Multipoint analysis of reduced 125I-meta-iodobenzylguanidine uptake and norepinephrine turnover in the hearts of mice with 1-methyl-4-phenyl-1,2,3,6-tetrahydroxypyridine-induced parkinsonism

Introduction125I-Meta-iodobenzylguanidine (MIBG) cardiac uptake is reduced in mice with 1-methyl-4-phenyl-1,2,3,6-tetrahydroxypyridine (MPTP)-induced parkinsonism, although the cause of disturbance of norepinephrine (NE) turnover is unclear.MethodsC57BL6 mice (15 weeks old) were divided into six groups (n=14 each) according to the timing of MPTP injection (40 mg/kg) before 125I-MIBG: Group A, control (no MPTP injection); Group B, 1 day; Group C, 4 days; Group D, 7 days; Group E, 21 days; Group F, 7, 14 and 21 days. 125I-MIBG (0.185 MBq) was injected and the cardiac percentage injected dose per gram of tissue (%ID/g), dopamine (DA) and NE concentrations were measured. The cardiac maximal binding potential (Bmax) of NE transporter (NET) was also calculated in 20 mice per group.ResultsThe %ID/g of B, C, D, E and F mice were significantly lower than in A; those of C, D and E were significantly higher than in B; and that of F was significantly lower than in E. The DA concentrations were similar among all groups. The NE concentrations of B, C and F mice were significantly lower than in A, while those of C, D, E and F were significantly higher than in B, and that of F was significantly lower than in E. The Bmax of NET in B was significantly lower than in A.ConclusionsThus, MPTP causes rapid reductions in cardiac 125I-MIBG uptake and Bmax of NET, followed by partial recovery of 125I-MIBG uptake. Changes in cardiac 125I-MIBG uptake and NE turnover were closely related in postganglionic cardiac sympathetic nerve terminals in mice with MPTP-induced parkinsonism

A radiobrominated tyrosine kinase inhibitor for egfr with l858r/t790m mutations in lung carcinoma

金沢大学疾患モデル総合研究センターActivating double mutations L858R/T790M in the epidermal growth factor receptor (EGFR) region are often observed as the cause of resistance to tyrosine kinase inhibitors (TKIs). Third‐generation EGFR‐TKIs, such as osimertinib and rociletinib (CO‐1686), was developed to target such resistance mutations. The detection of activating L858R/T790M mutations is necessary to select sensitive patients for therapy. Hence, we aimed to develop novel radiobromine‐labeled CO‐ 1686 as a positron emission tomography (PET) imaging probe for detecting EGFR L858R/T790M mutations. Nonradioactive brominated‐CO1686 (BrCO1686) was synthesized by the condensation of N‐(3‐[{2‐chloro‐5‐(trifluoromethyl)pyrimidin‐4‐yl}amino]‐5‐bromophenyl) acrylamide with the corresponding substituted 1‐(4‐[4‐amino‐3‐methoxyphenyl]piperazine‐1‐yl)ethan‐1‐one. The radi-obrominated [77 Br]BrCO1686 was prepared through bromodestannylation of the corresponding tributylstannylated precursor with [77Br]bromide and N‐chlorosuccinimide. Although we aimed to provide a novel PET imaging probe,77Br was used as an alternative radionuclide for76Br. We fun-damentally evaluated the potency of [77Br]BrCO1686 as a molecular probe for detecting EGFR L858R/T790M using human non‐small‐cell lung cancer (NSCLC) cell lines: H1975 (EGFR L858R/T790M), H3255 (EGFR L858R), and H441 (wild‐type EGFR). The BrCO1686 showed high cy-totoxicity toward H1975 (IC50 0.18 ± 0.06 μM) comparable to that of CO‐1686 (IC50 0.14 ± 0.05 μM). In cell uptake experiments, the level of accumulation of [77Br]BrCO1686 in H1975 was significantly higher than those in H3255 and H441 upon 4 h of incubation. The radioactivity of [77Br]BrCO1686 (136.3% dose/mg protein) was significantly reduced to 56.9% dose/mg protein by the pretreatment with an excess CO‐1686. These results indicate that the binding site of the radiotracers should be identical to that of CO‐1686. The in vivo accumulation of radioactivity of [77Br]BrCO1686 in H1975 tumor (4.51 ± 0.17) was higher than that in H441 tumor (3.71 ± 0.13) 1 h postinjection. Our results suggested that [77Br]BrCO1686 has specificity toward NSCLC cells with double mutations EGFR L858R/T790M compared to those in EGFR L858R and wild‐type EGFR. However, the in vivo accumulation of radioactivity in the targeted tumor needs to be optimized by structural modification. © 2021 by the authors. Licensee MDPI, Basel, Switzerland.CC-BY 4.

