Publications by authors named "Seigo Kinuya"

227 Publications

Development of Radiohalogenated Osimertinib Derivatives as Imaging Probes for Companion Diagnostics of Osimertinib.

J Med Chem 2022 Jan 11. Epub 2022 Jan 11.

Institute for Frontier Science Initiative, Kanazawa University, Kakuma-machi, Kanazawa, Ishikawa 920-1192, Japan.

Osimertinib is an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor approved for treating non-small-cell lung cancer (NSCLC) with EGFR mutations. Genetic testing is required to detect the mutation for selecting patients who can use osimertinib. Here, we report an attempt to develop nuclear imaging probes that detect the EGFR mutations. We designed and synthesized I-osimertinib and Br-osimertinib with a radioactive or nonradioactive halogen atom at an indole ring in osimertinib and evaluated them. assays suggested that both I-osimertinib and Br-osimertinib exhibit a specifically high activity toward NSCLC with EGFR L858R/T790M mutations. In biodistribution experiments, the accumulation of both [I]I-osimertinib and [Br]Br-osimertinib in tumors with mutations was significantly higher than that in blood and muscle. However, these osimertinib derivatives showed a significantly higher accumulation in lungs than in tumors. Therefore, for detecting the mutations in lung cancer, further structural modifications of the probes are required.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.jmedchem.1c01211DOI Listing
January 2022

Application of a tungsten apron for occupational radiation exposure in nursing care of children with neuroblastoma during I-meta-iodo-benzyl-guanidine therapy.

Sci Rep 2022 Jan 7;12(1):47. Epub 2022 Jan 7.

Department of Nuclear Medicine, Kanazawa University Hospital, 13-1 Takara-machi, Kanazawa, Ishikawa, 920-8641, Japan.

The use of effective shielding materials against radiation is important among medical staff in nuclear medicine. Hence, the current study investigated the shielding effects of a commercially available tungsten apron using gamma ray measuring instruments. Further, the occupational radiation exposure of nurses during I-meta-iodo-benzyl-guanidine (I-MIBG) therapy for children with high-risk neuroblastoma was evaluated. Attachable tungsten shields in commercial tungsten aprons were set on a surface-ray source with I, which emit gamma rays. The mean shielding rate value was 0.1 ± 0.006 for I. The shielding effects of tungsten and lead aprons were evaluated using a scintillation detector. The shielding effect rates of lead and tungsten aprons against I was 6.3% ± 0.3% and 42.1% ± 0.2% at 50 cm; 6.1% ± 0.5% and 43.3% ± 0.3% at 1 m; and 6.4% ± 0.9% and 42.6% ± 0.6% at 2 m, respectively. Next, we assessed the occupational radiation exposure during I-MIBG therapy (administration dose: 666 MBq/kg, median age: 4 years). The total occupational radiation exposure dose per patient care per I-MIBG therapy session among nurses was 0.12 ± 0.07 mSv. The average daily radiation exposure dose per patient care among nurses was 0.03 ± 0.03 mSv. Tungsten aprons had efficient shielding effects against gamma rays and would be beneficial to reduce radiation exposures per patient care per I-MIBG therapy session.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-021-03843-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8742119PMC
January 2022

Synthesis and evaluation of radiogallium-labeled long-chain fatty acid derivatives as myocardial metabolic imaging agents.

PLoS One 2021 15;16(12):e0261226. Epub 2021 Dec 15.

Institute for Frontier Science Initiative, Kanazawa University, Kakuma-machi, Kanazawa, Ishikawa, Japan.

Since long-chain fatty acids work as the primary energy source for the myocardium, radiolabeled long-chain fatty acids play an important role as imaging agents to diagnose metabolic heart dysfunction and heart diseases. With the aim of developing radiogallium-labeled fatty acids, herein four fatty acid-based tracers, [67Ga]Ga-HBED-CC-PDA, [67Ga]Ga-HBED-CC-MHDA, [67Ga]Ga-DOTA-PDA, and [67Ga]Ga-DOTA-MHDA, which are [67Ga]Ga-HBED-CC and [67Ga]Ga-DOTA conjugated with pentadecanoic acid (PDA) and 3-methylhexadecanoic acid (MHDA), were synthesized, and their potential for myocardial metabolic imaging was evaluated. Those tracers were found to be chemically stable in 0.1 M phosphate buffered saline. Initial [67Ga]Ga-HBED-CC-PDA, [67Ga]Ga-HBED-CC-MHDA, [67Ga]Ga-DOTA-PDA, and [67Ga]Ga-DOTA-MHDA uptakes in the heart at 0.5 min postinjection were 5.01 ± 0.30%ID/g, 5.74 ± 1.02%ID/g, 5.67 ± 0.22%ID/g, and 5.29 ± 0.10%ID/g, respectively. These values were significantly lower than that of [123I]BMIPP (21.36 ± 2.73%ID/g). For their clinical application as myocardial metabolic imaging agents, further structural modifications are required to increase their uptake in the heart.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0261226PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8673672PMC
December 2021

Safety and response after peptide receptor radionuclide therapy with Lu-DOTATATE for neuroendocrine tumors in phase 1/2 prospective Japanese trial.

J Hepatobiliary Pancreat Sci 2021 Dec 14. Epub 2021 Dec 14.

Department of Nuclear Medicine, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Japan.

Background: The present prospective phase 1/2 study aimed to elucidate the efficacy and safety of Lu-DOTATATE (four cycles of 7.4 GBq) in Japanese patients with unresectable, progressive neuroendocrine tumors (NETs).

Methods: From April 2018 to October 2020, 15 patients with advanced NETs (five midgut, eight pancreatic, and two lung NETs) were enrolled. Objective response rate (ORR), progression-free survival (PFS), and adverse events (AEs) were evaluated. Pharmacokinetics and dosimetry were also evaluated in three midgut patients.

Results: The mean absorbed doses of Lu-DOTATATE to the kidneys (20.7 Gy/29.6 GBq) and the bone marrow (0.631 Gy/29.6 GBq) were within the radiation tolerance doses. The ORR of the whole population was 53% (90% CI, 30%-76%). ORRs of the midgut and non-midgut NETs were 60% (90% CI, 19%-92%) and 50% (90% CI, 22%-78%), respectively. There was no difference in the maximum reduction rate of the sum of the target lesion diameters between patients with midgut and non-midgut NET. The median PFS was not reached; the PFS rate at 52 weeks was 80% (90% CI, 56.1%-91.7%). AEs of Grade 3 or higher were lymphopenia (47%) and leukopenia (7%).

Conclusion: Lu-DOTATATE demonstrated remarkable tumor shrinkage and tolerability in Japanese patients with advanced NETs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/jhbp.1101DOI Listing
December 2021

Volumetric evaluation of Tc-pyrophosphate SPECT/CT for transthyretin cardiac amyloidosis: Methodology and correlation with cardiac functional parameters.

J Nucl Cardiol 2021 Dec 14. Epub 2021 Dec 14.

