KSNM60: The History of Radiopharmaceutical Sciences in Korea

Abstract

A number of researchers in Korea have tried to set-up the production of radionuclides and develop new radiopharmaceuticals for several decades. Thanks to their 60-year endeavor to advance the field of radiopharmaceutical sciences, now we have a lot of research units and facilities in Korea. Still, there are huge number of issues to be solved in radiopharmaceutical sciences; however, our efforts will be continued to develop new radiopharmaceuticals and to apply the new radiopharmaceuticals into nuclear medicine field.

The Dawn of Radiopharmaceutical Sciences in Korea

The first medical use of radioisotope (RI) in Korea was the study of ¹³¹I uptake to the thyroid gland in hyperthyroidism by Prof. Moon Ho Lee of the Seoul National University (SNU) in 1959. Soon, many hospitals in Seoul started use of RI; however, there was no facility to produce RI in Korea at that time. They should have been imported. The Atomic Energy Research Institute (AERI) was founded in 1959 in the Seoul National University College of Industry. The first research reactor in Korea was planned by the president Syngman Rhee’s government in July 1959 and decided to construct TRIGA (Training, Research, Isotopes, General Atomics) Mark II (100~250 kWt), which started in 1959 and finished in 1962. Radiation Medicine Research Institute was founded in 1962. As the capacity of TRIGA Mark II was too small to produce enough RI, the second research reactor TRIGA Mark III (2 MWt) was planned by president Jeong-hee Park’s government and constructed from 1969 to 1972. AERI was renamed as Korea Atomic Energy Research Institute (KAERI) in 1973. Various RI such as ¹³¹I, ¹⁹⁸Au, and ⁵⁵Fe for medical use, ²⁴Na and ⁸²Br for industry, and ³²P and ³⁵S for life science were produced by these research nuclear reactors. TRIGA Mark II and TRIGA Mark III were constructed by the American technology. As the consumption of RI increased, a larger scale research nuclear reactor was planned by president Doo-Hwan Chun’s government and constructed by Korean technology from 1989 to 1995, which was named HANARO (Highly Advanced Neutron Application Reactor, 30 MWh). After foundation of KAERI and construction of research nuclear reactors, not only medical radionuclides but also various labeled compounds such as [^99mTc]Tc₂S₇ colloid, [^99mTc]Tc-MAA, and [^99mTc]Tc-ascorbate were synthesized. Although studies for development of new radiopharmaceuticals were performed by nuclear medicine physicians in several hospitals, KAERI was the most active in the field of commercialization until middle of 1980. Various cold vials for ^99mTc-labeling were produced by KAERI or imported from the USA, Japan, and UK. However, ⁹⁹Mo/^99mTc-generators were imported from Japan and the UK until the end of the twentieth century.

Development of Medical Cyclotron And Cyclotron-produced RI in Korea

The Division of Applied RI in Korea Institute of Radiological and Medical Sciences (KIRAMS) uses three medical cyclotrons (16.5, 30, 50 MeV) to produce medical RI and develop radiopharmaceuticals for brain diseases as well as cancers (Table 1). RI for cancer detection and myocardial SPECT image such as ⁶⁷Ga, ²⁰¹Tl, and ¹²³I were produced for the first time in Korea in 1989 and 1990, and distributed domestically. After installation of a 30 MeV cyclotron, a mass production of those RI became possible, which have been supplied to many hospitals since then. In 2007, ⁶⁴Cu and ¹²⁴I were successfully produced using 50 MeV cyclotron for the first time in Korea, and have been supplied to domestic researchers. In case of ⁶⁴Cu, ⁶⁴Ni-enriched plating system was designed on top of gold foil which is 13° tilted towards the beam irradiation, where nuclear reaction of ⁶⁴Ni(p, n)⁶⁴Cu at low energy under the degrader composed of Al and Ta foils is applied. An efficient ⁶⁴Cu separation method using plastic cartridge column was also developed (Fig. 1). ⁶⁴Cu was identified by multichannel analyzer installed for a HPGe detector and its utility was certified by microPET images of [⁶⁴Cu]Cu-ATSM using CT-26 tumor-bearing mouse. The microPET image quality of ⁶⁴Cu was also comparable to the image obtained using ¹⁸F (Fig. 2).

