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[ 18 F]-fluorodeoxyglucose (FDG) positron emission tomography (PET) is a well-established modality with high sensitivity for the diagnosis and staging of oncologic patients. FDG is taken up by the glucose transporter of the cell membrane and becomes trapped within the cell. In addition to malignant neoplasms, active inflammatory lesions and some kinds of benign tumors also accumulate FDG. Moreover, the degree of uptake into normal organs and tissues depends on various physiological conditions, which is affected by various medical procedures, treatments, and drugs. To avoid misleading interpretations, it is important to recognize possible situations of unexpected abnormal accumulation that mimic tumor lesions. In this review, we present various FDG findings associated with surgical or medical procedures and treatments. Some findings reflect the expected physiological reaction to treatment, and some show inflammation due to prior procedures. Occasionally, FDG-PET visualizes other disorders that are unrelated to the malignancy, which may be associated with the adverse effects of certain drugs that the patient is taking. Careful review of medical records and detailed interviews of patients are thus necessary., (© 2022. The Author(s).)

Pancreatic β-cell mass (BCM) has a central importance in the pathophysiology of diabetes mellitus. Recently, pancreatic β-cell-specific imaging, especially positron emission tomography (PET) with exendin-based probes, has emerged for non-invasive evaluation of BCM. We developed a novel exendin-based probe labeled with fluorine-18, [ 18 F]FB(ePEG12)12-exendin-4 ( 18 F-Ex4) for PET imaging. We subsequently conducted a first-in-human phase 1 study of 18 F-Ex4 PET/computed tomography (CT) and investigated the safety and utility for visualizing the pancreas. Six healthy male subjects were enrolled in this study. A low dose (37.0 MBq) of 18 F-Ex4 PET/CT was administered (first cohort: n = 2), and subsequently a higher dose (74.0 MBq) was administered (second cohort: n = 4). In the first and second cohorts, 38.6 ± 4.8 and 71.1 ± 4.8 MBq of 18 F-Ex4 were administered, respectively. No serious adverse events were observed in both groups. Only one participant in the first cohort showed transient hypoglycemia during the PET scans. 18 F-Ex4 PET/CT successfully visualized the pancreas in all participants. The mean standardized uptake value of the pancreas was found to be higher than that in the surrounding organs, except for the bladder and kidney, during the observation. Dosimetry analyses revealed the effective systemic doses of 18 F-Ex4 as 0.0164 ± 0.0019 mSv/MBq (first cohort) and 0.0173 ± 0.0020 mSv/MBq (second cohort). 18 F-Ex4 PET/CT demonstrated the safety and utility for non-invasive visualization of the pancreas in healthy male subjects. 18 F-Ex4 is promising for clinical PET imaging targeting pancreatic β cells., Competing Interests: NI received clinical commissioned/joint research grants from Mitsubishi Tanabe, AstraZeneca, Astellas, and Novartis Pharma and scholarship grants from Takeda, MSD, Ono, Sanofi, Japan Tobacco Inc., Mitsubishi Tanabe, Novartis, Boehringer Ingelheim, Kyowa Kirin, Astellas, Daiichi-Sankyo, and Taisho-Toyama Pharma. TS is the endowed chair of the sponsored-research program by Nihon Medi-Physics Co., Ltd. MH and AM are employed by Arkray, Inc.; and HN was employed by Arkray, Inc. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Fujimoto, Fujita, Hamamatsu, Murakami, Nakamoto, Saga, Ishimori, Shimizu, Watanabe, Sano, Harada, Nakamura, Toyoda, Kimura, Nakagawa, Hirai, Murakami, Ono, Togashi, Saji and Inagaki.)