Department of Nuclear Medicine, Kanazawa University Hospital, 13-1 Takara-machi, Kanazawa, 920-8641, Japan.

Background: Volumetric evaluation of Technetium-pyrophosphate (Tc-PYP) SPECT/CT is a useful method for assessing transthyretin cardiac amyloidosis (ATTR-CA). We investigated the methodology and assessed its relationship with conventional parameters.

Methods And Results: We retrospectively evaluated Tc-PYP SPECT/CT scans of 25 patients who underwent endomyocardial biopsy and/or gene testing. Fourteen (56%) patients were diagnosed with ATTR-CA. SPECT/CT images were acquired at 3 hours after injection. Total volumes of the myocardial regions where uptakes were > 1.2 and 1.4 × aortic blood pool SUVmax were evaluated and defined as cardiac pyrophosphate volume (CPV1.2 and CPV1.4). The heart-to-contralateral lung (H/CL) ratio and myocardial SUVmax were also calculated. CPV1.2 achieved the highest sensitivity and specificity in diagnosing ATTR-CA. In patients diagnosed with ATTR-CA (n = 14), CPV1.2 negatively correlated with left ventricular ejection fraction and positively correlated with left ventricular posterior wall thickness and QRS duration. The correlation was stronger in CPV1.2 than in the H/CL ratio and SUVmax.

Conclusion: Volumetric evaluation of Tc-PYP SPECT/CT may be superior to the H/CL ratio and SUVmax in assessing the disease burden of ATTR-CA. Larger studies are warranted to clarify whether volumetric measurement can assess prognosis and disease progression.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s12350-021-02857-7DOI Listing
December 2021

An open-label, single-arm, multi-center, phase II clinical trial of single-dose [I]meta-iodobenzylguanidine therapy for patients with refractory pheochromocytoma and paraganglioma.

Ann Nucl Med 2021 Dec 6. Epub 2021 Dec 6.

Department of Nuclear Medicine, Kanazawa University Hospital, 13-1 Takara-machi, Kanazawa, Ishikawa, 920-8641, Japan.

Objective: In this phase II study, we aimed to investigate the efficacy and safety of single-dose [I]meta-iodobenzylguanidine (I-mIBG) therapy in patients with refractory pheochromocytoma and paraganglioma (PPGL).

Patients And Methods: This study was designed as an open-label, single-arm, multi-center, phase II clinical trial. The enrolled patients were administered 7.4 GBq of I-mIBG. Its efficacy was evaluated 12 and 24 weeks later, and its safety was monitored continuously until the end of the study. We evaluated the biochemical response rate as the primary endpoint using the one-sided exact binomial test based on the null hypothesis (≤ 5%).

Results: Seventeen patients were enrolled in this study, of which 16 were treated. The biochemical response rate (≥ 50% decrease in urinary catecholamines) was 23.5% (90% confidence interval: 8.5-46.1%, p = 0.009). The radiographic response rates, determined with CT/MRI according to the response evaluation criteria in solid tumors (RECIST) version 1.1 and I-mIBG scintigraphy were 5.9% (0.3%-25.0%) and 29.4% (12.4%-52.2%), respectively. The most frequent non-hematologic treatment-emergent adverse events (TEAEs) were gastrointestinal symptoms including nausea, appetite loss, and constipation, which were, together, observed in 15 of 16 patients. Hematologic TEAEs up to grade 3 were observed in 14 of 16 patients. No grade 4 or higher TEAEs were observed. All patients had experienced at least one TEAE, but no fatal or irreversible TEAEs were observed.

Conclusion: A single dose I-mIBG therapy was well tolerated by patients with PPGL, and statistically significantly reduced catecholamine levels compared to the threshold response rate, which may lead to an improved prognosis for these patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s12149-021-01699-0DOI Listing
December 2021

Phase I/II clinical trial of high-dose [I] meta-iodobenzylguanidine therapy for high-risk neuroblastoma preceding single myeloablative chemotherapy and haematopoietic stem cell transplantation.

Eur J Nucl Med Mol Imaging 2021 Nov 27. Epub 2021 Nov 27.

Department of Nuclear Medicine, Kanazawa University Hospital, 13-1 Takara-machi, Kanazawa, Ishikawa, 920-8641, Japan.

Purpose: Paediatric high-risk neuroblastoma has poor prognosis despite modern multimodality therapy. This phase I/II study aimed to determine the safety, dose-limiting toxicity (DLT), and efficacy of high-dose I-meta-iodobenzylguanidine (I-mIBG) therapy combined with single high-dose chemotherapy (HDC) and haematopoietic stem cell transplantation (HSCT) in high-risk neuroblastoma in Japan.

Methods: Patients received 666 MBq/kg of I-mIBG and single HDC and HSCT from autologous or allogeneic stem cell sources. The primary endpoint was DLT defined as adverse events associated with I-mIBG treatment posing a significant obstacle to subsequent HDC. The secondary endpoints were adverse events/reactions, haematopoietic stem cell engraftment and responses according to the Response Evaluation Criteria in Solid Tumours version 1.1 (RECIST 1.1) and I-mIBG scintigraphy. Response was evaluated after engraftment.

Results: We enrolled eight patients with high-risk neuroblastoma (six females; six newly diagnosed and two relapsed high-risk neuroblastoma; median age, 4 years; range, 1-10 years). Although all patients had adverse events/reactions after high-dose I-mIBG therapy, we found no DLT. Adverse events and reactions were observed in 100% and 25% patients during single HDC and 100% and 12.5% patients during HSCT, respectively. No Grade 4 complications except myelosuppression occurred during single HDC and HSCT. The response rate according to RECIST 1.1 was observed in 87.5% (7/8) in stable disease and 12.5% (1/8) were not evaluated. Scintigraphic response occurred in 62.5% (5/8) and 37.5% (3/8) patients in complete response and stable disease, respectively.

Conclusion: I-mIBG therapy with 666 MBq/kg followed by single HDC and autologous or allogeneic SCT is safe and efficacious in patients with high-risk neuroblastoma and has no DLT.

Trial Registration Number: jRCTs041180030.

Name Of Registry: Feasibility of high-dose iodine-131-meta-iodobenzylguanidine therapy for high-risk neuroblastoma preceding myeloablative chemotherapy and haematopoietic stem cell transplantation (High-dose iodine-131-meta-iodobenzylguanidine therapy for high-risk neuroblastoma). URL OF REGISTRY: https://jrct.niph.go.jp/en-latest-detail/jRCTs041180030 .

Date Of Enrolment Of The First Participant To The Trial: 12/01/2018.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00259-021-05630-7DOI Listing
November 2021

Feasibility of I-RGD uptake as a marker of angiogenesis after myocardial infarction.

Ann Nucl Med 2021 Nov 26. Epub 2021 Nov 26.

Department of Nuclear Medicine, Kanazawa University Hospital, 13-1 Takara-machi, Kanazawa, 920-8641, Japan.

Objective: Angiogenesis is an important process facilitating the healing process after myocardial infarction. I-RGD imaging may be a promising candidate to image angiogenesis but may also detect inflammation.

