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“Radiotheranostics” is a term used in nuclear medicine to refer to the use of radioisotope (RI)-labeled agents to perform simultaneous imaging and therapy of a target lesion. A radiotheranostics system uses radiolanthanides as diagnostic and therapeutic RIs. In this review, we discuss radiotheranostics with radiolanthanides, focusing on the design, development strategies, and medical applications of radiolanthanide-labeled probes. We also discuss the potential and future uses of radiolanthanides in radiotheranostics.

Background The aim of this study is to investigate the underlying biologic mechanisms of 2-[18F]-fluoro-2-deoxy- d -glucose (18F-FDG) uptake on positron emission tomography (PET) in non-small cell lung cancer (NSCLC). Methods One-hundred forty patients with NSCLC who underwent 18F-FDG PET were included in the study. Tumor sections were stained by immunohistochemistry for glucose transporter 1 (GLUT1), GLUT3, hypoxia-inducible factor-1 alpha (HIF-1α), hexokinase I, vascular endothelial growth factor (VEGF), microvessels (CD34), epidermal growth factor receptor (EGFR), and molecules relevant to PI3K/Akt/mTOR signaling pathway (PTEN, p-Akt, p-mTOR and p-S6). We also conducted in vitro studies of 18F-FDG uptake and mTOR inhibition in NSCLC cells. Results High 18F-FDG uptake was significantly associated with poor prognosis in NSCLC patients. 18F-FDG uptake was significantly correlated with GLUT1, hexokinase I, HIF-1α, VEGF, CD34, p-Akt, p-mTOR and EGFR. PTEN expression showed inverse correlation with 18F-FDG uptake. In in vitro study, 18F-FDG uptake was markedly decreased by the inhibition of GLUT1 and GLUT1 upregulation by the induction of HIF-1α increased the 18F-FDG uptake. Inhibition of both mTOR complex1 (mTORC1) and mTORC2 suppressed cell growth, but activity of mTORC1 regulated the 18F-FDG uptake. NCI-H1650 cells with PTEN loss showed the highest 18F-FDG uptake and the least sensitivity to mTOR inhibitors. Conclusion The amount of 18F-FDG accumulation is associated with molecules relevant to glucose metabolism, hypoxia, angiogenesis and mTOR signaling pathway. Especially, PTEN status may affect not only 18F-FDG uptake but also effect of mTOR inhibitors on the growth of NSCLC.

A 12-membered polyazamacrocycle, 1-oxa-4,7,10-triazacyclododecane-N,N',N″-triacetic acid (ODTA), has been reported to provide an indium chelate of net neutral charge with thermodynamic stability higher than 1,4,7,10-tetraazacyclododecane-N,N',N″,N‴-tetraacetic acid (DOTA). However, neither synthetic procedure for a C-functionalized ODTA (C-ODTA) nor its chelating ability with a trace amount of radioactive indium-111 ((111)In) has been elucidated. We herein present a facile synthetic procedure for C-ODTA, and estimated its ability as a chelating agent for radiolabeling peptides and proteins with (111)In. The synthetic procedure involves the synthesis of a linear precursor using a para-substituted phenylalanine derivative as a starting material. The following intramolecular cyclization reaction was best performed (>73% yield) when Boc-protected linear compound and the condensation reagent, HATU, were simultaneously added to the reaction vessel at the same flow rate. The cyclic compound was then reduced with BH(3) and alkylated with tert-butyl bromoacetate. The synthetic procedure was straightforward and some optimization would be required. However, most of the intermediate compounds were obtained easily in good yields, suggesting that the present synthetic procedure would be useful to synthesize C-ODTA derivatives. The intramolecular cyclization reaction might also be applicable to synthesize polyazamacrocycles of different ring sizes and cyclic peptides. In (111)In radiolabeling reactions, C-ODTA provided (111)In chelates in higher radiochemical yields at low ligand concentrations when compared with C-DOTA. The (111)In-labeled C-ODTA remained unchanged in the presence of apo-transferrin. The biodistribution studies also showed that the (111)In-labeled compound was mainly excreted into urine as intact. These findings indicate that C-ODTA would be useful to prepare (111)In-labeled peptides of high specific activities in high radiochemical yields.