Table 1.

Cyclotrons and radioisotope production status at KIRAMS

Energy (proton beam)	Producer	Beam	Target Isotopes
50 MeV	Scantronix (1985)	Alpha Deuteron Proton	18F(PET),11C(PET),64Cu (PET),124I (PET),89Zr(PET),44Sc(PET),117mSn(conversion electron),211At(alpha),67Cu(beta)
30 MeV	IBA (2000)	Proton	18F(PET),11C(PET),123I(SPECT),201Tl(SPECT),225Ac(alpha)
16.5 MeV	GE (2018)	Deuteron Proton	18F(PET),11C(PET)

Fig. 1.

Gamma spectrum of purified ⁶⁴Cu fraction

Fig. 2.

Transverse images of resolution phantom filled with ⁶⁴Cu (left) and ¹⁸F (right) solutions

KIRAMS successfully produced ⁸⁹Zr in 2014. KIRAMS has provided ⁶⁴Cu (3,903 mCi/year), ¹²⁴I (156 mCi/year), and ⁸⁹Zr (120 mCi/year) to 12 research institutes and hospitals since then. For the production of ⁸⁹Zr, a nuclear reaction of ⁸⁹Y(p, n)⁸⁹Zr using a solid ⁸⁹Y-foil irradiated with an extracted proton beam (20 μA, 18−20 MeV) from 50 MeV medical cyclotron was used. After purification, ⁸⁹Zr was identified by a specific gamma energy of 909 keV using HPGe detector, and the radiochemical purity was more than 99% (74−185 MBq/mL in 1M oxalic acid), which was confirmed using radio-ITLC (Fig. 3).

Fig. 3.

Small-animal PET images of [⁸⁹Zr]Zr-oxalate in mice bearing an orthotopically implanted U87MG tumor (left shoulder) and inflammation (right thigh)

KIRAMS produced 13 MeV cyclotron (KIRAMS-13) and installed seven regional cyclotron centers in Korea (2003~2007). The cyclotron was optimized for ¹⁸F production. KIRAMS also installed it at two sites (Da Nang General Hospital, Hanoi Irradiation Center) in Vietnam. Additionally, KIRAMS tried to develop 30 MeV cyclotron based on KIRAMS-13 development experiences (2005~2009). Finally, it successfully installed in KIRAMS at Jeongup city as producing and studying medical RI like ⁶⁸Ga, ⁸⁹Zr, and ⁶⁷Cu. These projects effected to decrease the cyclotron price of international companies. It has also contributed to [¹⁸F]FDG supply for nuclear medicine growth and people health in Korea.

Currently, KIRAMS is preparing to produce therapeutic RI including ⁶⁷Cu, ^117mSn, and ²¹¹At, which emit beta and alpha particles. For ²¹¹At production, ²⁰⁹Bi(α,d)²¹¹At reaction was applied using ²⁰⁹Bi irradiated at 5 uA for 1h by 50 MeV cyclotron (Fig. 4). ²¹¹At was purified and the identity was confirmed by HPGe detector. It was quite encouraging the ²¹⁰At was not detected at all (Fig. 5). In addition to the production of various RI, KIRAMS are actively developing radiopharmaceuticals for cancer detection and therapy as well as diagnosis of brain diseases such as depression and Alzheimer’s disease (AD) using radiolabeled biomolecules including antibodies, peptides, and small molecules.

Fig. 4.

Development of ²⁰⁹Bi target for ²¹¹At production

Fig. 5.

Gamma spectrum with HPGe detector for ²¹¹At

Research for the Development of New Radiopharmaceuticals

There have been great efforts of researchers on radiopharmaceutical sciences in Korea, and here we described typical examples of their efforts. Studies for the development of new radiopharmaceuticals for clinical application are being actively conducted by several Korean researchers. The following is an introduction to the research achievements of some laboratories.

