Yuki Okumura

A Novel CYP11B2-Specific Imaging Agent for Detection of Unilateral Subtypes of Primary Aldosteronism

CONTEXT Although adrenal vein sampling is the standard method to distinguish unilateral from bilateral forms of primary aldosteronism, it is an invasive and technically difficult procedure. (11)C-metomidate (MTO)-positron emission tomography was reported as a potential replacement for adrenal vein sampling. However, MTO has low selectivity for CYP11B2 over CYP11B1. OBJECTIVE This study aimed to determine the selectivity of (18)F-CDP2230, a new imaging agent, for CYP11B2 over CYP11B1 and determine whether the biodistribution profile of (18)F-CDP2230 is favorable for imaging CYP11B2. METHODS The IC50 of CDP2230 for the enzymatic activities of CYP11B2 and CYP11B1 was determined using cells with stable expression of either enzyme. In vitro autoradiography of human adrenal sections with aldosterone-producing adenomas was performed to confirm the specific binding ability of (18)F-CDP2230 to CYP11B2-expressing regions. Furthermore, positron emission tomography and magnetic resonance imaging were performed to evaluate the biodistribution of (18)F-CDP2230 in rats. RESULTS Although CDP2230 showed a significantly lower affinity for CYP11B2 and CYP11B1 than did MTO analogues, its selectivity for CYP11B2 over CYP11B1 was higher than that of MTO analogues. In vitro autoradiography revealed that the binding of (18)F-CDP2230 to CYP11B2-expressing regions in the adrenal gland was more specific than that of (123)I-IMTO. Moreover, the biodistribution study showed that (18)F-CDP2230 accumulated in adrenal glands with low background uptake. CONCLUSIONS Our study showed a high selectivity of (18)F-CDP2230 for CYP11B2 over CYP11B1 with a favorable biodistribution for imaging CYP11B2. (18)F-CDP2230 is a promising imaging agent for detecting unilateral subtypes of primary aldosteronism.

Preclinical properties and human in vivo assessment of 123I-ABC577 as a novel SPECT agent for imaging amyloid-β

Although PET amyloid-β imaging agents are available, they cannot be used with SPECT scanners. Maya et al . report that a novel SPECT imaging agent, 123I-ABC577, has a high affinity for amyloid-β, and differentiates Alzheimers disease patients from healthy controls, with low non-specific retention in the white matter.

The Thymidine Phosphorylase Imaging Agent 123I-IIMU Predicts the Efficacy of Capecitabine

Recently, companion diagnostics with nuclear medicine techniques have been anticipated as more suitable means than biopsy for predicting treatment efficacy. The anticancer effect of capecitabine, an orally administered chemotherapeutic agent activated by thymidine phosphorylase (TP), is positively associated with tumor TP expression levels. This study aimed to assess whether TP imaging using a radiolabeled uracil derivative, 123I-5-iodo-6-[(2-iminoimidazolidinyl)methyl]uracil (123I-IIMU), could predict the efficacy of capecitabine treatment. Methods: Sensitivity to doxifluridine, a metabolite of capecitabine and direct substrate for TP, was assessed by water-soluble tetrazolium salt assays in vitro for 3 human colon cancer cell lines with different TP expression profiles. The intracellular uptake and retention of 123I-IIMU were evaluated. Mice inoculated with each cell line were treated with capecitabine for 2 wk, and tumor growth was compared. In vivo distribution studies and SPECT/CT imaging of 123I-IIMU were performed in inoculated mice. Results: In vitro experiments showed a positive relation between TP expression levels and doxifluridine sensitivity. In vitro studies revealed that intracellular uptake and retention of 123I-IIMU were dependent on TP expression levels. In vivo experiments in inoculated mice showed that 123I-IIMU accumulation in tumor tissue was in line with TP expression levels and susceptibility to capecitabine treatment. Moreover, SPECT/CT imaging of 123I-IIMU in tumor-inoculated mice showed that 123I-IIMU reflects TP expression levels in tumor tissues. Conclusion: 123I-IIMU could be used as an in vivo companion diagnostic for predicting the efficacy of capecitabine treatment.

Design, Synthesis, and Preliminary Evaluation of SPECT Probes for Imaging β-Amyloid in Alzheimer’s Disease Affected Brain

In this study, we synthesized of a series of 2-phenyl- and 2-pyridyl-imidazo[1,2- a]pyridine derivatives and examine their suitability as novel probes for single-photon emission computed tomography (SPECT)-based imaging of β-amyloid (Aβ). Among the 11 evaluated compounds, 10 showed moderate affinity to Aβ(1-42) aggregates, exhibiting half-maximal inhibitory concentrations (IC50) of 14.7 ± 6.07-87.6 ± 39.8 nM. In vitro autoradiography indicated that 123I-labeled triazole-substituted derivatives displayed highly selective binding to Aβ plaques in the hippocampal region of Alzheimers disease (AD)-affected brain. Moreover, biodistribution studies performed on normal rats demonstrated that all 123I-labeled probes featured high initial uptake into the brain followed by a rapid washout and were thus well suited for imaging Aβ plaques, with the highest selectivity observed for a 1 H-1,2,3-triazole-substituted 2-pyridyl-imidazopyridine derivative, [123I]ABC577. This compound showed good kinetics in rat brain as well as moderate in vivo stability in rats and is thus a promising SPECT imaging probe for AD in clinical settings.

P2-086: Synthesis and evaluation of novel amyloid binding compounds as PET/SPECT imaging agents for amyloid plaques

Background: Non-invasive -amyloid imaging technique with positron emission tomography (PET) or single photon emission computed tomography (SPECT) is believed to be effective in both the early diagnosis of Alzheimer’s disease (AD) and the monitoring of anti-amyloid therapy. Methods: The objective is to identify novel -amyloid imaging tracers for clinical use. For the purpose, we designed imidazopyridine-phenol derivatives as candidates and identified several desirable amyloid-binding compounds (ABCs). In this study, ABCs were radio-labeled and conducted biological evaluation. Results: Radio-labeling (F or I) of ABCs was respectively achieved based on each precursor and moderate level of yield was obtained. Consequently ABCs showed high binding affinity for A (142) fibrils in vitro assay and moderate blood-brain barrier penetration was observed in normal rodents. On the other hand, in vitro autoradiography studies showed that ABCs clearly demonstrated not only specific binding to amyloid plaques, but also very low nonspecific binding to white matter in postmortem AD brain sections and transgenic mouse model (Tg2576). In addition, the binding affinity of ABCs to ninety-one types of receptors and transporters (e.g., DA, 5-HT, GABA, Histamine) resulted to be lower than 1/1000 worth the maximum affinity for amyloid. These findings indicate that ABCs can provide specific PET or SPECT images with low background noise. Also safety studies such as single-dose toxicity study or genotoxicity test demonstrated safety of ABCs. Conclusions: These results suggest that ABCs will be potential compounds as novel PET or SPECT tracers for clinical use.