Introduction 3-[ 18 F]fluoro-α-methyl-l-tyrosine ([ 18 F]FAMT) is a useful amino acid tracer for positron emission tomography (PET) imaging of malignant tumors. FAMT analogs labeled with 76 Br, a positron emitter with a long half-life ( t 1/2 =16.1 h), could potentially be widely used as amino acid tracers for tumor imaging. In this study, 3-[ 76 Br]bromo-α-methyl-l-tyrosine ([ 76 Br]BAMT) was designed, and its usefulness was evaluated as a novel PET tracer for imaging malignant tumors. Methods In this study, both [ 76 Br]BAMT and [ 77 Br]BAMT were prepared. The in vitro and in vivo stability of [ 77 Br]BAMT was evaluated by HPLC analysis. Cellular uptake and retention of [ 77 Br]BAMT and [ 18 F]FAMT were evaluated using LS180 colon adenocarcinoma cells. Biodistribution studies were performed in normal mice and in LS180 tumor-bearing mice, and the tumors were imaged with a small-animal PET scanner. Results [ 77 Br]BAMT was stable in vitro but was catabolized after administration in mice. Cellular accumulation and retention of [ 77 Br]BAMT were significantly higher than those of [ 18 F]FAMT. In biodistribution studies, the tumor accumulation of [ 77 Br]BAMT was higher than that of [ 18 F]FAMT. However, some level of debromination was seen, which caused more retention of radioactivity in the blood and organs than was seen with [ 18 F]FAMT. PET imaging with [ 76 Br]BAMT enabled clear visualization of the tumor, and the whole-body image using [ 76 Br]BAMT was similar to that using [ 18 F]FAMT. Conclusions [ 77 Br]BAMT showed high levels of tumor accumulation, and [ 76 Br]BAMT enabled clear visualization of the tumor by PET imaging. Although an improvement in stability is still needed, 76 Br-labeled FAMT analogs could potentially serve as PET tracers for the imaging of malignant tumors.

Matrix metalloproteinases (MMPs) are endopeptidases responsible for degrading the extracellular matrix (ECM) and remodeling tissue in both physiological and pathological processes. MMP2 and membrane-type 1 MMP (MT1-MMP) have been associated with tumor invasion, metastasis and angiogenesis; therefore, a molecular imaging strategy assessing their activity may help to predict the malignancy of tumors. Here, we established a novel method of specifically tagging the surface of MMP2- and MT1-MMP-positive cells, and applied it to the development of an optical imaging probe. We constructed a protein-based probe composed of a glutathione-S-transferase (GST)-tag (Inhibitory [I]-domain), a polypeptide as a specific substrate for both MMP2 and MT1-MMP (Cleaved [C]-domain), a transmembrane domain of the epidermal growth factor receptor (Transmembrane [TM]-domain), and DsRed2 (Fluorescent [F]-domain). In vitro experiments clearly demonstrated that, after the probe was cleaved at the C-domain by the MMPs, the resultant TM–F-domain was inserted into the cellular membrane. Optical imaging experiments in vivo demonstrated that the probe was cleaved and specifically remained in tumor xenografts in a MMP-dependent manner. These results indicate that the release of the I–C-domain through the proteolytic cleavage of the C-domain by MMP2 and MT1-MMP triggers the tagging of cellular membranes with the TM–F-domain. The present feasibility study opens the door to the development of a novel imaging probe for tumor malignancy using positron emission tomography as well as an optical imaging device.

