Introduction of nuclear medicine research in Japan.

There were many interesting presentations of unique studies at the Annual Meeting of the Japanese Society of Nuclear Medicine, although there were fewer attendees from Europe than expected. These presentations included research on diseases that are more frequent in Japan and Asia than in Europe, synthesis of original radiopharmaceuticals, and development of imaging devices and methods with novel ideas especially by Japanese manufacturers. In this review, we introduce recent nuclear medicine research conducted in Japan in the five categories of Oncology, Neurology, Cardiology, Radiopharmaceuticals and Technology. It is our hope that this article will encourage the participation of researchers from all over the world, in particular from Europe, in scientific meetings on nuclear medicine held in Japan.

Efficient syntheses of [¹¹C]zidovudine and its analogs by convenient one-pot palladium(0)-copper(I) co-mediated rapid C-[¹¹C]methylation.

The nucleosides zidovudine (AZT), stavudine (d4T), and telbivudine (LdT) are approved for use in the treatment of human immunodeficiency virus (HIV) and hepatitis B virus (HBV) infections. To promote positron emission tomography (PET) imaging studies on their pharmacokinetics, pharmacodynamics, and applications in cancer diagnosis, a convenient one-pot method for Pd(0)-Cu(I) co-mediated rapid C-C coupling of [(11)C]methyl iodide with stannyl precursor was successfully established and applied to synthesize the PET tracers [(11)C]zidovudine, [(11)C]stavudine, and [(11)C]telbivudine. After HPLC purification and radiopharmaceutical formulation, the desired PET tracers were obtained with high radioactivity (6.4-7.0 GBq) and specific radioactivity (74-147 GBq/µmol) and with high chemical (>99%) and radiochemical (>99.5%) purities. This one-pot Pd(0)-Cu(I) co-mediated rapid C-[(11)C]methylation also worked well for syntheses of [methyl-(11)C]thymidine and [methyl-(11)C]4'-thiothymidine, resulting twice the radioactivity of those prepared by a previous two-pot method. The mechanism of one-pot Pd(0)-Cu(I) co-mediated rapid C-[(11)C]methylation was also discussed.

Interim 4'-[methyl-11C]-thiothymidine PET for predicting the chemoradiotherapeutic response in head and neck squamous cell carcinoma: comparison with [18F]FDG PET.

PURPOSE: We investigated the potential of interim 4'-[methyl-11C]thiothymidine ([11C]4DST) PET for predicting the chemoradiotherapeutic response for head and neck squamous cell carcinoma (HNSCC), in comparison with 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) PET. METHODS: A total of 32 patients with HNSCC who underwent both [11C]4DST and [18F]FDG PET/CT before therapy (baseline) and at approximately 40 Gy point during chemoradiotherapy (interim) were available for a retrospective analysis of prospectively collected data. The baseline was treatment-naïve PET/CT scan as part of staging. The maximum standardized uptake value (SUVmax), metabolic tumor volume (MTV) from [18F]FDG PET or proliferative tumor volume (PTV) from [11C]4DST PET, and total lesion glycolysis (TLG) from [18F]FDG PET or total lesion proliferation (TLP) from [11C]4DST PET were measured. MTV or PTV was defined as the volume with an SUVmax greater than 2.5. The differences in SUVmax (ΔSUVmax), MTV (ΔMTV) or PTV (ΔPTV) and TLG (ΔTLG) or TLP (ΔTLP) from baseline to interim PET scans were calculated. Patients without or with evidence of residual or recurrent disease at 3 months after completion of chemoradiotherapy were classified as showing a complete response (CR) and non-CR, respectively. RESULTS: All patients showed increased uptake in primary tumor on baseline [11C]4DST and [18F]FDG PET studies. All patients showed increased uptake on interim [18F]FDG PET, whereas 18 patients showed no increased uptake on interim [11C]4DST PET. After chemoradiotherapy, 25 patients were found to be in CR group and 7 to be in non-CR group. [11C]4DST ΔSUVmax, ΔPTV, and ΔTLP for CR group showed significantly greater reductions than the corresponding values for non-CR group (P = 0.044, < 0.001, < 0.001, respectively). However, there were no significant differences in [18F]FDG ΔSUVmax, ΔMTV, or ΔTLG between CR group and non-CR group. [11C]4DST ΔMTV of -90 was the best cutoff value for the early identification of patients with non-CR. CONCLUSION: These preliminary results suggest that interim [11C]4DST PET might be useful for predicting the chemoradiotherapeutic response in patients with HNSCC, in comparison with [18F]FDG PET.