Positron emission tomography (PET) scanners and baby cyclotrons (13~16.5 MeV) were first introduced to SNUH and Samsung Medical Center (SMC) in 1994, and since then, short-lived RI, such as ¹⁵O, ¹³N, ¹¹C, and ¹⁸F were used for preparation of PET radiopharmaceuticals for routine clinical use and for development of various PET radiopharmaceuticals. 2-[¹⁸F]Fluoro-2-deoxyglucose (FDG) was the first PET radiopharmaceutical to be produced. After that, sodium [¹⁸F]fluoride was produced for bone imaging. ¹¹C-Acetic acid, the first ¹¹C-labeled agent, was produced in 1994. With introduction of ¹¹C-methyl iodide synthesizer to Korea since 1995, ¹¹C-methionine, ¹¹C-raclopride, and ¹¹C-flumazenil were synthesized. The first ¹¹C-methyl iodide synthesizer was a wet type, which includes trapping and reducing ¹¹C-carbon dioxide by using a lithium aluminum hydride (LAH) solution in tetrahydrofuran. However, this method required extremely high caution to handle LAH solution, because it reacted with ¹¹C-carbon dioxide and water in the air very rapidly, and thus resulted in the decreased molar activity of the final product. A dry type ¹¹C-methyl iodide synthesizer was distributed by GE Healthcare since 1995, which synthesizes ¹¹C-methyl iodide by reacting ¹¹C-methane with iodine vapor at high temperature. Higher molar activity products could be obtained by using a dry type synthesizer (Fig. 6). ¹³N-Ammonia for myocardial perfusion imaging was the only ¹³N-labeled radiopharmaceutical. Its synthesis was easily conducted using a very simple module. ¹⁵O-Water for brain or myocardial perfusion imaging was easy to synthesize but had an economical issue. With an accelerated deuteron beam, ¹⁵O can be synthesized economically by ¹⁴N(d,n)¹⁵O reaction using a natural nitrogen gas as a target. However, with a proton-only cyclotron, a very expensive ¹⁵N target gas was used to synthesize ¹⁵O by ¹⁵N(p,n)¹⁵O reaction.

Fig. 6.

Wet type and dry type synthesis of [¹¹C]CH₃I

[¹⁸F]Fluoroacetate was synthesized by Prof. Jeong’s group of SNUH for myocardial imaging [1], [¹⁸F]fluoroflumazenil for benzodiazepine receptor imaging [2–4], [¹⁸F]human serum albumin for blood pool imaging [5], ¹⁸F-cEFQ for metabotropic glutamate receptor imaging [6], and ¹⁸F-labeled RGD derivative for angiogenesis imaging [7]. Beta-amyloid plaque (Aβ) imaging agents for the diagnosis of the AD such as benzylidene aniline derivatives and benzothiophene derivatives [8, 9]. Interesting studies were performed about easy labeling of ¹⁸F in aqueous solution by using aluminum fluoride (Fig. 7) [10, 11]. Significant studies were performed for therapy using ¹⁸⁸Re which was obtained from ¹⁸⁸W/¹⁸⁸Re-generator. ¹⁸⁸Re in lipiodol solution was developed for liver cancer therapy (Fig. 8) [12–20], [¹⁸⁸Re]Re-tin colloid was developed for rheumatoid arthritis therapy [21–24], ¹⁸⁸Re-paper was developed for skin cancer therapy (Fig. 9), and [¹⁸⁸Re]Re-DTPA was developed for coronary artery balloon brachytherapy [25, 26]. As the introduction of ⁶⁸Ge/⁶⁸Ga-generator, a lot of studies for developing ⁶⁸Ga-labeled compounds were performed. ⁶⁸Ga-labeled RGD derivative was developed for angiogenesis imaging (Fig. 10) [27–34], a BAPEN derivative was developed for myocardial imaging [35], nitroimidazole derivatives were developed for hypoxia imaging [36–38], amino acid derivatives were developed for cancer imaging [39, 40], and a glu-urea-lys (GUL) derivative for prostate cancer imaging [41]. Currently, the prostate cancer targeting is a very important issue for theranostics. Targeting sentinel lymph node or lymphoscintigraphy using mannosylated human serum albumin (MSA) was actively studied. Macrophages have mannose receptor which also is called as CD206. The human serum albumin (HSA) having mannose residues can be used for targeting macrophages that exist in lymph node, liver, spleen, or atherosclerosis [42–45]. On the other hand, if galactose or lactose is conjugated with HSA, then it could be used for imaging hepatocyte representing liver function [46, 47]. As the versatility and utility of nanoparticles are proved, a lot of studies to develop multifunctional nanoparticles were performed. A one-pot single step method to introduce multifunction by using a one-tail amphiphiles was developed [41, 48, 49]. These nanoparticles might be very useful for therapy of various cancers or detection of sentinel lymph nodes. However, their clinical application might require time and money to get manufacturing approval.

