Radiolabeled Curcumin as β Amyloid Imaging and Tumor Targeting Imaging Agents

Curcumin, a polyphenolic compound, derived from the rhizomes of Curcuma longa L. Curcumin shows potential pharmacological action against numerous disorders, including cancer, neurodegenerative, and infection diseases. Curcumin-based molecular imaging agents could be useful for early detection of Alzheimer Disease and tumor and monitor the progress of therapy. Radiolabeled curcumin and its derivatives become promising compounds as imaging agents. In this review, radiolabeled curcumin bearing radionuclides including fluorine-18, Technetium-99m, Iodine-125, and Gallium-68 are reviewed as an effort to develop curcumin-based probes not only for β amyloid imaging but also for tumor imaging.


I. Introduction
The accumulation of β-amyloid (Aβ) aggregates and neurofibrillary tangles in human brain are still considered some of the key features for neurodegenerative disorder namely Alzheimer's disease (AD) (Uzuegbunam, Librizzi and Yousefi, 2020). Histological examination of brain sample is still required to assign a definitive diagnosis of AD (Takizawa et al., 2015). However, using cerebrospinal fluid (CSF) biomarkers and positron emission tomography (PET) agents of patient which combined with several new clinical criteria, AD can be early diagnosed and monitored (Budson and Solomon, 2012;Jack et al., 2018). PET imaging is a non-invasive imaging technique that allows identifying the patients who are at risk of developing AD, and also to monitor disease progression or both (Steven T DeKosky and Marek, 2003;Reiman and Jagust, 2012). Hence, PET imaging agent may serve as an attractive diagnostic tool to monitor disease progression and the interaction of ligands with their targets (Bailey et al., 2005). Aβ is the most studied and first target for the neuroimaging of AD (Filippi et al., 2018), hence it is no surprise that there are already selective PET radiotracers for its imaging. Recently, several studies reported that curcumin showed high affinity toward Aβ plaques. Curcumin, 1,7-bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione, is a yellow-polyphenol pigment isolated from the rhizomes of Curcuma longa L and commonly known as turmeric (Hewlings and Kalman, 2017). The structure of curcumin shown in Figure 1. Curcumin has a wide spectrum of pharmacological actions and it has been reported to have anti-inflammatory (Zhu et al., 2014), anti-microbial (Chen et al., 2016), antioxidant (Banez et al., 2020), anti-carcinogenic (Perrone et al., 2015;Zhao et al., 2017;Walker and Mittal, 2020) activities. Because of its distinctive uptake in normal and cancer cells (Kunwar et al., 2008;Heger et al., 2014), radiolabeled curcumin is one of attractive agents for tumor targeting radiopharmaceuticals. The present work introduces radiolabeled curcumin and its derivatives focusing on radiotracers for cancer and Aβ imaging.

II. Research Method II.1 Radiolabeled curcumin
Molecular imaging is a type of noninvasively medical imaging that allows to visualize, characterize, and measure the biological processes at molecular and cellular levels (Mankoff, 2007). Nuclear medicine is a revolutionized invention in diagnostic imaging using radiopharmaceuticals because it can be utilized to diagnose diseases noninvasively and facilitate monitoring disease progression or response to treatment of therapy repeatedly. Using single photon-emission computed tomography (SPECT) and PET imaging the diagnosis and progress of therapy the molecular target can be assessed (Fass, 2008;Cunha et al., 2014). SPECT has some merits such as low cost and more assessable than PET, even though PET has better sensitivity and resolution (Galbán et al., 2010). Due to its pharmacological and biological actions, radiolabeled curcumin and their derivatives could be potential biomarkers for imaging of Alzheimer's disease and cancer by means of nuclear medicine imaging techniques which could be useful for early detection of them and contribute to personalized medicine.
As promising compound, radiolabeled curcumin and its derivatives have been developed and evaluated their feasibilities as imaging agents. Radiogallium (Orteca et al., 2019) and radioiodinated (Kumar, Subramanian and Samuel, 2016) curcumin have been reported as cancer imaging agents. Other studies showed the 99m Tc (Sagnou et al., 2011) and 18 F (Kim et al., 2019) labeled curcumin have been used as β-amyloid plaques imaging agents.