Objectives: The aim of this study was to assess the clinical value of [ 11 C]4DST uptake in patients with lung nodules, including benign and malignant tumors, and to assess the correlation between [ 11 C]4DST uptake and proliferative activity of tumors in comparison with [ 18 F]FDG uptake., Methods: Twenty-six patients (22 males and 4 females, mean age of 65.5-year-old) were analyzed in this prospective study. Patients underwent [ 11 C]4DST and [ 18 F]FDG PET/CT imaging on the same day. Diagnosis of each lung nodule was confirmed by histopathological examination of tissue specimens at surgery, or during clinical follow-up after the PET/CT studies. To assess the utility of the semi-quantitative evaluation method, the SUV max was calculated of [ 11 C]4DST and [ 18 F]FDG uptake by the lesion. Proliferative activities of each tumor as indicated by the immunohistochemical Ki-67 index was also estimated using surgical specimens of patients. Then the relationship between the SUV max of both PET/CT and the Ki-67 index was examined. Furthermore, the relationship between the uptake of [ 11 C]4DST or [ 18 F]FDG and the histopathological findings, the clinical stage, and the clinical outcome of patients were also assessed., Results: There was a positive linear relationship between the SUV max of [ 11 C]4DST images and the Ki-67 index (Correlation coefficients = 0.68). The SUV max of [ 11 C]4DST in the 26 lung nodules were 1.65 ± 0.40 for benign lesions, 3.09 ± 0.83 for adenocarcinomas (P < 0.001 between benign and adenocarcinoma), and 2.92 ± 0.58 for SqCCs (P < 0.001 between benign and SqCC). Whereas, the SUVmax of [ 18 F]FDG were 2.38 ± 2.27 for benign lesions, 6.63 ± 4.24 for adenocarcinomas (n.s.), and 7.52 ± 2.84 for SqCCs (n.s.). The relationship between TNM tumor stage and the SUV max of [ 11 C]4DST were 2.54 ± 0.37 for T1, 3.48 ± 0.57 for T2, and 4.17 ± 0.72 for T3 (P < 0.005 between T1 and T2, and P < 0.001 between T1 and T3). In comparison with the TNM pathological stage, SUVmax of [ 11 C]4DST were 2.63 ± 0.49 for stage I, 3.36 ± 0.23 for stage II, 3.40 ± 1.12 for stage III, and 4.65 for stage IV (P < 0.05 between stages I and II). In comparison of the clinical outcome, the SUV max of [ 11 C]4DST were 2.72 ± 0.56 for the no recurrence (No Rec.) group, 3.10 ± 0.33 for the recurrence-free with adjuvant chemotherapy after the surgery (the No Rec. Adjv. CTx. group) and 4.66 ± 0.02 for the recurrence group (Rec. group) (P < 0.001 between the No Rec and Rec. groups, and P < 0.005 between the No Rec. Adjv. CTx. and Rec. groups)., Conclusions: PET/CT with [ 11 C]4DST is as feasible for imaging of lung tumors as [ 18 F]FDG PET/CT. For diagnosing lung tumors, [ 11 C]4DST PET is useful in distinguishing benign nodules from malignancies. [ 11 C]4DST uptake in lung carcinomas is correlated with the proliferative activity of tumors, indicating a promising noninvasive PET imaging of DNA synthesis in malignant lung tumors.

Background: CD73 is an ectonucleotidase regulating extracellular adenosine concentration and plays an important role in adenosine-mediated immunosuppressive pathways. The efficacy of CD73-targeted therapy depends on the expression levels of CD73; therefore, monitoring CD73 status in cancer patients would provide helpful information for selection of patients who would benefit from CD73-targeted therapy. Here, we evaluated the ability of 111 In-labeled antibody 067-213, which has high affinity for human CD73, to act as a noninvasive imaging probe., Methods: Cell binding and competitive inhibition assays for 111 In-labeled 067-213 were conducted using MIAPaCa-2 (high CD73 expression) and A431 (low CD73 expression) cells. For in vivo assessments, biodistribution and SPECT/CT studies were conducted in MIAPaCa-2 and A431 tumor-bearing mice. To estimate the absorbed dose in humans, biodistribution and SPECT/CT studies were conducted in healthy rats., Results: 111 In-labeled 067-213 bound to MIAPaCa-2 and A431 cells in a CD73-dependent manner and the affinity loss after 111 In-labeling was limited. Biodistribution and SPECT/CT studies with 111 In-labeled 067-213 in mice showed high uptake in MIAPaCa-2 tumors and lower uptake in A431 tumors. In rats, the probe did not show high uptake in normal organs, including endogenously CD73-expressing organs. The estimated absorbed doses in humans were reasonably low., Conclusions: 111 In-labeled 067-213 showed CD73-expression-dependent tumor uptake and low uptake in normal organs and tissues. Radiolabeled 067-213 holds promise as an imaging probe for noninvasive evaluation of CD73 expression levels in patients. Our data encourage further clinical studies to clarify a role for CD73 monitoring in patients receiving CD73-targeted immune therapy.