Fig. 7.

¹⁸F-labeling in aqueous solution by using aluminum fluoride salt

Fig. 8.

Lipophilic diaminedisulfur compound having long aliphatic chain for preparation of [¹⁸⁸Re]Re-lipiodol solution

Fig. 9.

Preparation of ¹⁸⁸Re-labeled paper for treatment of skin cancer

Fig. 10.

⁶⁸Ga-labeled RGD compound for angiogenesis imaging

Prof. Chi and his coworkers have studied facile fluorination protocols, as well as developing ¹⁸F PET (positron emission tomography) applications. Firstly, they reported a facile fluorination reaction using KF as a fluorine source for a nucleophilic substitution reaction of a mesylate 1 using ionic liquid ([bmim][BF₄]) in the presence of water as an additive (Fig. 11) [50, 51]. The reaction was completed in 1.5 h in acetonitrile to afford desired product 2 without significant formation of byproducts. In this reaction, the presence of small amount of water turned out to be critical for the high reactivity and selectivity towards fluorinated product 2. This ionic liquid media fluorination also showed good performance in the ¹⁸F labeling reaction [52]. It is well-known that protic solvents do not provide the proper medium for most nucleophilic substitution reactions because of strong interaction between nucleophile and protic solvent. However, Chi and his coworkers reported novel concepts for metal fluoride activation and mechanistic investigation to utilize simple and small organic molecules, particularly using the protic solvents (t-BuOH and glycols) properly designed to promote fluorination reactions with unprecedented efficiency (Fig. 12) [53, 54]. Although protic solvents have been known to be inferior for nucleophilic displacement reactions to aprotic polar solvents such as CH₃CN and DMF, they discovered that protic solvents such as t-amyl alcohol and glycols could indeed facilitate various fluorination reaction with significant efficiency by allowing bifunctional activation of metal fluorides and substrates. Because this protic media fluorination protocol could become possible to produce [¹⁸F]FP-CIT and [¹⁸F]FLT automatically and routinely by ¹⁸F radiolabeling, these radiopharmaceuticals could be commercially available to be used clinically in Korea [55]. In addition, Chi and his coworkers reported that the synergistic effect of two solvents—ionic liquid and protic solvent—in one molecule showed a good performance in the nucleophilic fluorination reaction [56]. These protic molecules tethered ionic liquids can be regarded as an alternative to replace the conventional phase transfer catalytic system.

Fig. 11.

Nucleophilic fluorination reaction in ionic liquid [bmim] [BF₄]

Fig. 12.

Protic media catalyzed nucleophilic fluorination reaction and ¹⁸F radiofluorination