III.1 18 F-curcumin
Fluorine-18 ( 18 F) is one of PET radionuclides that routinely utilized in radiolabeling of biomolecules with half-life of 109.8 min (Alauddin, 2012). High spatial resolution and high sensitivity are two vaporable properties of PET imaging agent. However, high cost in preparation limited its use. Radiofluorinated-curcumin as imaging agents have been developed as detailed follow:

[ 18 F]F-labeled hydrazinocurcumin derivative ([ 18 F]FHC)
In 2015, Shin at al. reported their studies in preparation of radiofluorinated hydrazinocurcumin derivatives (Figure 3). This probe was accumulated in human umbilical vascular endothelial cells and rat C6 glioma cells.   (Shin et al., 2015), reproduced by permission of The Royal Society of Chemistry

III.2 99m Tc-curcumin
Technetium-99m ( 99m Tc) is generated by transportable 99 Mo-99m Tc generator, readily available, and inexpensive. 99m Tc is an attractive radionuclide for SPECT imaging due to its favorable physical and chemical properties, such as a low γrays emission (140 keV, 89% abundance) and a moderate half-life (6 h) which is sufficient for preparation of 99m Tc-based radiopharmaceuticals (International Atomic Energy Agency (IAEA), 2009; Boschi, Uccelli and Martini, 2019). 99m Tclabeled curcumin as Aβ imaging agents have been reported, some of them detailed as below:

III.3 125 I-curcumin
Radionuclides of iodine have been widely used in various fields of medicinal and biological sciences. These radionuclides insert into bioactive molecules to visualize the molecular target non-invasively and to diagnose the particular disease (Effendi et al., 2019). There are some types of iodine radionuclides with different type of ray emission, such as iodine-123 (SPECT), iodine-124 (PET), iodine-125 (preclinical research and Auger therapy), iodine-131 (β-therapy) (Dubost et al., 2020). Identical chemical properties of iodine radionuclides allow the in vitro and in vivo information from one radioiodine nuclide bearing bioactive compound serve as basic data for further work (Effendi et al., 2018). Radioiodine-labeled curcumin probes have been reported, some of them described as follow:

125 I-curcumin
In 2013, Kumar et al. reported their studies in preparation of radioiodinated curcumin as tumortargeting probes. Using iodogen method, Iodine-125 was inserted into curcumin to obtain 125 I-curcumin ( Figure 5) with radiochemical yield more than 75% and high purity (>95). Accumulation of 125 Icurcumin in EL4 murine lymphoma cells reached 6.8% dose/500,000 cells. The tumor uptake of 125 Icurcumin in lymphoma-tumor model mice reached 3.3% ID/gram at 3 h post-injection. The biodistribution data exhibited that 125 I-curcumin was washed-out slowly from blood and other nontargeted tissues (Kumar, Subramanian and Samuel, 2016).

III.4 68 Ga-curcumin
The radionuclide 68 Ga has a great potential property for clinical PET and could be an attractive alternative to 18 F which require an on-site cyclotron in production. 68 Ga is a generatorproduced radionuclide with a half-life of 68 min. In principle, the long half-life of the parent nuclide 67 Ge (270.8 days) provides a generator with a long life span (Martiniova et al., 2016). Radionuclide Ga-67 usually was used in initial evaluation of radiogallium complexes due to it is an easy-tohandle radioisotope with a longer half-life (3.3 days) than 68 Ga. The following is detailed some curcuminbased radiogallium probes as tumor-targeting and Aβ imaging agents.
In another year, this group (Rubagotti et al., 2016) continued the evaluation of these radiogallium probes and explored their feasibility as Aβ imaging agents. They reported that [ 68 Ga](CUR)2 + and [ 68 Ga](DAC)2 + complexes have high binding affinity for synthesized Aβ fibrils and medium affinity has been shown by [ 68 Ga](bDHC)2 + (in vitro study). On the other hand, in in vivo study using post-mortem brain cryosections of male Tg2576 mice, all of gallium complexes could not visualize amyloid plaques. Low in vivo stability of complexes and a hampered passage across the blood-brain barrier might be involved in this result (Rubagotti et al., 2016).  Ga]DOTA-C21 retained for long enough in blood and some others non-targeted tissues such as small intestine, kidney, and lung (Orteca et al., 2019).

IV. Conclusions
In this review, we introduced a variety of radiolabeled curcumin as Aβ imaging or tumortargeting imaging agents. Curcumin has a wide spectrum of biological and pharmacological actions. Anti-inflammatory, anti-microbial, anti-oxidant, and anti-carcinogenic activities of curcumin have been studied. A sufficient binding affinity of curcumin for β amyloid as one of biomarker for Alzheimer's Disease encourage curcumin become a promising compound for Aβ imaging and tumor targeting imaging. Nuclear medicine imaging as non-invasively technique to visualize the molecular target in order to get early detection of disease and monitor the progress of treatment has attractive attention oncologist and researchers. Some promising curcumin-bearing radionuclide derivatives have been developed in recent years as introduced some of them in this review. However, structure modification of them is still needed to guarantee an appropriate imaging agent not only for Aβ imaging but also for tumor imaging. Hopefully, novel curcumin-based imaging agents with promising properties could be developed in the near future.

V. Conflict of Interest
The author declares that there is no conflict of interest regarding the publication of this paper.