Evaluation of Ga-DOTA-(D-Asp)n as bone imaging agents: D-aspartic acid peptides as carriers to bone

金沢大学新学術創成研究機構67Ga-DOTA-(L-Asp)11 and 67Ga-DOTA-(L-Asp)14, which have been developed as bone imaging agents, showed a high accumulation in bone and a rapid blood clearance in mice. However, peptides composed of D-amino acids are more stable in vivo than those composed of their L-equivalents. In this study, 67Ga-DOTA-(D-Asp)n (n = 2, 5, 8, 11, or 14) were synthesized using the Fmoc-based solid-phase methodology and evaluated. In hydroxyapatite binding assay, binding of 67Ga-DOTA-(D-Asp)n tended to increase with increasing length of the amino acid chain. 67Ga-DOTA-(D-Asp)11 and 67Ga-DOTA-(D-Asp)14 caused a high accumulation of radioactivity in the bones of the mice. However, the results for 67Ga-DOTA-(D-Asp)n and 67Ga-DOTA-(L-Asp)n were comparable. In urine analyses, the proportion of intact complex after injection of 67Ga-DOTA-(D-Asp)14 was significantly higher than that of 67Ga-DOTA-(L-Asp)14. Although 67Ga-DOTA-(D-Asp)14 was more stable than 67Ga-DOTA-(L-Asp)14, the properties of 67Ga-DOTA-(D-Asp)n and 67Ga-DOTA-(L-Asp)n as bone imaging agents may be comparable. © 2017 The Author(s)

Radiobrominated benzimidazole-quinoline derivatives as Platelet-derived growth factor receptor beta (PDGFRβ) imaging probes

金沢大学疾患モデル総合研究センターPlatelet-derived growth factor receptor beta (PDGFRβ) affects in numerous human cancers and has been recognized as a promising molecular target for cancer therapies. The overexpression of PDGFRβ could be a biomarker for cancer diagnosis. Radiolabeled ligands having high affinity for the molecular target could be useful tools for the imaging of overexpressed receptors in tumors. In this study, we aimed to develop radiobrominated PDGFRβ ligands and evaluate their effectiveness as PDGFRβ imaging probes. The radiolabeled ligands were designed by modification of 1-{2-[5-(2-methoxyethoxy)-1H- benzo[d]imidazol-1-yl]quinolin-8-yl}piperidin-4-amine (1), which shows selective inhibition profile toward PDGFRβ. The bromine atom was introduced directly into C-5 of the quinoline group of 1, or indirectly by the conjugation of 1 with the 3-bromo benzoyl group. [77Br]1-{5-Bromo-2-[5-(2-methoxyethoxy)-1H-benzo[d]imidazol-1-yl]quinoline-8-yl}piperidin-4-amine ([77Br]2) and [77Br]-N-3-bromobenzoyl-1-{2-[5-(2-methoxyethoxy)-1H-benzo[d]imidazol-1-yl]quinolin-8-yl}-piperidin-4-amine ([77Br]3) were prepared using a bromodestannylation reaction. In a cellular uptake study, [77Br]2 and [77Br]3 more highly accumulatd in BxPC3-luc cells (PDGFRβ-positive) than in MCF7 cells (PDGFRβ-negative), and their accumulation was significantly reduced by pretreatment with inhibitors. In biodistribution experiments, [77Br]2 accumulation was higher than [77Br]3 accumulation at 1 h postinjection. These findings suggest that [76Br]2 is more promising for positron emission tomography (PET) imaging of PDGFRβ than [76Br]3. © 2018 The Author(s).CC-BY 4.