Prof. Choe’s group at SMC has studied on PET radioligands for imaging the molecular targets of AD. First, they developed radioligands for in vivo mapping of acetylcholinesterase (AChE) [57–62]. In these studies, they used a two-step ¹⁸F-labeling strategy; synthesis of [¹⁸F]fluorobenzaldehyde from 2- or 4-formyl-N,N,N-trimethylanilinium triflate and n-Bu₄N[¹⁸F]F followed by reductive alkylation with a piperidine precursor. The most promising radioligand was 2-[¹⁸F]fluoro-CP-118,954 [60], and its mouse brain PET images showed high uptake in the striatum, an AChE-rich region, which was also blocked by a known AChE inhibitor (Fig. 13A) [63]. Surprisingly, 4-[¹⁸F]fluoro-donepezil did not have specific uptake in the striatum (Fig. 13B), even though donepezil (Aricept®) is an FDA-approved drug used to improve symptoms of AD [63]. They also developed radioligands for imaging of Aβ plaques, another molecular target of AD. Curcumin was the molecule of interest because dietary curcumin reduced the Aβ plaque burden in the hippocampus and cortex regions of transgenic mouse brains [64]. They developed ¹⁸F-labeled curcumin for Aβ plaque imaging (Fig. 14) [65]. In this study, they showed a direct evidence that the F-substituted curcumin as well as curcumin has the excellent in vitro binding affinity for Aβ aggregates. Later, radiolabeled curcumin derivatives were further modified to improve their brain permeability (Fig. 14) [66]. In another work, they added a methyl group to both C2- and C4-positions of curcumin to prevent reductive metabolism on the olefinic double bonds of curcumin (Fig. 14) [67]. Moreover, they developed ¹⁸F-labeled styryltriazole for Aβ plaque imaging, which showed favorable brain pharmacokinetics in mice (Fig. 15) [68]. When a novel radioligand is developed, metabolic characterization of the radioligand is required. In this regard, they developed a simple and efficient in vitro method for metabolism studies of radioligands using hepatic microsomes or S9 fractions that contain metabolizing enzymes [69, 70]. Prof. Choe's another main research topic was to study radiolabeled vascular endothelial growth factor (VEGF) derivatives [71–74] as well as radiolabeled small molecules [75–79] for tumor angiogenesis imaging. They developed radiometal (⁶⁴Cu or ⁶⁸Ga)-labeled NOTA or NODAGA-VEGF₁₂₁ (Fig. 16) [71, 72]. The radiolabeled VEGF₁₂₁ showed specific binding to VEGF receptor (VEGFR) and high tumor uptake in U87MG tumor-bearing mice [72, 73]. In another study, they used a streptavidin/biotin platform to develop a hybrid PET/optical imaging probe for VEGFR imaging [74]. This hybrid probe appears to be a promising candidate for hybrid PET/optical imaging of VEGFR expression.

Fig. 13.

Transaxial microPET images of ICR mouse brains; the 0–30-min dynamic images obtained after injection of 2-[¹⁸F]fluoro-CP-118,954 (A) and 4-[¹⁸F]fluoro-donepezil (B), and the 31–60-min images blocked with 0.5 mg/kg of CP-118,954 (A) and donepezil (B)

Fig. 14.

Structures of curcumin, ¹⁸F-labeled curcumin derivatives, and 2,6-dimethylcurcumin

Fig. 15.

Structure of ¹⁸F-labeled styryltriazole

Fig. 16.