Objective: False-positive bone lesions (bone pseudometastases) have been often reported in patients with esophageal cancer (EsoC). This study aimed to evaluate the vertebral 2-deoxy-2-[ 18 F] fluoro-D-glucose (FDG) accumulation pattern in patients with newly diagnosed esophageal cancers and other malignancies (OtherT) to elucidate the possible mechanism that causes bone pseudometastasis., Methods: FDG positron emission tomography/computed tomography performed for 90 patients with EsoC, and 112 patients with OtherT was retrospectively evaluated. The uptake pattern in the thoracic (Th) and lumbar (L) vertebrae was visually assessed regarding predominance (TL, Th ≒ L; Td, Th > L; Ld, L > Th), main intensity compared with the uptake in the blood pool (BP) (Grade 1 < BP, Grade 2 ≒ BP, or Grade 3 > BP), and homogeneity (homogeneous, heterogeneous, marginal, or spotty). The patterns between EsoC and OtherT and between Th and L were compared., Results: TL, Td, and Ld patterns were observed in 51.1%, 48.9%, and 0% in EsoC and 79.7%, 20.3%, and 0% in OtherT. Though Grade 2 was most frequently observed in both groups, the ratio of Grade 3 in Th and Grade 1 in L was significantly higher in EsoC than in OtherT. Heterogeneous and spotty patterns were more frequently observed in L and in EsoC, and these were strongly associated with Td pattern., Conclusion: Td pattern was frequently seen, especially in EsoC, and was strongly associated with a heterogeneous or marginal pattern in the L. Heterogeneous marrow distribution with declined lumbar uptake is suspected as the mechanism of bone pseudometastasis.

This first-in-man study was carried out to evaluate the safety, whole-body distribution, dose estimation, and lesion accumulation of 18 F-FSU-880, a newly developed probe targeting prostate-specific membrane antigen. Six prostate cancer patients with known metastatic lesions underwent serial whole-body PET/computed tomography (CT) with 18 F-FSU-880. Blood and urine were analyzed before and after PET/CT. Accumulation of 18 F-FSU-880 in organs and metastatic lesions in serial PET images were evaluated by measuring the standardized uptake values. From the biodistribution data, the organ doses and whole-body effective dose were calculated using OLINDA/EXM software was developed by Dr. Michael Stabin of Vanderbilt University, Nashville, Tennessee, USA. 18 F-FSU-880 PET/CT could be carried out without significant adverse effects. High physiological uptake was observed in the salivary/lachrymal glands and kidneys. The effective dose was calculated to be 0.921 × 10 -2 mSv/MBq. Known metastatic lesions were clearly visualized with high image contrast that increased with time, except in 1 patient, whose bone metastases were well-controlled and inactive. The PET/CT with 18 F-FSU-880 could be carried out safely and could clearly visualize active metastatic lesions. The present results warrant further clinical studies with a larger number of cases to verify the clinical utility of 18 F-FSU-880 PET/CT in the management of prostate cancer patients., (© 2018 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Upregulated monocarboxylate transporters (MCTs) in tumors are considered diagnostic imaging targets. Herein, we synthesized the positron emission tomography probe candidates coumarin analogs 2 and 3, and showed 55 times higher affinity of 2 for MCTs than a representative MCT inhibitor. Whereas [ 11 C]2 showed low tumor accumulation, probably due to adduct formation with plasma proteins, [ 11 C]2 showed high initial brain uptake, suggesting that the scaffold of 2 has properties that are preferable in imaging probes for the astrocyte-neuron lactate shuttle. Although further optimization of 2 is required, our findings can be used to inform the development of MCT-targeted imaging agents., (Copyright © 2017 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Objective: Copper-67 (Cu) is one of the most promising radionuclides for internal radiation therapy. Globally, several projects have recently been initiated for developing innovative approaches for the large-scale production of Cu. Encouraged by these, we performed Cu-radiolabeling of a tetrameric cyclic Arg-Gly-Asp (cRGD) peptide conjugate, cyclam-RAFT-c(-RGDfK-)4, which selectively targets αVβ3 integrin (αVβ3), the transmembrane receptor involved in tumor invasion, angiogenesis, and metastasis. We also evaluated the therapeutic potential and safety of this radiocompound., Materials and Methods: Cu, produced through the Ni(α, p)Cu reaction, was used for the radiolabeling of cyclam-RAFT-c(-RGDfK-)4 at 70°C for 10 min. The radiolabeling efficiency and product stability were assessed using reversed-phase high-performance liquid chromatography and/or thin-layer chromatography. Mice with subcutaneous αVβ3-positive U87MG-glioblastoma xenografts received a single intravenous injection of one of the following: Cu-cyclam-RAFT-c(-RGDfK-)4 (11.1 MBq), peptide control, or vehicle solution. The tumor volumes were measured, side effects were assessed in terms of body weight, routine hematology, and hepatic and renal functions, and the mouse radiation dosimetry was estimated., Results: Cu-cyclam-RAFT-c(-RGDfK-)4 was produced with a radiochemical purity of 97.9±2.4% and a specific activity of 2.7±0.6 MBq/nmol and showed high in-vitro and in-vivo plasma stability. The administration of a single dose of Cu-cyclam-RAFT-c(-RGDfK-)4 resulted in significant tumor growth delay in comparison with that observed upon vehicle or peptide control administration, with an estimated tumor-absorbed dose of 0.712 Gy. No significant toxicity was observed in Cu-cyclam-RAFT-c(-RGDfK-)4-treated mice., Conclusion: Cu-cyclam-RAFT-c(-RGDfK-)4 would be a promising therapeutic agent for αVβ3 integrin-targeted internal radiotherapy.