Amino Acid and Proliferation PET/CT for the Diagnosis of Multiple Myeloma.

Multiple myeloma (MM) is a hematologic malignancy characterized by infiltration of monoclonal plasma cells in the bone marrow (BM). The standard examination performed for the assessment of bone lesions has progressed from radiographic skeletal survey to the more advanced imaging modalities of computed tomography (CT), magnetic resonance imaging (MRI), and positron emission tomography/computed tomography (PET/CT). The Durie-Salmon PLUS staging system (upgraded from the Durie-Salmon staging system) applies 2-[18F]-fluoro-2-deoxy-glucose (18F-FDG) PET/CT, and MRI findings to the staging of MM, and 18F-FDG PET/CT has been incorporated into the International Myeloma Working Group (IMWG) guidelines for the diagnosis and staging of MM. However, 18F-FDG PET/CT has significant limitations in the assessment of diffuse BM infiltration and in the differentiation of MM lesions from inflammatory or infectious lesions. The potential of several new PET tracers that exploit the underlying disease mechanism of MM has been evaluated in terms of improving the diagnosis. L-type amino acid transporter 1 (LAT1), a membrane protein that transports neutral amino acids, is associated with cell proliferation and has strong ability to represent the status of MM. This review evaluates the potential of amino acid and proliferation PET tracers for diagnosis and compares the characteristics and accuracy of non-FDG tracers in the management of patients with MM.

Texture indices of 4'-[methyl-11C]-thiothymidine uptake predict p16 status in patients with newly diagnosed oropharyngeal squamous cell carcinoma: comparison with 18F-FDG uptake.

BACKGROUND: In oropharyngeal squamous cell carcinoma (OPSCC), human papillomavirus (HPV)/p16 status is important as a prognostic biomarker. PURPOSE: We evaluated the relationship between 4'-[methyl-11C]-thiothymidine (11C-4DST) and 18F-FDG PET texture indices and p16 status in patients with newly diagnosed OPSCC. METHODS: We retrospectively reviewed the collected data of 256 consecutive, previously untreated patients with primary head and neck tumors enrolled between November 2011 and October 2019. Complete data on both 11C-4DST and 18F-FDG PET/CT studies before therapy, patients with OPSCC, and p16 status were available for 34 patients. Six of them were excluded because they did not exhibit sufficient 11C-4DST and/or 18F-FDG tumor uptake to perform textural analysis. Finally, 28 patients with newly diagnosed OPSCC were investigated. The maximum standardized uptake value (SUVmax) and 6 texture indices (homogeneity, entropy, short-run emphasis, long-run emphasis, low gray-level zone emphasis, and high gray-level zone emphasis) were derived from PET images. The presence of p16 expression in tumor specimens was examined by immunohistochemistry and compared with the PET parameters. RESULTS: Using 11C-4DST, the expression of p16 was associated with a higher homogeneity (P = 0.012), lower short-run emphasis (P = 0.005), higher long-run emphasis (P = 0.009), and lower high-gray-level-zone emphasis (P = 0.042) values. There was no significant difference between 18F-FDG PET parameters and p16 status. CONCLUSION: Texture indices of the primary tumor on 11C-4DST PET, but not 18F-FDG PET, may be of value in predicting the condition's p16 status in patients with newly diagnosed OPSCC.

4'-[methyl-11C]-thiothymidine as a proliferation imaging tracer for detection of colorectal cancer: comparison with 18F-FDG.