Methods: Left coronary artery was occluded for 30 min, followed by reperfusion in a rat model (n = 31). One, 3, 7 and 14 days, 1 and 2 months later, Triple-tracer autoradiography was performed. I-RGD (1.5 MBq) and Tl (15 MBq) were injected at 80 and 10 min before sacrifice. Left coronary artery was reoccluded and Tc-MIBI (150-180 MBq) was injected 1 min before sacrifice to verify the area at risk. Angiogenesis and macrophage infiltration were evaluated by immunohistochemical analysis with anti-alpha-smooth muscle actin and anti-CD68, respectively.

Results: I-RGD uptake ratio in the area at risk was weak at day 3 (1.23 ± 0.23 but increased markedly and peaked at day 7 (2.27 ± 0.37) followed by a gradual reduction until 1 and 2 months later (1.93 ± 0.16 at 1 month, 1.58 ± 0.15 at 2 month). In the immunohistochemical analysis, copious staining of anti-CD68 cells was observed, with anti-SMA cells stained only minimally at day 3. The number of anti-CD68 cells was decreased significantly at day 7 but largely absent at 1 month. Anti-SMA positive cells peaked at day 7 and reduced gradually until 1 month.

Conclusions: Myocardial I-RGD uptake reflects angiogenesis rather than inflammation after myocardial infarction.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s12149-021-01695-4DOI Listing
November 2021

Synthesis and Evaluation of a Dimeric RGD Peptide as a Preliminary Study for Radiotheranostics with Radiohalogens.

Molecules 2021 Oct 10;26(20). Epub 2021 Oct 10.

Graduate School of Medical Sciences, Kanazawa University, Kanazawa 920-1192, Japan.

We recently developed I- and At-labeled monomer RGD peptides using a novel radiolabeling method. Both labeled peptides showed high accumulation in the tumor and exhibited similar biodistribution, demonstrating their usefulness for radiotheranostics. This study applied the labeling method to a dimer RGD peptide with the aim of gaining higher accumulation in tumor tissues based on improved affinity with αβ integrin. We synthesized an iodine-introduced dimer RGD peptide, E[c(RGDfK)] (), and an I-labeled dimer RGD peptide, E[c(RGDfK)]{[I]c[RGDf(4-I)K]} ([I]), and evaluated them as a preliminary step to the synthesis of an At-labeled dimer RGD peptide. The affinity of for αβ integrin was higher than that of a monomer RGD peptide. In the biodistribution experiment at 4 h postinjection, the accumulation of [I] (4.12 ± 0.42% ID/g) in the tumor was significantly increased compared with that of I-labeled monomer RGD peptide (2.93 ± 0.08% ID/g). Moreover, the accumulation of [I] in the tumor was greatly inhibited by co-injection of an excess RGD peptide. However, a single injection of [I] (11.1 MBq) did not inhibit tumor growth in tumor-bearing mice. We expect that the labeling method for targeted alpha therapy with At using a dimer RGD peptide could prove useful in future clinical applications.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/molecules26206107DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8539346PMC
October 2021

Prognostic factors for refractory pheochromocytoma and paraganglioma after I-metaiodobenzylguanidine therapy.

Ann Nucl Med 2022 Jan 13;36(1):61-69. Epub 2021 Oct 13.

Department of Nuclear Medicine, Kanazawa University Hospital, 13-1 Takara-machi, Kanazawa, Ishikawa, 920-8641, Japan.

Objective: Given the rarity of refractory pheochromocytoma and paraganglioma (PPGL), outcomes and prognostic factors after I-metaiodobenzylguanidine (I-mIBG) treatment still remain unclear. Therefore, this study evaluated whether baseline characteristics at initial I-mIBG therapy and imaging response to repeated I-mIBG therapy could be prognostic factors for refractory PPGL.

Methods: All patients [n = 59 (male/female = 35/24), median age; 49.3 years] with refractory PPGL who received I-mIBG therapy at our institution between September 2009 and September 2019 were retrospectively reviewed for the effects of the following factors on overall survival: age, sex, hypertension, diabetes mellitus, palpitations, constipation, cancer pain, catecholamines values, past history of therapy (external beam radiation for bone metastasis, operation, and chemotherapy), metastasis sites, and response to I-mIBG treatments.

Results: Throughout the follow-up period, 18 patients died from disease exacerbation. The estimated 5- and 10-year survival rates were 79.4% and 67.2% from the initial diagnoses of refractory PPGL and 68.5% and 49.9% from the first I-mIBG therapy, respectively. The multivariate Cox proportional hazards model showed that progressive disease (PD) [hazard ratio (HR) 96.3, P = 0.011] and constipation (HR 8.2, P = 0.024) were adverse prognostic factors for overall survival after initial I-mIBG therapy. The log-rank test demonstrated that PD in response to I-mIBG therapies (P < 0.0001) and constipation (P < 0.01) were correlated with poor survival rates.

Conclusions: Response to repeated I-mIBG treatment can be a strong predictor of prognosis after initial I-mIBG therapy for refractory PPGL. Repeated I-mIBG therapy may be a good option for controlling refractory PPGL.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s12149-021-01685-6DOI Listing
January 2022

[Exploratory Analysis Results from Post-marketing Surveillance Study of Radium-223 in Japanese Patients with Castration-resistant Prostate Cancer and Bone Metastases: Subgroup Analysis by Age].

Kaku Igaku 2021 ;58(1):91-101

Department of Nuclear Medicine, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University.

Objective: To perform an exploratory analysis on the safety and effectiveness of radium-223 (Ra-223) by patient baseline age, using the results of a post-marketing surveillance study of Ra-223 in castration-resistant prostate cancer patients with bone metastasis in Japan.

Method: The safety analysis population of 296 patients was stratified into two groups based on age (<75 and ≥ 75 years-old [yo]), and their characteristics, drugrelated treatment-emergent adverse events (TEAEs), and clinical laboratory values were evaluated. Additionally, these endpoints were evaluated in patients aged ≥ 80 yo.

Results: There were 148 patients in each of the <75-yo and ≥ 75-yo age groups, and 69 patients in the ≥ 80-yo age group. The characteristics of patients in the <75-yo group were suggestive of more aggressive disease at diagnosis of prostate cancer and a greater proportion of patients had prior chemotherapy compared with patients in the ≥ 75-yo age group. The incidences of overall drugrelated TEAEs and drug-related hematological TEAEs were slightly higher in the <75-yo age group; however, there was little difference in the incidences of drug-related TEAEs leading to drug discontinuation (1.4-4.1%) between patient groups. Changes in total alkaline phosphatase and prostate-specific antigen values were similar in all groups.

Conclusions: Ra-223 therapy seemed tolerable regardless of age in real-world practice in Japan. Especially, there were no new safety concerns of Ra-223 in elderly patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.18893/kakuigaku.oa.2105DOI Listing
December 2021

Convolutional neural network-based automatic heart segmentation and quantitation in I-metaiodobenzylguanidine SPECT imaging.