MicroPET image of a U87MG tumor-bearing mouse injected with ⁶⁸Ga-NODAGA-VEGF₁₂₁

Prof. Min, Prof. Kim and their colleagues at Chonnam National University Hwasun Hospital focuses on tracers such as radiopharmaceuticals and optical dyes conjugated small molecules; these conjugates are used for diagnosis and treatment of diseases. Not only medical radionuclides, such as ¹⁸F, ¹¹C, ¹²³I, ¹³¹I, and ¹³N, but also emerging radionuclides such as ⁶⁸Ga, ⁶⁴Cu, and ⁸⁹Zr, are used to synthesize positron emission tomography (PET) radiotracers for imaging. Furthermore, they aim to develop novel imaging strategies to address as-yet un-met clinical needs. Such strategies include ¹⁸F-labeled myocardial imaging agents, synthetic modules for routine [¹¹C]acetate production, ⁶⁴Cu-labeled artificial protein binders, and ¹⁸F-labeled tracers to visualize malignant melanoma. First, is development of ¹⁸F-labeled myocardial imaging agents [80–88]. ¹⁸F-labeled phosphonium cations accumulate to a higher degree in cardiomyocytes than in normal cells due to the higher mitochondrial membrane potential (MMP) in the latter. This type of mitochondrial voltage sensor will be useful for detecting myocardial abnormalities; this is because loss of MMPs is an early event in cell death caused by myocardial ischemia. Thus, they developed several kinds of ¹⁸F-labeled fluoroalkylphosphonium derivatives ([¹⁸F]FATPs) and examined their in vivo characteristics. [¹⁸F]FATPs showed stable uptake in the myocardium and rapid clearance from the blood and other organs, which results in excellent image quality (Fig. 17). Thus, [¹⁸F]FATPs are promising ¹⁸F-labeled radiopharmaceuticals for evaluating myocardial perfusion by PET. Second, is development of a [¹¹C]acetate synthesis module for routine production [89]. [¹¹C]Acetate is metabolized rapidly in human cells to yield acetyl-CoA, which can enter the tricarboxylic acid cycle and participate in cell membrane lipid synthesis in tumor cells. Thus, [¹¹C]acetate, a radiotracer for PET imaging, is under investigation for use in a number of cancers. They developed an optimized synthetic module and confirmed its high reproducibility and simplicity; also, it has a high radiochemical yield for routine clinical use. Third, is development of a method of labeling artificial protein binders with ⁶⁴Cu [90]. ⁶⁴Cu has the longest half-life among positron emitters (12.7 h), which allows imaging at later time points than ¹⁸F (half-life = 109.7 min); thus it is appropriate for imaging of protein binders. Therefore, they optimized ⁶⁴Cu-labeling methods using three kinds of chelator (NOTA, DOTA, and DTPA) and reported the in vivo characteristics of artificial protein binders (repebodies) that have high affinity for the epidermal growth factor receptor (EGFR). The rapid and prolonged retention of three types of [⁶⁴Cu]Cu-repebody in the tumor, but not blood or muscle, suggests that these molecules can be used as imaging agents to obtain high-contrast PET images of EGFR expression at tumor sites shortly after injection (Fig. 18). The favorable in vivo kinetics and specific tumor uptake of repobodies warrants their further investigation as imaging agents for EGFR-positive tumors. Last, is development of ¹⁸F-labeled imaging agents for detecting malignant melanoma [91, 92]. Malignant melanoma is one of the most lethal cancers because of its high systemic metastatic potential. Benzamide derivatives have selective affinity for melanin; over the past two decades, these agents have been investigated extensively with a view to developing single photon emission computed tomography (SPECT) agents for melanoma detection. Thus, they modified the structure of bezamide and labeled it with ¹⁸F to develop a novel PET tracer to visualize malignant melanoma. They synthesized N-(2-(dimethylamino)ethyl)-4-¹⁸F-fluorobenzamide ([¹⁸F]DMFB), pyridine-based benzamide derivatives, N-(2-(dimethylamino)ethyl)-5-[¹⁸F]fluoropicolinamide ([¹⁸F]DMPY2), and N-(2-(dimethylamino)ethyl)-6-[¹⁸F]fluoronicotinamide ([¹⁸F]DMPY3), and then evaluated them to identify best one. Among them, [¹⁸F]DMPY2 showed excellent performance with respect to detection of melanoma cells. The specific/rapid targeting, prolonged retention, and rapid clearance of [¹⁸F]DMPY2 from primary and metastatic tumors suggests that this radiotracer could be used as a PET imaging agent to obtain outstanding image quality for diagnosis of melanoma (Fig. 19). The excellent characteristics of [¹⁸F]DMPY2 warrant further investigation to determine whether it can be translated to the clinic and used for theranostic approaches.

Fig. 17.

Coronal small-animal PET images of rats at taken 30 and 60 minutes after intravenous injection of 37 MBq of [¹⁸F]FATPs. The heart is visible, with excellent heart-to-background contrast at each time point after tracer injection. A (5-[¹⁸F]fluoropentyl)triphenylphosphonium cation ([¹⁸F]FPTP); B (6-[¹⁸F]fluorohexyl)triphenylphosphonium cation ([¹⁸F]FHxTP); C (7-[¹⁸F]fluoroheptyl)triphenylphosphonium cation ([¹⁸F]FHtTP); D (8-[¹⁸F]fluorooctyl)triphenylphosphonium cation ([¹⁸F]FOTP); E (2-(2-[¹⁸F]fluoroethoxy)ethyl)triphenylphosphonium cation ([¹⁸F]FETP); and F (2-(2-[¹⁸F]fluoroethoxy)ethyl)tris(4-methoxyphenyl)phosphonium cation ([¹⁸F]FETMP)). H, heart; L, liver

Fig. 18.

