Hiroki Ashino

Synthesis and evaluation of a novel 68Ga-chelate-conjugated bisphosphonate as a bone-seeking agent for PET imaging

INTRODUCTION (68)Ga is a positron-emitting nuclide that has significant imaging potential given that, unlike cyclotron-produced (18)F, the isotope can be produced on-site utilizing a (68)Ge/(68)Ga generator. We recently synthesized a novel bone-seeking agent by coupling a bisphosphonate with the (68)Ga chelator 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA). This study presents a first report on the potential of this (68)Ga bone-seeking radiopharmaceutical in the detection of bone metastases. METHODS 4-Amino-1-hydroxybutylidene-1,1-bisphosphonate was conjugated with 2-[4,7-di(carboxymethyl)-1,4,7-triazonan-1-yl]pentanedioic acid, yielding 2-[4,7-di(carboxymethyl)-1,4,7-triazonan-1-yl]-5-[(4-hydroxy-4,4-diphosphonobutyl)amino]-5-oxopentanoic acid (NOTA-BP). (68)Ga-labeled NOTA-BP ([(68)Ga]NOTA-BP) was prepared by complexation of NOTA-BP with [(68)Ga] gallium chloride and evaluated in in vitro experiments, biodistribution experiments and micro-positron emission tomography (PET) imaging experiments. RESULTS The labeling of NOTA-BP with (68)Ga was completed by heating for 10 min. [(68)Ga]NOTA-BP was determined to have a radiochemical purity of over 95%, a high affinity for hydroxyapatite and a high stability in plasma. In in vivo biodistribution experiments, [(68)Ga]NOTA-BP demonstrated high bone uptake potential. Compared with (99m)Tc-labeled methylene diphosphonate ([(99m)Tc]MDP) and [(18)F]fluoride, [(68)Ga]NOTA-BP exhibited faster blood clearance and a higher bone-to-blood ratio. In addition, mouse model bone metastasis was detected by micro-PET imaging at 1 h postinjection of [(68)Ga]NOTA-BP. CONCLUSION We have developed a novel (68)Ga-radiolabeled bone-seeking agent. This [(68)Ga]NOTA-BP complex was found to have a high bone affinity and rapid blood clearance, and may thus prove to be useful as a bone-seeking agent for clinical PET.

In Vivo SPECT Imaging of Amyloid-β Deposition with Radioiodinated Imidazo[1,2-a]Pyridine Derivative DRM106 in a Mouse Model of Alzheimer's Disease

Noninvasive determination of amyloid-β peptide (Aβ) deposition has important significance for early diagnosis and medical intervention for Alzheimers disease (AD). In the present study, we investigated the availability of radiolabeled DRM106 (123/125I-DRM106 [6-iodo-2-[4-(1H-3-pyrazolyl)phenyl]imidazo[1,2-a]pyridine]), a compound with sufficient affinity for the synthesis of human Aβ fibrils and satisfactory metabolic stability, as a SPECT ligand in living brains. Method: The sensitivity of 125I-DRM106 for detecting Aβ deposition was compared with that of 125I-IMPY (2-(4′-dimethylaminophenyl)-6-iodo-imidazo[1,2-a]pyridine), a well-known amyloid SPECT ligand, by ex vivo autoradiographic analyses in 18-mo-old amyloid precursor protein transgenic mice. To verify the sensitivity and quantitation of radiolabeled DRM106 for in vivo imaging, we compared the detectability of Aβ plaques with 123I-DRM106 and a well-known amyloid PET agent, 11C-labeled Pittsburgh compound B (11C-PiB), in 29-mo-old transgenic mice and age-matched nontransgenic littermates. Additionally, we compared the binding characteristics of 125I-DRM106 with those of 11C-PiB and 11C-PBB3, which selectively bind to Aβ plaques and preferentially to tau aggregates, respectively, in postmortem AD brain sections. Results: Ex vivo autoradiographic analysis showed that measurement with 125I-DRM106 has a higher sensitivity for detecting Aβ accumulation than with 125I-IMPY in transgenic mice. SPECT imaging with 123I-DRM106 also successfully detected Aβ deposition in living aged transgenic mice and showed strong correlation (R = 0.95, P < 0.01) in quantitative analysis for Aβ plaque detection by PET imaging with 11C-PiB, implying that sensitivity and quantitation of SPECT imaging with 123I-DRM106 are almost as good as 11C-PiB PET for the detectability of Aβ deposition. Further, the addition of nonradiolabeled DRM106 fully blocked the binding of 125I-DRM106 and 11C-PiB, but not 11C-PBB3, to AD brain sections, and 125I-DRM106 showed a lower binding ratio of the diffuse plaque–rich lateral temporal cortex to the dense-cored/neuritic plaque–rich hippocampal CA1 area, compared with 11C-PiB. Conclusion: All of these data demonstrated the high potential of 123I-DRM106 for amyloid imaging in preclinical and clinical application, and it might more preferentially detect dense-cored/neuritic amyloid deposition, which is expected to be closely associated with neuropathologic changes of AD.

Synthesis and biological evaluation of novel radioiodinated imidazopyridine derivatives for amyloid-β imaging in Alzheimer's disease.

Non-invasive detection for amyloid-β peptide (Aβ) deposition has important significance for the early diagnosis and medical intervention for Alzheimers disease (AD). In this study, we developed a series of imidazopyridine derivatives as potential imaging agents for single-photon emission computed tomography (SPECT). Two of them, compounds DRK092 and DRM106, showed higher affinity for synthetic human Aβ 1-40 fibrils than did the well-known amyloid-imaging agent IMPY. A metabolite analysis revealed brain-permeable radioactive metabolites of (125)I-labeled DRK092 and IMPY; no radioactive metabolites from (125)I-labeled DRM106 ([(125)I]DRM106) were detected. In addition, in vitro autoradiography clearly demonstrated specific binding of [(125)I]DRM106 in the hippocampal region of AD enriched with Aβ plaques. Thus, our results strongly suggested that compound DRM106 can be used as an imaging agent for SPECT to detect Aβ deposition in AD brain.