EJNMMI Res 2021 Oct 12;11(1):105. Epub 2021 Oct 12.

Department of Nuclear Medicine, Kanazawa University, Kanazawa, Japan.

Background: Since three-dimensional segmentation of cardiac region in I-metaiodobenzylguanidine (MIBG) study has not been established, this study aimed to achieve organ segmentation using a convolutional neural network (CNN) with I-MIBG single photon emission computed tomography (SPECT) imaging, to calculate heart counts and washout rates (WR) automatically and to compare with conventional quantitation based on planar imaging.

Methods: We assessed 48 patients (aged 68.4 ± 11.7 years) with heart and neurological diseases, including chronic heart failure, dementia with Lewy bodies, and Parkinson's disease. All patients were assessed by early and late I-MIBG planar and SPECT imaging. The CNN was initially trained to individually segment the lungs and liver on early and late SPECT images. The segmentation masks were aligned, and then, the CNN was trained to directly segment the heart, and all models were evaluated using fourfold cross-validation. The CNN-based average heart counts and WR were calculated and compared with those determined using planar parameters. The CNN-based SPECT and conventional planar heart counts were corrected by physical time decay, injected dose of I-MIBG, and body weight. We also divided WR into normal and abnormal groups from linear regression lines determined by the relationship between planar WR and CNN-based WR and then analyzed agreement between them.

Results: The CNN segmented the cardiac region in patients with normal and reduced uptake. The CNN-based SPECT heart counts significantly correlated with conventional planar heart counts with and without background correction and a planar heart-to-mediastinum ratio (R = 0.862, 0.827, and 0.729, p < 0.0001, respectively). The CNN-based and planar WRs also correlated with and without background correction and WR based on heart-to-mediastinum ratios of R = 0.584, 0.568 and 0.507, respectively (p < 0.0001). Contingency table findings of high and low WR (cutoffs: 34% and 30% for planar and SPECT studies, respectively) showed 87.2% agreement between CNN-based and planar methods.

Conclusions: The CNN could create segmentation from SPECT images, and average heart counts and WR were reliably calculated three-dimensionally, which might be a novel approach to quantifying SPECT images of innervation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13550-021-00847-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8511236PMC
October 2021

Safety and efficacy of peptide receptor radionuclide therapy with Lu-DOTA-Tyr-octreotate in combination with amino acid solution infusion in Japanese patients with somatostatin receptor-positive, progressive neuroendocrine tumors.

Ann Nucl Med 2021 Dec 17;35(12):1332-1341. Epub 2021 Sep 17.

Department of Oncology, Oncology Division, Yokohama City University Graduate School of Medicine, 3-9, Fuku-ura, Kanazawa-ku, Yokohama, 236-0004, Japan.

Purpose: Peptide receptor radionuclide therapy (PRRT) with Lu-DOTA-Tyr-octreotate (Lu-DOTATATE) is one of the most reliable treatments for unresectable, progressive neuroendocrine tumors (NETs) with somatostatin receptor expression. We have, for the first time, reported the results of the tolerability, safety, pharmacokinetics, dosimetry, and efficacy of this treatment for Japanese patients with NET.

Methods: Patients with unresectable, somatostatin receptor scintigraphy (SRS)-positive NETs were enrolled in this phase I clinical trial. They were treated with 29.6 GBq of Lu-DOTATATE (four doses of 7.4 GBq) combined with amino acid solution infusion plus octreotide long-acting release (LAR) 30 mg. The primary objective of this study was to evaluate the tolerability, safety, pharmacokinetics, and dosimetry of a single administration of this treatment in patients with SRS-positive NETs.

Results: Six Japanese patients (three men and three women; mean age 61.5 years; range 50-70 years) with SRS-positive unresectable NETs were recruited. Lu-DOTATATE was eliminated from the blood in a two-phase manner. Cumulative urinary excretion of radioactivity was 60.1% (range 49.0%-69.8%) within the initial 6 h. The cumulative renal absorbed dose for 29.6 GBq of Lu-DOTATATE was 16.8 Gy (range 12.0-21.2 Gy), and the biological effective dose was 17.0 Gy (range 12.2-21.5 Gy). Administration of Lu-DOTATATE was well tolerated, with no dose-limiting toxicities. Grade 3 lymphopenia occurred in two (33.3%) cases, but there were no other severe toxicities. Four patients achieved partial response (objective response rate, 66.7%), one patient had stable disease, and one patient had progressive disease.

Conclusion: PRRT with Lu-DOTATATE was well-tolerated and showed good outcomes in Japanese patients with unresectable NETs. Peptide receptor radionuclide therapy, Lu-DOTA-Tyr-octreotate .
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s12149-021-01674-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8557155PMC
December 2021

Ga- and At-Labeled RGD Peptides for Radiotheranostics with Multiradionuclides.

Mol Pharm 2021 09 17;18(9):3553-3562. Epub 2021 Aug 17.

Department of Nuclear Medicine, Kanazawa University Hospital, Kanazawa University, Takara-machi 13-1, Kanazawa, Ishikawa 920-8641, Japan.

Probes for radiotheranostics could be produced by introducing radionuclides with similar chemical characteristics into the same precursors. We recently developed an At-labeled RGD peptide and a corresponding radioiodine-labeled RGD peptide. Both labeled peptides accumulated in large quantities in the tumor with similar biodistribution, demonstrating their usefulness for radiotheranostics. In this study, we hypothesized that probes for radiotheranostics combined with multiradionuclides, such as Ga and At, have useful clinical applications. New radiolabeled RGD peptide probes were synthesized via a molecular design approach, with two labeling sites for metal and halogen. These probes were evaluated in biodistribution experiments using tumor-bearing mice. [Ga]Ga-DOTA-c[RGDf(4-I)K] ([Ga]), Ga-DOTA-[I]c[RGDf(4-I)K] ([I]), and Ga-DOTA-[At]c[RGDf(4-At)K] ([At]) showed similar biodistribution, with high and equivalent accumulation in tumors. These results indicate the usefulness of these probes in radiotheranostics with multiradionuclides, such as a radiometal and a radiohalogen, and they could contribute to a personalized medicine regimen.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.molpharmaceut.1c00460DOI Listing
September 2021

[Radiation Protection Against Exposure from Patients Receiving I-MIBG and Released from Radiation Treatment Room].

Kaku Igaku 2021 ;58(1):59-66

Department of Nuclear Medicine, Kanazawa University Hospital.

I-3-iodobenzylguanidine or I-iobenguane (3-(I) iodobenzylguanidine or I-iobenguane [I-MIBG]) is a radioactive agent that is specifically accumulated in tumor cells such as pheochromocytoma and neuroblastoma. Due to its cytotoxic beta ray emitted from I, it has been developed as an agent for radioisotope therapy and some researchers have reported its effectiveness. In this study, based on the patients' data from previous clinical trials of I-MIBG therapy, we evaluated the radiation safety for public exposure caused by radiation emitted from patients who received I-MIBG. In results, it was considered that public exposure and medical exposure of visitors and caregivers to the patients were less than their dose limit and dose constraint by complying the current criteria of the release of patients after therapy with I.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.18893/kakuigaku.tr.2106DOI Listing
December 2021

Visualization of Dynamic Expression of Myocardial Sigma-1 Receptor After Myocardial Ischemia and Reperfusion Using Radioiodine-Labeled 2-[4-(2-iodophenyl)piperidino]cyclopentanol (OI5V) Imaging.