(64)Cu-diacetyl-bis (N(4)-methylthiosemicarbazone) ((64)Cu-ATSM) is a potential theranostic agent targeting the over-reduced state under hypoxia within tumors. Recent clinical Cu-ATSM positron emission tomography studies have revealed a correlation between uptake and poor prognosis; however, the reason is unclear. Here, using a human colon carcinoma HT-29 model, we demonstrated that the intratumoral (64)Cu-ATSM high-uptake regions exhibited malignant characteristics, such as upregulated DNA repair and elevated %CD133(+) cancer stem-like cells. Based on this evidence, we developed a strategy to enhance the efficacy of (64)Cu-ATSM internal radiotherapy (IRT) by inhibiting DNA repair with a nucleic acid (NA) antimetabolite. The results of the analyses showed upregulation of pathways related to DNA repair along with NA incorporation (bromodeoxyuridine uptake) and elevation of %CD133(+) cells in (64)Cu-ATSM high-uptake regions. In an in vivo(64)Cu-ATSM treatment study, co-administration of an NA antimetabolite and (64)Cu-ATSM synergistically inhibited tumor growth, with little toxicity, and effectively reduced %CD133(+) cells. (64)Cu-ATSM therapy targeted malignant tumor regions with activated DNA repair and high concentrations of CD133(+) cells in the HT-29 model. NA antimetabolite co-administration can be an effective approach to enhance the therapeutic effect of (64)Cu-ATSM IRT., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

This study evaluated the prognostic value of positron emission tomography/computed tomography (PET/CT) using (18) F-fluoroazomycin arabinoside (FAZA) in patients with advanced non-small-cell lung cancer (NSCLC) compared with (18) F-fluorodeoxyglucose (FDG). Thirty-eight patients with advanced NSCLC (stage III, 23 patients; stage IV, 15 patients) underwent FAZA and FDG PET/CT before treatment. The PET parameters (tumor-to-muscle ratio [T/M] at 1 and 2 h for FAZA, maximum standardized uptake value for FDG) in the primary lesion and lymph node (LN) metastasis and clinical parameters were compared concerning their effects on progression-free survival (PFS) and overall survival (OS). In our univariate analysis of all patients, clinical stage and FAZA T/M in LNs at 1 and 2 h were predictive of PFS (P = 0.021, 0.028, and 0.002, respectively). Multivariate analysis also indicated that clinical stage and FAZA T/M in LNs at 1 and 2 h were independent predictors of PFS. Subgroup analysis of chemoradiotherapy-treated stage III patients revealed that only FAZA T/M in LNs at 2 h was predictive of PFS (P = 0.025). The FDG PET/CT parameters were not predictive of PFS. No parameter was a significant predictor of OS. In patients with advanced NSCLC, FAZA uptake in LNs, but not in primary lesions, was predictive of treatment outcome. These results suggest the importance of characterization of LN metastases in advanced NSCLC patients., (© 2015 The Authors. Cancer Science published by Wiley Publishing Asia Pty Ltd on behalf of Japanese Cancer Association.)