Introduction We have developed a method for producing no-carrier-added 64 Cu by using chelating resin bearing iminodiacetic acid groups. Methods We optimized the conditions for the selective separation of radioactive Cu from Ni and Co using the chelating resin and produced no-carrier-added 64 Cu under the optimized conditions. We analyzed the amounts of the metal ions present in 64 Cu by inductively coupled-plasma mass spectroscopy (ICP-MS) and optical emission spectroscopy (ICP-OES), and performed radiolabeling of monoclonal antibodies in order to investigate the quality of the 64 Cu produced in this study. Results Radioactive Cu was separated from Ni and Co with 0.1 and 2 M HCl solutions. The yield of 64 Cu isolated from the 64 NiO target was almost 87%. The radiochemical purity of 64 Cu obtained from different amounts of 64 NiO targets was >99% in all cases. We found that the 64 Cu solution presented extremely low amounts of the metal ions and showed high specific activity (average: 595 GBq/μmol). Moreover, the antibodies were labeled with 64 Cu with a high average efficiency (average: 88%). Conclusions We could efficiently separate 64 Cu by using short ion-exchange columns. The chelating ion-exchange method provides a high quality of 64 Cu that is sufficient for the synthesis of 64 Cu-labeled antibodies and medical applications.

Since elevated levels of gelatinases [matrix metalloproteinase (MMP)-2 and MMP-9] are associated with a poor prognosis in cancer patients, these enzymes are potential targets for tumor imaging. In the present study, a cyclic decapeptide, cCTTHWGFTLC (CTT), was selected as a mother compound because of its selective inhibitory activity toward gelatinases. For imaging gelatinase activity in tumors, we designed a CTT-based radiopharmaceutical taking into consideration that (1) the HWGF motif of the peptide is important for the activity, (2) hydrophilic radiolabeled peptides show low-level accumulation in the liver and (3) an increase in the negative charge of radiolabeled peptides is effective in reducing renal accumulation. Thus, a highly hydrophilic and negatively charged radiolabel, indiun-111-diethylenetriaminepentaacetic acid ( 111 In-DTPA), was attached to an N-terminal residue distant from the HWGF motif ( 111 In-DTPA-CTT). In MMP-2 inhibition assays, In-DTPA-CTT significantly inhibited the proteolytic activity in a concentration-dependent fashion. When injected into normal mice, 111 In-DTPA-CTT showed low levels of radioactivity in the liver and kidney. A comparison of the pharmacokinetic characteristics of 111 In-DTPA-CTT with those of other CTT derivatives having different physicochemical properties revealed that the increase in hydrophilicity and negative charge caused by the conjugation of 111 In-DTPA reduced levels of radioactivity in the liver and kidney. In tumor-bearing mice, a significant correlation was observed between the accumulation in the tumor as well as tumor-to-blood ratio of 111 In-DTPA-CTT and gelatinase activity. These findings support the validity of the chemical design of 111 In-DTPA-CTT for reducing accumulation in nontarget tissues and maintaining the inhibitory activity of the mother compound. Furthermore, 111 In-DTPA-CTT derivatives would be potential radiopharmaceuticals for the imaging of gelatinase activity in metastatic tumors in vivo.

The chemokine receptor CXCR4 is highly expressed in tumor cells and plays an important role in tumor metastasis. The aim of this study was to develop a radiopharmaceutical for the imaging of CXCR4-expressing tumors in vivo. Based on structure-activity relationships, we designed a 14-residue peptidic CXCR4 inhibitor, Ac-TZ14011, as a precursor for radiolabeled peptides. For 111In-labeling, diethylenetriaminepentaacetic acid (DTPA) was attached to the side chain of d-Lys(8) which is distant from the residues indispensable for the antagonistic activity. In-DTPA-Ac-TZ14011 inhibited the binding of a natural ligand, stromal cell-derived factor-1alpha, to CXCR4 in a concentration-dependent manner with an IC50 of 7.9 nM (Ac-TZ14011: 1.2 nM). In biodistribution experiments, more 111In-DTPA-Ac-TZ14011 accumulated in the CXCR4-expressing tumor than in blood or muscle. Furthermore, the tumor-to-blood and tumor-to-muscle ratios were significantly reduced by coinjection of Ac-TZ14011, indicating a CXCR4-mediated accumulation in tumor. These findings suggested that 111In-DTPA-Ac-TZ14011 would be a potential agent for the imaging of CXCR4 expression in metastatic tumors in vivo.