Circ J 2021 Oct 26;85(11):2102-2108. Epub 2021 Jun 26.

Department of Nuclear Medicine, Kanazawa University Hospital.

Background: This study chronologically evaluated the expression of the intensity and distribution of the sigma-1 receptor (σ1R) demonstrated by radiolabeled 2-[4-(2-iodophenyl)piperidino]cyclopentanol (OI5V) in a rat model of myocardial ischemia and reperfusion.Methods and Results:The left coronary artery was occluded for 30 min, followed by reperfusion. Dual-tracer autoradiography with I-OI5V and Tc-MIBI was performed to assess the spatiotemporal changes in I-OI5V uptake (n=5-6). Significant and peaked I-OI5V uptake in the ischemic area was observed at 3 days after reperfusion, and the I-OI5V uptake ratio of ischemic area to normally perfused left ventricular area decreased gradually from 3 to 28 days (mean value±SD; 0.90±0.12 at 1 day, 1.89±0.19 at 3 days, 1.52±0.17 at 7 days, 1.34±0.13 at 14 days, and 1.16±0.14 at 28 days, respectively). Triple-tracer autoradiography with I-OI5V, Tc-MIBI, and TlCl was performed to evaluate I-OI5V uptake in the ischemic area in relation to the residual perfusion at 7 days (n=4). The I-OI5V uptake ratio of the non-salvaged area was higher compared to that of the salvaged area in the ischemic area. I-OI5V and Tc-MIBI SPECT/CT was performed 3 days after reperfusion (n=3), and the in vivo images showed clear uptake of I-OI5V in the perfusion defect area.

Conclusions: The present study confirmed the spatiotemporal expression pattern of σ1R expression. Non-invasive σ1R imaging with I or I-OI5V was feasible to monitor the expression of σ1R after myocardial ischemia and reperfusion.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1253/circj.CJ-21-0320DOI Listing
October 2021

[A Report on Health Resource Use in Internal Radiation Therapy Using Lu-DOTA-TATE].

Kaku Igaku 2021 ;58(1):39-46

Health Insurance Affairs Committee, Japanese Society of Nuclear Medicine.

Internal radiation therapy using lutetium-177(Lu)-DOTA-TATE injection will be applied in actual clinical practice soon. However, the NHI medical technical fee for the use of Lu-DOTA-TATE injection has not yet been set. The Japanese Society of Nuclear Medicine surveyed health resource use in internal radiation therapy using Lu via questionnaires sent to medical institutions that have used Lu-DOTA-TATE injection. Results showed that the necessary cost per patient is 1,912,404 JPY, based on the Draft Proposal for Medical Examination Value (Ver. 7.2) of the Japanese Health Insurance Federation for Surgery. Lu-DOTA-TATE injection is supposed to be administered 4 times to each patient at 8-week intervals, and the fee per treatment was calculated to be 478,101 JPY. The appropriate NHI medical technical fee is thus considered to be 47,810 points per patient per treatment, which can be claimed 4 times per patient. In addition, it costs 649,030 JPY per patient to take special measures to make the hospital room similar to the radiation therapy room. The cost other than the basic hospitalization fee per day was calculated to be 81,129 JPY. The appropriate additional points for NHI basic hospitalization fee is thus considered to be 8,113 points per patient per day.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.18893/kakuigaku.tr.2104DOI Listing
December 2021

[A Report on Health Resource Use in Internal Radiation Therapy with I-MIBG].

Kaku Igaku 2021 ;58(1):33-38

Health Insurance Affairs Committee, Japanese Society of Nuclear Medicine.

Internal radiation therapy using 3-iodobenzylguanidine (I) injection (I-MIBG injection) will be applied in actual clinical practice soon. However, the NHI medical technical fee for the use of 131I-MIBG injection has not yet been set. The Japanese Society of Nuclear Medicine surveyed health resource use for internal radiation therapy using I via questionnaires sent to medical institutions that have used I-MIBG injection. Results showed that the necessary cost per patient is 1,912,671 JPY, which was based on the Draft Proposal for Medical Examination Value (Ver. 7.2) of the Japanese Health Insurance Federation for Surgery. I-MIBG injection is supposed to be administered once to each patient and the patient is followed up for 4 months after administration. The fee per treatment is calculated to be 478,168 JPY per month. The appropriate NHI medical technical fee is thus considered to be 47,817 points per month per patient per treatment, which can be claimed up to 4 times.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.18893/kakuigaku.tr.2103DOI Listing
December 2021

Manual on the proper use of sodium astatide ([At]NaAt) injections in clinical trials for targeted alpha therapy (1st edition).

Ann Nucl Med 2021 Jul 12;35(7):753-766. Epub 2021 May 12.

Chiyoda Technol Corporation, 1-7-12 Yushima, Bunkyo-ku, Tokyo, 113-8681, Japan.

We present the guideline for use of [At] sodium astatide (NaAt) for targeted alpha therapy in clinical trials on the basis of radiation safety issues in Japan. This guideline was prepared by a study supported by the Ministry of Health, Labour, and Welfare, and approved by the Japanese Society of Nuclear Medicine on 8th Feb, 2021. The study showed that patients receiving [At]NaAt do not need to be admitted to a radiotherapy room and outpatient treatment is possible. The radiation exposure from the patient is within the safety standards of the ICRP and IAEA recommendations for the general public and caregivers. Precautions for patients and their families, safety management associated with the use of [At]NaAt, education and training, and disposal of medical radioactive contaminants are also included in this guideline. Treatment using [At]NaAt in Japan should be carried out according to this guideline. Although this guideline is applied in Japan, the issues for radiation protection and evaluation methodology shown here are considered internationally useful as well.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s12149-021-01619-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8197710PMC
July 2021

Comparison of the detecting capability between I-mIBG and post-therapeutic I-mIBG scintigraphy for curie scoring in patients with neuroblastoma after chemotherapy.

Ann Nucl Med 2021 Jun 17;35(6):649-661. Epub 2021 Apr 17.

Department of Nuclear Medicine, Kanazawa University Hospital, 13-1 Takara-machi, Kanazawa, Ishikawa, 920-8641, Japan.

Objective: To evaluate the detecting capability between planar imaging (PI) and PI combined with single-photon emission computed tomography/computed tomography (PICWS), including I- and I-labeled metaiodobenzylguanidine (mIBG) and to compare the detecting capability between I-mIBG and post-therapeutic I-mIBG scintigraphy including PI and PICWS for Curie scoring in patients with neuroblastoma.

Methods: Sixty-two patients with 66 pairs of complete images with neuroblastoma were enrolled in this retrospective study.