Distinct binding of amyloid imaging ligands to unique amyloid-β deposited in the presubiculum of Alzheimer's disease

Non‐invasive determination of amyloid‐β peptide (Aβ) deposition with radioligands serves for the early diagnosis and clarification of pathogenetic mechanisms of Alzheimers disease (AD). The polymorphic binding site on multimeric Aβ for current radioligands, however, is little understood. In this study, we investigated the binding of several radioligands including 11C‐Pittsburgh Compound B (11C‐PiB), 3H‐AZD2184, and two recently developed compounds, 125I‐DRM106 and 125I‐DRK092, with unique presubicular Aβ deposits lacking interaction with the commonly used amyloid dyes FSB. 11C‐PiB, 3H‐AZD2184, and 125I‐DRK092 showed overt binding to presubicular Aβ deposits, while 125I‐DRM106 barely bound to these aggregates despite its strong binding in the hippocampal CA1 sector. Unlike neuritic plaques in the CA1, Aβ lesions in the presubiculum were not accompanied by inflammatory gliosis enriched with 18‐kDa translocator protein (TSPO). Thus, there are at least two different components in Aβ aggregates providing distinct binding sites for the current amyloid radioligands, and one of these binding components is distinctly present in the presubicular Aβ deposits. Amyloid radioligands lacking affinity for this component, such as 125I‐DRM106, may selectively capture Aβ deposits tightly associated with TSPO neuroinflammation and neurodegeneration as exemplified by CA1 neuritic plaques. Hence, comparative autoradiographic assessments of radioligand binding in CA1 and presubiculum could serve for the development of an amyloid PET imaging agent visualizing neurotoxicity‐related Aβ pathologies.

SPECT Imaging of Mice with 99mTc-Radiopharmaceuticals Obtained from 99Mo Produced by 100Mo(n,2n)99Mo and Fission of 235U

The distribution of 99mTc-radiopharmaceutical in mouse was determined by single photon emission computed tomography (SPECT) for the first time using 99mTc, which was separated by thermochromatograp...

Magnetic resonance-based visualization of thermal ablative margins around hepatic tumors by means of systemic ferucarbotran administration before radiofrequency ablation: animal study to reveal the connection between excess iron deposition and T2*-weighted hypointensity in ablative margins.

Objective The objective of this study was to demonstrate experimentally that radiofrequency ablation (RFA) of ferucarbotran-accumulated healthy liver tissues causes excess iron deposition in the ablated liver tissues on postablation days and produces sustained T2*-weighted low signals indicative of ablative margins surrounding hepatic tumors. Materials and Methods We conducted 3 experiments using 30 rats. In experiment 1, we administered either ferucarbotran (n = 6) or saline (n = 4), acquired T2*-weighted images (T2*-WIs) of the liver by using a 3-T magnetic resonance scanner, and subsequently performed RFA of healthy liver lobes. We acquired follow-up T2*-WIs up to day 7 and histologically analyzed the liver specimens. In another 4 rats, we performed sham operation, instead of RFA, in ferucarbotran-accumulated liver lobes, followed by the same image acquisition and histological analysis. In experiment 2, we administered 59Fe-labeled ferucarbotran, subsequently performed either RFA (n = 4) or sham operation (n = 4) in the liver, and acquired autoradiograms of the liver specimens on day 7. In experiment 3, we conducted RFA treatment for 8 rats bearing orthotopic hepatic tumors after ferucarbotran administration and monitored tumor growth by using serial T2*-WIs. Results On days 4 and 7 of the experiment 1, T2*-WIs of 6 rats with systemic ferucarbotran administration and subsequent hepatic RFA showed low-signal regions indicative of ablated liver tissues, whereas high-signal areas were seen in 4 saline-administered rats. Neither high nor low signal areas were detected in 4 sham-operated rats. Histologically, larger amounts of iron were observed in the RFA-induced necrotic liver tissues in the ferucarbotran-administered rats than in the saline-administered-rats. The 59Fe autoradiography of the rats in experiment 2 revealed accumulation of ferucarbotran-derived iron in necrotic liver tissues. Among 6 hepatic tumors grown in 6 rats of the experiment 3, a total of 4 tumors were stable in size, but the other 2 increased markedly on day 7. Retrospectively, T2*-WIs showed the former tumor sites surrounded completely by low-signal areas on day 4. Conclusions The RFA of ferucarbotran-accumulated healthy liver tissues in the rats caused excess iron deposition in the ablated liver tissues and produced sustained T2*-weighted hypointense regions. Similar hypointense regions surrounding hepatic tumors were indicative of ablative margins.

SPECT IMAGING FOR AMYLOID PLAQUES WITH A NOVEL RADIOIODINATED LIGAND IN AN ALZHEIMER'S DISEASE MODEL

of AD was performed. All animal experiments were carried out under the approval of the relevant Institutional Animal Review Committee of Ege University, (Number: 2010-155) Izmir, Turkey. Results: Higher uptakes on hippocampus were observed at Ab 1-42 injected side in animal model of AD when compared with the control and na€ive groups. Saturated studies with Bioquin-7-carboxylic acid compound showed that 99mTc labeled Bioquin-HMPAO compound has specificity on amyloid plaques (Figure 1). Conclusions: Consequences of the whole experimental studies, it is proposed that the radiolabeled compound (99m Tc-Bioquin-HMPAO) might be improved and used as a novel brain amyloid plaque specific agent promising early diagnosis potential of AD.