Radiolabeling of NOTA-, DOTA-, and DTPA-conjugated repebodies. The right-most panel shows coronal small-animal PET images of nude mice bearing H1650 (white arrows) tumors at 1, 6, and 24 h after tail veil injection of the ⁶⁴Cu-labeled NOTA-, DOTA-, or DTPA-repebodies (each used at 7.4 MBq)

Fig. 19.

Representative microPET images showing mice bearing B16F10 (A white arrow) and SK-MEL-3 (B blue arrow) tumors at 30 and 60 min post-injection of [¹⁸F]DMPY2 (n = 5). C MicroPET image and photograph of a mouse bearing two different types of tumor (red arrow, B16F10; yellow arrow, U87MG) at 60 min post-injection of [¹⁸F]DMPY2. D MicroPET and autoradiographic images of [¹⁸F]DMPY2 in a lung metastasis model. E MicroPET image (yellow arrow) and pathological examination of [¹⁸F]DMPY2 in a lymph node metastasis model

Clinical Uses and Regulations of Radiopharmaceuticals in Korea

In Korea, we can use radiopharmaceuticals in clinic as following three different ways. Firstly, the manufactured radiopharmaceutical, which is approved by Ministry of Food and Drug Safety (MFDS, earlier Korean Food and Drug Agent (KFDA)), secondly, in-house preparation using MFDS-approved kit by the simple mixing with RI, lastly, a radiopharmaceutical listed in pharmacopeia, but is not manufactured by any company or hospital, can be used by in-house preparation after the declaration to the local public health center without approval from MFDS.

Because the Pharmaceutical Affairs Act does not properly reflect the reality of the use of radiopharmaceuticals in clinical practice, especially in-house preparation or compounding of radiopharmaceuticals, more than 3 decades, Radiopharmaceutical Committee (RC) of KSNM was trying to persuade MFDS to setup several ¹⁸F and ¹¹C-labeled radiopharmaceuticals as hospital compounding rather than having manufacturing approval of MFDS. Because, those agents are produced only in hospital in small amount by the order of physician. After the approval of several ¹⁸F-labeled radiopharmaceuticals from MFDS, unfortunately, such a discussion and negotiation was stopped because RC lost the rationale to claim the in-house preparation or compounding of radiopharmaceuticals without MFDS approval. Anyway, ¹¹C-labeled radiopharmaceuticals could be used as compounded radiopharmaceuticals because of their very short half-lives.

Currently, Korea has joined Pharmaceutical Inspection Co-operation Scheme (PIC/S) and MFDS required hospitals to fallow good manufacturing practice (GMP) for the preparation of MFDS-approved radiopharmaceuticals. However, still ¹¹C-labeled radiopharmaceuticals could be used as compounded radiopharmaceuticals because of their very short half-lives. After a lot of debates, now many hospitals had GMP approval from MFDS.

Conclusion

Although a lot of studies to develop new radiopharmaceuticals have been conducted for a long time, not many new radiopharmaceuticals have been approved for manufacturing. There are huge number of issues to be solved for the approval, such as the market size, safety and efficacy, and GMP-related issues. A lot of cost and time will be required to solve all these issues. Fortunately, due to the recent great success of therapeutic radiopharmaceuticals, we hope that a new radiopharmaceutical blockbuster will be developed in Korea soon and open the new gate of theranostics in Nuclear Medicine field.

Declarations

Conflict of Interest

Ran Ji Yoo, Yun-Sang Lee, Kyo Chu Lee, Dong Wook Kim, Dong-Yeon Kim, Yearn Seong Choe, and Jae Min Jeong declare no conflict of interests.

Ethical Approval and Consent to Participate

No need for ethical approval and informed consent.