Results: Comparing the Curie scoring between I-mIBG PI and PICWS and between post-therapeutic I-mIBG PI and PICWS, findings were concordantly negative in 28.79% and 18.18% of studies, concordantly positive in 66.67% and 74.24% of studies, and discordant in 4.54% and 7.58% of studies, respectively. PICWS was superior to PI including I- and I-mIBG in the evaluation of Curie scoring for neuroblastoma patients (both P < 0.001). Comparing the Curie scores between I- and post-therapeutic I-mIBG PI and between I- and post-therapeutic I-mIBG PICWS, concordantly negative imaging was visualized in 22.73% and 19.70% of studies, concordantly positive imaging in 66.67% and 69.70% of studies, and discordant imaging in 10.60% and 10.60% of studies, respectively. Post-therapeutic I-mIBG was significantly better than that of I-mIBG scintigraphy including PI and PICWS in detecting the Curie scoring for neuroblastoma patients (both P < 0.001).

Conclusion: The present study demonstrates that I- or I-mIBG PICWS are more helpful in the evaluation of Curie scores than that of conventional PI and that post-therapeutic I-mIBG is superior to I-mIBG scintigraphy for the detecting capability of Curie scoring in patients with neuroblastoma.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s12149-020-01569-1DOI Listing
June 2021

A Radiobrominated Tyrosine Kinase Inhibitor for EGFR with L858R/T790M Mutations in Lung Carcinoma.

Pharmaceuticals (Basel) 2021 Mar 12;14(3). Epub 2021 Mar 12.

Graduate School of Medical Sciences, Kanazawa University, Kakuma-machi, Kanazawa, Ishikawa 920-1192, Japan.

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 -(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 radiobrominated [Br]BrCO1686 was prepared through bromodestannylation of the corresponding tributylstannylated precursor with [Br]bromide and chlorosuccinimide. Although we aimed to provide a novel PET imaging probe, Br was used as an alternative radionuclide for Br. We fundamentally evaluated the potency of [Br]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 cytotoxicity toward H1975 (IC 0.18 ± 0.06 µM) comparable to that of CO-1686 (IC 0.14 ± 0.05 µM). In cell uptake experiments, the level of accumulation of [Br]BrCO1686 in H1975 was significantly higher than those in H3255 and H441 upon 4 h of incubation. The radioactivity of [Br]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 [Br]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 [Br]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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ph14030256DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7998589PMC
March 2021

Skeletal muscle metabolism on whole-body positron emission tomography during pitching.

J Int Soc Sports Nutr 2021 Mar 6;18(1):21. Epub 2021 Mar 6.

Department of Orthopaedic Surgery, Graduate School of Medical Science, Kanazawa University, 13-1 Takaramachi, Kanazawa, 920-0934, Japan.

Background: Electromyography (EMG) has been used for evaluating skeletal muscle activity during pitching. However, it is difficult to observe the influence of movement on skeletal muscle activity in deep-lying regions of the trunk and extremities using EMG. An alternative method that may be used is the measurement of glucose metabolism of skeletal muscle using positron emission tomography-computed tomography (PET-CT). This technique is a reliable measure of muscle metabolism, demonstrating a high correlation with the intensity of muscle activity. This study aimed to evaluate whole-body skeletal muscle metabolism during pitching using PET-CT.

Methods: Ten uninjured, skilled, adult pitchers, who were active at college or professional level, threw 40 baseballs at maximal effort before an intravenous injection of 37 MBq of F-fluorodeoxyglucose (FDG). Subsequently, additional 40 balls were pitched. PET-CT images were obtained 50 min after FDG injection, and regions of interest were defined within 72 muscles. The standardized uptake value (SUV) of FDG by muscle tissue per unit volume was calculated, and the mean SUV of the pitchers was compared with that of a healthy adult control group who did not exercise before the measurements. Statistical analysis was performed using a t-test, and P < 0.05 was considered statistically significant.

Results: Whole-body PET images showed a significant increase in glucose metabolism in the muscle groups of the fingers and toes in both the throwing and non-throwing sides. Additionally, asymmetric increases in glucose metabolism were observed in the muscles of the thigh.

Conclusions: This is the first study to evaluate whole-body muscle metabolism during pitching using PET-CT. Our findings would be useful in determining the training required for pitchers, and can be further applied to other sporting activities that involve throwing.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12970-021-00418-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7937262PMC
March 2021

Real-world safety and effectiveness of radium-223 in Japanese patients with castration-resistant prostate cancer (CRPC) and bone metastasis: exploratory analysis, based on the results of post-marketing surveillance, according to prior chemotherapy status and in patients without concomitant use of second-generation androgen-receptor axis-targeted agents.

Int J Clin Oncol 2021 Apr 11;26(4):753-763. Epub 2021 Feb 11.

Department of Urology, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki-cho, Kita-gun, Kagawa, Japan.

Background: Based on results from Japanese post-marketing surveillance, exploratory analyses were performed to investigate real-world outcomes of radium-223 for metastatic CRPC (mCRPC) according to patient characteristics.

Methods: This non-interventional, prospective study enrolled mCRPC patients selected for radium-223 treatment in clinical practice. Six-month safety and effectiveness were evaluated in subgroups who had/had not received prior chemotherapy (prior-chemo/no prior-chemo groups), and a subgroup who had not received concomitant androgen-receptor axis-targeted agents (ARATs).

Results: In the overall population (n = 296), the prior-chemo group (n = 126) tended to have more bone metastases, more analgesic use, and higher prostate-specific antigen values than the no prior-chemo group (n = 170). Incidences of treatment-emergent adverse events (TEAEs), drug-related TEAEs, and ≥ grade 3 drug-related hematological TEAEs were 47% vs. 53%, 25% vs. 29%, and 4% vs. 7% in the no prior-chemo and prior-chemo groups, respectively. Incidences of TEAEs (61%), drug-related TEAEs (36%), and ≥ grade 3 drug-related hematological events (12%) were numerically higher in 33 patients who had received two lines of prior chemotherapy. Multivariate analysis showed that two lines of prior chemotherapy, and hemoglobin, platelet, and lactate dehydrogenase values were baseline factors significantly related to ≥ grade 2 platelet count decreased. Safety and effectiveness in patients without concomitant ARATs (n = 201) were similar to those in the overall population.

Conclusion: In a real-life setting, radium-223 was well tolerated irrespective of prior chemotherapy, but relatively higher incidences of TEAEs and hematotoxicities were suggested in patients with two lines of prior chemotherapy, possibly reflecting more advanced disease. Radium-223 safety and effectiveness in patients without concomitant ARATs were favorable.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s10147-020-01850-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7979648PMC
April 2021

Clinical practice guidelines for high-resolution breast PET, 2019 edition.

Ann Nucl Med 2021 Mar 25;35(3):406-414. Epub 2021 Jan 25.

Health Insurance Committee, Japanese Society of Nuclear Medicine, Tokyo, Japan.