Evaluation of radiobromine-labeled 5-bromo-4\u27-thio-2\u27-deoxyuridine uptake in ACHN cells after treatment with 5-fluorouracil: comparison with 3H-FLT uptake.

Objectives: We have recently developed the radiobromine-labeled 5-bromo 4\u27-thio-2\u27-deoxyuridine (BTdU) as an imaigng agent for tumor proliferation. The aim of this study was to evaluate the potential usefulness of radiobromine-labeled BTdU as an imaging agent for detecting the early therapeutic effects of 5-fluorouracil (5-FU) compared with 3H-FLT uptake. \nMethods: The radiolabeling of BTdU with 77Br was achieved by a destannylation reaction of tributylstannyl precursor. 3H-FLT was commerically available. The cells of human renal cacinoma cell line, ACHN, were treated with various concentrations of 5-FU (0.01-300 µM). At 36 hr after 5-FU addition, double tracer cell uptake studies were performed. 2.0x10-2 MBq of 77Br-BTdU and 3.7x10-2 MBq of 3H-FLT were simaltaneously added to the cells and incubated for 15min, 30min, 60min. After 3 times washing, cells were lysed, and then the radioactivity and protein content were measured. \nResults: The radiochemical yield of 77Br-BTdU was about 40% and the radiochemical purity was more than 99%. Uptakes of 77Br-BTdU and 3H-FLT were increased with time. There was not significant differences between the uptake of 77Br-BTdU and that of 3H-FLT in control group at 60min (77Br-BTdU: 18.5 +- 2.0,3H-FLT: 20.3 +- 2.7 %ID/mg protein). Compared with control the uptake of 77Br-BTdU was significantlty decreased from 0.3 µM of 5-FU (One-way ANOVA with a post hoc Dunnett\u27s Multiple Comparison Test). However, the uptake of 3H-FLT was significantly decreased from 300 µM of 5-FU. These results suggest that 77Br-BTdU could detect the earlier effect of 5-FU compared with 3H-FLT. \nConclusions: Radiobromine-labeled BTdU is potentially useful as an imaging agent for detecting the early therapeutic effects of anticancer therapy with 5-FU in patients with renal cell carcinomaSNM 2011 Annual Meetin

Norepinephrine Transporter Imaging in the Brain of a Rat Model of Depression Using Radioiodinated (2S, αS)-2-(α-(2-iodophenoxy)benzyl)morpholine

To visualize the norepinephrine transporters (NETs) in various brain diseases, we developed radioiodinated (2S,αS)-2-(α-(2-iodophenoxy)benzyl)morpholine ((S,S)-IPBM). This radioligand achieved the basic requirements for NET imaging. In this study, we assessed the potential of radioiodinated (S,S)-IPBM as an imaging biomarker of NET to obtain diagnostic information about depression in relation to NET expression in the brain using a rat depression model. The ex vivo autoradiographic experiments using the (S,S)-[ 125 I]IPBM showed significantly lower accumulation of radioactivity in the locus coeruleus (LC) and the anteroventricular thalamic nucleus (AVTN) of the depression group than in those of the control group. Consequently, in vitro autoradiographic experiments showed that NET maximum binding (B max ) values in the LC and AVTN, known as NET-rich regions, were significantly decreased in the rat model of depression when compared to those of the control rats. In addition, there was an extremely good correlation between NET B max and (S,S)-IPBM accumulation ( r = .98), an indication of radioiodinated IPBM as a quantitative NET imaging biomarker. The reduction in(S,S)-[ 125 I]IPBM accumulation in the rat model of depression correlated with that of NET density. These results suggest that (S,S)-[ 123 I]IPBM has potential as an imaging biomarker of NET to obtain diagnostic information about major depression

Automated synthesis of 16b-[18F]fluoro-5a-dihydrotestosterone using a plastic cassette-type FDG synthesizer

SNM 2010 Annual Meetin