fast neutrons from intermediate energy accelerators. With enhancing interest in versatile accelerators to produce novel medical radionuclides, the need of relevant nuclear data research is continuing.

Author Contributions

SQ developed the concept. MH elaborated the section on standardization of data. IS reviewed experimental data and calculated radionuclide yields. BN advised on new directions in medical applications. All authors contributed to the writing of the article and approved the submitted version.

Conflict of Interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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