Breast positron emission tomography (PET) has had insurance coverage when performed with conventional whole-body PET in Japan since 2013. Together with whole-body PET, accurate examination of breast cancer and diagnosis of metastatic disease are possible, and are expected to contribute significantly to its treatment planning. To facilitate a safer, smoother, and more appropriate examination, the Japanese Society of Nuclear Medicine published the first edition of practice guidelines for high-resolution breast PET in 2013. Subsequently, new types of breast PET have been developed and their clinical usefulness clarified. Therefore, the guidelines for breast PET were revised in 2019. This article updates readers as to what is new in the second edition. This edition supports two different types of breast PET depending on the placement of the detector: the opposite-type (positron emission mammography; PEM) and the ring-shaped type (dedicated breast PET; dbPET), providing an overview of these scanners and appropriate imaging methods, their clinical applications, and future prospects. The name "dedicated breast PET" from the first edition is widely used to refer to ring-shaped type breast PET. In this edition, "breast PET" has been defined as a term that refers to both opposite- and ring-shaped devices. Up-to-date breast PET practice guidelines would help provide useful information for evidence-based breast imaging.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s12149-021-01582-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7902575PMC
March 2021

Metal artifact reduction for improving quantitative SPECT/CT imaging.

Ann Nucl Med 2021 Mar 18;35(3):291-298. Epub 2021 Jan 18.

Department of Nuclear Medicine, Kanazawa University Hospital, 13-1 Takara-machi, Kanazawa, Ishikawa, 920-8641, Japan.

Objective: This study aimed to evaluate the effect of the metal artifact reduction (MAR) method on quantitative single-photon emission computed tomography (SPECT)/computed tomography (CT) to reveal the usefulness of MAR in patients with metal implants.

Methods: We performed a phantom experiment simulating patients with artificial hip prostheses using SPECT/CT equipped with the iterative MAR (iMAR). The phantom was filled with Tc-99m solution (29.5 kBq/mL). For the CT scan conditions, tube current time products were applied to obtain volume CT dose indexes (CTDIvols) of 1.4, 2.8, and 5.6 mGy. Six types of quantitative SPECT images were reconstructed using data from different doses of CT processed with and without iMAR for CT attenuation correction. Thirty circular regions of interest (ROIs) were placed in each of the dark-band artifact areas, the white-streak artifact areas, and the non-artifact areas. We calculated radioactivity concentrations from quantitative SPECT images with and without iMAR to evaluate the quantitative accuracy. The differences of the effect of iMAR with different CT doses were also evaluated.

Results: The results obtained using CT data with a CTDIvol of 2.8 mGy are described below. For quantitative SPECT data without iMAR, we observed the underestimation of radioactivity concentration in the dark-band artifact areas and overestimation in the white-streak artifact areas. We observed quantification errors ranging from - 41.1% to + 20.0% without iMAR, depending on the ROI localization. When iMAR was used, these errors were reduced to a range of - 22.8% to + 14.2%. The mean absolute error from the true value in the artifact regions was also significantly reduced from 4.00 to 1.74 kBq/mL. In the non-artifact areas, the radioactivity concentrations obtained from the quantitative SPECT data with and without iMAR were equivalent to the true value and did not differ significantly between the two conditions. Similar results were observed for procedures with CTDIvols of 1.4 and 5.6 mGy.

Conclusions: This study indicated that iMAR could improve the quantitative accuracy of SPECT/CT independent of the CT dose. iMAR can serve as a practicable technique for quantitative SPECT/CT in patients with metal implants.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s12149-020-01560-wDOI Listing
March 2021

In vitro and in vivo evaluation of [I]-2-[4-(2-iodophenyl)piperidino]cyclopentanol([I]-OI5V) as a potential sigma-1 receptor ligand for SPECT.

Ann Nucl Med 2021 Feb 8;35(2):167-175. Epub 2021 Jan 8.

Division of Tracer Kinetics, Advanced Science Research Center, Kanazawa, Ishikawa, Japan.

Introduction: We investigated the characteristics of radio-iodinated 2-[4-(2-iodophenyl)piperidino]cyclopentanol (OI5V) as a single photon emission computed tomography (SPECT) ligand for mapping sigma-1 receptor (σ-1R), which plays an important role in stress remission in many organs.

Methods: OI5V was synthesized from o-bromobenzaldehyde in three steps. OI5V was evaluated for its affinity to VAChT, σ-1 and σ-2 receptor by in vitro competitive binding assays using rat tissues and radioligands, [H]vesamicol, ( +)-[H]pentazocine and [H]DTG, respectively. [I]OI5V was prepared from o-trimethylstannyl-cyclopentanevesamicol (OT5V) by the iododestannylation reaction under no-carrier-added conditions. In vivo biodistribution study of [I]OI5V in blood, brain regions and major organs of rats was performed at 2, 10, 30 and 60 min post-injection. In vivo blocking study and ex vivo autoradiography were performed to assess the binding selectivity of [I]OI5V for σ-1 receptor. SPECT-CT imaging study was performed using [I]OI5V.

Results: OI5V demonstrated high selective binding affinity for σ-1R in vitro. In the biodistribution study, the blood-brain barrier (BBB) permeability of [I]OI5V was high and the accumulation of [I]OI5V in the rat cortex at 2 min post-injection exceeded 2.00%ID/g. In the in vivo blocking study, the accumulation of [I]OI5V in the brain was significantly blocked by co-administration of 0.5 μmol of SA4503 and 1.0 μmol of pentazocine. Ex vivo autoradiography revealed that the regional brain accumulation of [I]OI5V was similar to σ-1R-rich regions of the rat brain. SPECT images of [I]OI5V in the rat brain reflected the distribution of sigma receptors in the brain.

Conclusions: This study confirmed that [I]OI5V selectively binds σ-1R in the rat brain in vivo. [I]OI5V was suggested to be useful as a σ-1R ligand for SPECT.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s12149-020-01552-wDOI Listing
February 2021

Colchicine treatment early after infarction attenuates myocardial inflammatory response demonstrated by C-methionine imaging and subsequent ventricular remodeling by quantitative gated SPECT.

Ann Nucl Med 2021 Feb 3;35(2):253-259. Epub 2021 Jan 3.

Department of Nuclear Medicine, Kanazawa University Hospital, 13-1 Takara-machi, Kanazawa, Ishikawa, 920-8641, Japan.

Objective: Colchicine has been used as an anti-inflammatory agent and may be cardioprotective after acute myocardial infarction (AMI). We investigated how colchicine administration after AMI affects the myocardial inflammatory response using C-methionine and subsequent ventricular remodeling using single-photon emission computed tomography (SPECT) in a rat model of AMI.

Methods: The left coronary artery (LCA) was occluded for 30 min followed by reperfusion. C-methionine was injected at 20 min before sacrifice. The LCA was re-occluded at 1 min before sacrifice and Tc-methoxyisobutylisonitrile (Tc-MIBI) was injected. Colchicine was administered intraperitoneally from day 1 to the day before C-methionine injection. Dual-tracer autoradiography of the left ventricular short-axis slices was performed. The methionine uptake ratio in an ischemic area was calculated. Tc-MIBI gated SPECT assessed end-diastolic volume (EDV), end-systolic volume (ESV) and left ventricular ejection fraction (LVEF). On Cluster of Differentiation 68 with 4',6-diamidino-2-phenylindole (CD68/DAPI) staining the positive myocardial cell percentage in an ischemic area was calculated.