OBJECTIVE: The novel radiotracer, 4'-[methyl-11C]-thiothymidine (11C-4DST), was developed based on the DNA incorporation method as a cell proliferation marker. This study investigated the feasibility of 11C-4DST positron emission tomography/computed tomography (PET/CT) for detection of colorectal cancer, as compared with 2-deoxy-2-18F-fluoro-D-glucose (18F-FDG) PET/CT, and to correlate the two radiotracers with proliferative activity. METHODS: A total of 18 patients with newly diagnosed colorectal cancer underwent both 11C-4DST and 18F-FDG PET/CT. Tumor lesions were identified as areas of focally increased uptake, exceeding that of adjacent normal tissue. For semiquantitative analysis, the maximal standardized uptake value (SUVmax) was calculated. Proliferative activity as quantified by the Ki-67 index was estimated in tumor specimens. RESULTS: In all 18 patients, colorectal cancers were detected by both 11C-4DST and 18F-FDG PET/CT. The median (± SD) SUVmax for 11C-4DST (6.02 ± 2.55) was significantly lower than that for 18F-FDG (13.91 ± 7.62) (P < 0.001). 11C-4DST SUVmax and 18F-FDG SUVmax showed a significant correlation (r = 0.69, P = 0.002). 11C-4DST SUVmax and Ki-67 index were weakly correlated (r = 0.50, P = 0.04). 18F-FDG SUVmax and Ki-67 index were not significantly correlated (r = 0.44, P = 0.06). CONCLUSIONS: Despite a significantly lower uptake of 11C-4DST than that of 18F-FDG, detection of colorectal cancer was also feasible with 11C-4DST PET/CT. 11C-4DST PET/CT might have a role in the noninvasive assessment of proliferation in colorectal cancer.

PET Imaging of 18F-FDG, 11C-methionine, 11C-flumazenil, and 11C-4DST in Progressive Multifocal Leukoencephalopathy.

The use of positron emission tomography (PET) imaging in progressive multifocal leukoencephalopathy (PML) has rarely been reported. We herein report a set of PET images in a 63-year-old patient with PML. In PML lesions, the uptake of 18F-fluorodeoxyglucose, 11C-methionine, 11C-flumazenil, and [methyl-11C]4'-thiothymidine was decreased, increased, decreased, and unchanged, respectively. These results suggest that glucose metabolism decreased, protein synthesis increased, neuronal integrity decreased, and the DNA synthesis and cellular proliferation of host cells were not activated in PML lesions. These results may reflect very little infiltration by inflammatory cells and active infection with JC virus in this case.

Influence of volumetric 4'-[methyl-11C]-thiothymidine PET/CT parameters for prediction of the clinical outcome of head and neck cancer patients.

OBJECTIVE: This prospective study compared the value of pretreatment 4'-[methyl-11C]-thiothymidine (11C-4DST) volumetric parameters and those of 2-deoxy-2-[18F] fluoro-D-glucose (18F-FDG) in predicting the clinical outcome in patients with head and neck squamous cell carcinoma (HNSCC). METHODS: Fifty patients with HNSCC underwent 11C-4DST PET/CT and 18F-FDG PET/CT prior to anticancer therapy. 18F-FDG metabolic tumor volume (18F-FDG MTV) and total lesion glycolysis (TLG) were calculated from 18F-FDG PET, and 11C-4DST MTV and total lesion proliferation (TLP) were calculated from 11C-4DST PET. All parameters were measured for the primary lesion and metastatic lymph nodes. Associations between clinical factors and PET/CT parameters and prognostic value were analyzed. RESULTS: Receiver-operating characteristic analysis revealed that MTV, TLG, and TLP acquired from the primary lesion and metastatic lymph nodes were good parameters for predicting disease relapse and death. The area under the curves (AUCs) ranged from 0.63 to 0.71 for 18F-FDG PET/CT parameters. The AUCs of 11C-4DST PET/CT parameters were larger than those of 18F-FDG (range 0.72-0.81). Univariate analysis revealed that individuals with tumors showing a high value for any PET/CT parameter were at a significantly increased risk of relapse. Upon multivariate analysis, 18F-FDG MTV, 11C-4DST MTV and 11C-4DST TLP were significant independent factors for relapse-free survival (P = 0.04, P = 0.0001 and P = 0.0005, respectively). CONCLUSION: Pretreatment 11C-4DST PET/CT volume-based parameters can provide important prognostic information about patients with HNSCC.

Correlation of 4'-[methyl-(11)C]-thiothymidine uptake with Ki-67 immunohistochemistry and tumor grade in patients with newly diagnosed gliomas in comparison with (11)C-methionine uptake.