Results: In control rats, C-methionine uptake ratios on day 3 and 7 were 1.87 ± 0.15 and 1.39 ± 0.12, respectively. With colchicine, the uptake was reduced on days 3 (1.56 ± 0.26, p = 0.042) and 7 (1.23 ± 0.10, p = 0.030). Colchicine treated rats showed smaller EDV, ESV, and higher LVEF compared with control rats. At 8 weeks, those in control rats were 864 ± 115 μL, 620 ± 100 μL, 28.4 ± 2.5%, and in colchicine rats 665 ± 75 μL, 390 ± 97 μL, 42.2 ± 8.5% (p = 0.012, 0.0061, 0.0083), respectively. In control rats, CD68/DAPI positive myocardial cell percentages on days 3 and 7 were 38.4 ± 1.9% and 24.0 ± 2.4%, respectively. With colchicine, the percentages were reduced significantly on both days 3 (31.5 ± 2.0%, p < 0.0001) and 7 (12.0 ± 1.6%, p < 0.0001) as compared with the control.

Conclusions: Short-term colchicine treatment after AMI attenuated the post-AMI inflammatory response and subsequent ventricular remodeling and dysfunction. C-methionine imaging and gated Tc-MIBI SPECT would be feasible to monitor the effectiveness of anti-inflammatory therapy and left ventricular function.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s12149-020-01559-3DOI Listing
February 2021

Development of Radiogallium-Labeled Peptides for Platelet-Derived Growth Factor Receptor (PDGFR) Imaging: Influence of Different Linkers.

Molecules 2020 Dec 23;26(1). Epub 2020 Dec 23.

Institute for Frontier Science Initiative, Kanazawa University, Kakuma-machi, Kanazawa, Ishikawa 920-1192, Japan.

The purpose of this study is to develop peptide-based platelet-derived growth factor receptor (PDGFR) imaging probes and examine the effects of several linkers, namely un-natural amino acids (D-alanine and -alanine) and ethylene-glycol (EG), on the properties of Ga-DOTA-(linker)-IPLPPPRRPFFK peptides. Seven radiotracers, Ga-DOTA-(linker)-IPLPPPRRPFFK peptides, were designed, synthesized, and evaluated. The stability and cell uptake in PDGFR positive peptide cells were evaluated in vitro. The biodistribution of [Ga]Ga-DOTA-EG-IPLPPPRRPFFK ([Ga]) and [Ga]Ga-DOTA-EG-IPLPPPRRPFFK ([Ga]), which were selected based on in vitro stability in murine plasma and cell uptake rates, were determined in BxPC3--bearing nu/nu mice. Seven Ga-labeled peptides were successfully synthesized with high radiochemical yields (>85%) and purities (>99%). All evaluated radiotracers were stable in PBS (pH 7.4) at 37 °C. However, only [Ga] and [Ga] remained more than 75% after incubation in murine plasma at 37 °C for 1 h. [Ga] exhibited the highest BxPC3- cell uptake among the prepared radiolabeled peptides. As regards the results of the biodistribution experiments, the tumor-to-blood ratios of [Ga] and [Ga] at 1 h post-injection were 2.61 ± 0.75 and 2.05 ± 0.77, respectively. Co-injection of [Ga] and an excess amount of IPLPPPRRPFFK peptide as a blocking agent can significantly decrease this ratio. However, tumor accumulation was not considered sufficient. Therefore, further probe modification is required to assess tumor accumulation for in vivo imaging.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/molecules26010041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7795354PMC
December 2020

Calibrated scintigraphic imaging procedures improve quantitative assessment of the cardiac sympathetic nerve activity.

Sci Rep 2020 12 14;10(1):21834. Epub 2020 Dec 14.

Department of Nuclear Medicine, Kanazawa University Hospital, 13-1 Takara-machi, Kanazawa, Ishikawa, 920-8641, Japan.

The I-labeled meta-iodobenzylguanidine (MIBG) is an analogue of noradrenaline that can evaluate cardiac sympathetic activity in scintigraphy. Quantitative analysis of I-MIBG images has been verified in patients with heart failure and neurodegenerative diseases. However, quantitative results differ due to variations in scintigraphic imaging procedures. Here, we created and assessed the clinical feasibility of a calibration method for I-MIBG imaging. The characteristics of scintigraphic imaging systems were determined using an acrylic calibration phantom to generate a multicenter phantom imaging database. Calibration factors corresponding to the scintigraphic imaging procedures were calculated from the database and applied to a clinical study. The results of this study showed that the calibrated analysis eliminated inter-institutional differences among normal individuals. In summary, our standardization methodology for I-MIBG scintigraphy could provide the basis for improved diagnostic precision and better outcomes for patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-020-78917-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7736873PMC
December 2020

Diagnostic Use of Post-therapy I-Meta-Iodobenzylguanidine Scintigraphy in Consolidation Therapy for Children with High-Risk Neuroblastoma.

Diagnostics (Basel) 2020 Sep 2;10(9). Epub 2020 Sep 2.

Department of Nuclear Medicine, Kanazawa University Hospital, 13-1 Takara-machi, Kanazawa, Ishikawa 920-8641, Japan.

I-meta-iodobenzylguanidine (I-mIBG) scintigraphy is used for evaluating disease extent in children with neuroblastoma. I-mIBG therapy has been used for evaluation in children with high-risk neuroblastoma, and post-therapy I-mIBG scintigraphy may detect more lesions compared with diagnostic I-mIBG scintigraphy. However, no studies have yet revealed the detection rate of hidden mIBG-avid lesions on post-therapy I-mIBG whole-body scan (WBS) and SPECT images in neuroblastoma children without mIBG-avid lesions as demonstrated by diagnostic I-mIBG scintigraphy. We retrospectively examined the diagnostic utility of post-therapy I-mIBG scintigraphy in children who received I-mIBG as consolidation therapy. Nineteen children with complete response to primary therapy were examined. Post-therapy I-mIBG scintigraphy was performed four days after injection. The post-therapy I-mIBG scintigraphy, 4 children exhibited abnormal uptake on the WBS. Post-therapy I-mIBG SPECT/CT provided additional information in 2 cases. In total, 6 children exhibited abnormal uptake. The site of abnormal accumulation was on the recurrence site in one case, operation sites in five cases, and bone metastasis in one case. Post-therapy I-mIBG scintigraphy could detect residual disease that was not recognized using diagnostic I-mIBG scintigraphy in 32% of children with high-risk neuroblastoma and ganglioneuroblastoma. The diagnostic use of post-therapy I-mIBG scintigraphy can provide valuable information for detecting residual disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/diagnostics10090663DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7555271PMC
September 2020
-->