OBJECTIVE: A novel radiopharmaceutical, 4'-[methyl-(11)C]thiothymidine ((11)C-4DST), has been developed as an in vivo cell proliferation marker based on the DNA incorporation method. The purpose of this study was to evaluate (11)C-4DST uptake in patients with newly diagnosed glioma and to correlate the results with proliferative activity and tumor grade, in comparison with L-[methyl-(11)C]-methionine ((11)C-MET). METHODS: Investigations of (11)C-4DST and (11)C-MET PET/CT were performed retrospectively in 23 patients with newly diagnosed glioma. The maximum standardized uptake value (SUVmax) for tumor (T) and the mean SUV for normal contralateral hemisphere (N) were calculated, and the tumor-to-normal (T/N) ratio was determined. Metabolic tumor volume (MTV) was defined as the volume with a threshold of 40% of the SUVmax. Proliferative activity as indicated by the Ki-67 index was estimated in tissue specimens. RESULTS: Of 23 gliomas examined, (11)C-4DST PET/CT and (11)C-MET PET/CT detected 20 and 22, respectively. Linear regression analysis between (11)C-4DST and (11)C-MET indicated a weak correlation for SUVmax (r = 0.54, P < 0.008), for T/N ratio (r = 0.56, P < 0.006), and for MTV (r = 0.60, P < 0.003). Linear regression analysis indicated a weak correlation between (11)C-4DST and Ki-67 index for SUVmax (r = 0.46, P < 0.03), for T/N ratio (r = 0.43, P < 0.05), and for MTV (r = 0.68, P < 0.001) and between (11)C-MET MTV and Ki-67 index (r = 0.43, P < 0.04). Using (11)C-4DST, there was a significant difference in SUVmax between grades II and IV (P < 0.03) and in MTV between grades II and IV (P < 0.009) and grades III and IV (P < 0.02). Using (11)C-MET, there was a significant difference in SUVmax (P < 0.009) and T/N ratio (P < 0.02) between grades II and IV and in MTV between grades II and IV (P < 0.03) and grades III and IV (P < 0.02). CONCLUSION: (11)C-4DST PET/CT is feasible for imaging of brain gliomas, as well as (11)C-MET PET/CT. Especially, it showed the highest correlation coefficient between (11)C-4DST MTV and Ki-67 index in newly diagnosed gliomas.

Whole-body pharmacokinetics of HDAC inhibitor drugs, butyric acid, valproic acid and 4-phenylbutyric acid measured with carbon-11 labeled analogs by PET.

The fatty acids, n-butyric acid (BA), 4-phenylbutyric acid (PBA) and valproic acid (VPA, 2-propylpentanoic acid) have been used for many years in the treatment of a variety of CNS and peripheral organ diseases including cancer. New information that these drugs alter epigenetic processes through their inhibition of histone deacetylases (HDACs) has renewed interest in their biodistribution and pharmacokinetics and the relationship of these properties to their therapeutic and side effect profiles. In order to determine the pharmacokinetics and biodistribution of these drugs in primates, we synthesized their carbon-11 labeled analogues and performed dynamic positron emission tomography (PET) in six female baboons over 90 min. The carbon-11 labeled carboxylic acids were prepared by using (11)CO2 and the appropriate Grignard reagents. [(11)C]BA was metabolized rapidly (only 20% of the total carbon-11 in plasma was parent compound at 5 min post injection) whereas for VPA and PBA 98% and 85% of the radioactivity were the unmetabolized compound at 30 min after their administration respectively. The brain uptake of all three carboxylic acids was very low (<0.006%ID/cc, BA>VPA>PBA), which is consistent with the need for very high doses for therapeutic efficacy. Most of the radioactivity was excreted through the kidneys and accumulated in the bladder. However, the organ biodistribution between the drugs differed. [(11)C]BA showed relatively high uptake in spleen and pancreas whereas [(11)C]PBA showed high uptake in liver and heart. Notably, [(11)C]VPA showed exceptionally high heart uptake possibly due to its involvement in lipid metabolism. The unique biodistribution of each of these drugs may be of relevance in understanding their therapeutic and side effect profile including their teratogenic effects.