Background: The clinical usefulness of positron emission tomography (PET) with (18)F-fluorodeoxyglucose (FDG) for the detection of recurrent hepatocellular carcinoma (HCC) is controversial because HCC displays varying FDG avidity. The purposes of this study were to re-evaluate the utility of FDG PET for the detection of recurrent HCC, and to assess its prognostic value in a large series of postoperative patients., Methods: We retrospectively reviewed 113 scans in 86 patients undergoing FDG PET after curative surgery for HCC. These scans were performed for suspected recurrence on radiologic imaging (group A: n = 44) because of an elevated tumor marker level with negative prior imaging results (group B: n = 32) or with no suspicion of recurrence (group C: n = 37). FDG PET's accuracy for recurrence detection and its value as a predictor of survival were assessed., Results: The sensitivity, specificity, and diagnostic accuracy were 53, 100, and 55 % for group A; 34, 100, and 41 % for group B; and 11, 100, and 78 % for group C, respectively. A change in therapy resulted from the scan results in 7, 9, and 8 % in groups A, B, and C, respectively. The combined sensitivities for intra- and extrahepatic recurrence were 30 and 42 %, respectively. Histopathological features at initial surgery did not affect the sensitivity. The overall survival of patients with positive scans was significantly poorer than that of patients with negative scans (P = 0.008)., Conclusions: The sensitivity of FDG PET for recurrent HCC was low, with little change in treatment resulting. However, it can predict prognosis in postoperative patients.

The purpose of this study was to develop a clinically relevant orthotopic xenotransplantation model of pancreatic cancer and to perform a preclinical evaluation of a new positron emission tomography (PET) imaging probe, ⁶⁴Cu-labeled cyclam-RAFT-c(-RGDfK-)₄ peptide (⁶⁴Cu-RAFT-RGD), using this model. Varying degrees of αvβ₃ integrin expression in several human pancreatic cancer cell lines were examined by flow cytometry and Western blotting. The cell line BxPC-3, which is stably transfected with a red fluorescence protein (RFP), was used for surgical orthotopic implantation. Orthotopic xenograft was established in the pancreas of recipient nude mice. An in vivo probe biodistribution and receptor blocking study, preclinical PET imaging coregistered with contrast-enhanced computed tomography (CECT) comparing ⁶⁴Cu-RAFT-RGD and ¹⁸F-fluoro-2-deoxy-d-glucose (¹⁸F-FDG) accumulation in tumor, postimaging autoradiography, and histologic and immunohistochemical examinations were done. Biodistribution evaluation with a blocking study confirmed that efficient binding of probe to tumor is highly αvβ₃ integrin specific. ⁶⁴Cu-RAFT-RGD PET combined with CECT provided for precise and easy detection of cancer lesions. Autoradiography, histologic, and immunohistochemical examinations confirmed the accumulation of ⁶⁴Cu-RAFT-RGD in tumor versus nontumor tissues. In comparative PET studies, ⁶⁴Cu-RAFT-RGD accumulation provided better tumor contrast to background than ¹⁸F-FDG. Our results suggest that ⁶⁴Cu-RAFT-RGD PET imaging is potentially applicable for the diagnosis of αvβ₃ integrin-expressing pancreatic tumors.

Background: We evaluated whether or not PET or PET/CT using L-methyl-[11C]-methionine (MET) can allow for the early prediction of local recurrence and metastasis, as well as the prognosis (disease-specific survival), in patients with adenoid cystic carcinoma of the head and neck treated by carbon ion beam radiotherapy., Methods: This was a retrospective cohort study of sixty-seven patients who underwent a MET-PET or PET/CT study prior to and one month after the completion of carbon ion radiotherapy (CIRT). The minimum follow-up period for survivors was 12 months. The MET accumulation of the tumor was evaluated using the semiquantitative tumor to normal tissue ratio (TNR). A univariate analysis was conducted using the log-rank method, and the Cox model was used in a multivariate survival regression analysis., Results: The average TNR prior to and following treatment was 4.8 (±1.5) and 3.0 (±1.3), respectively, showing a significant decrease following treatment. In the univariate analysis, a high TNR prior to treatment (TNRpre) was a significant factor for predicting the occurrence of metastasis and the disease-specific survival. A high TNR following treatment (TNRpost) was a significant factor for predicting the development of local recurrence. The residual ratio of TNR changes (TNRratio) seemed to be less useful than the TNRpre. In the multivariate analysis, the TNRpost and tumor size were the factors found to significantly influence the risk of local recurrence. The TNRpre, TNRratio and tumor size were all significant factors influencing the occurrence of metastasis. Regarding the disease-specific survival, the TNRpre and age were the only factors with a significant influence on the outcome., Conclusions: The TNRpre was a factor that was significantly related to the occurrence of metastasis and the disease-specific survival after CIRT for adenoid cystic carcinoma of the head and neck. The TNRpost was a factor that was significantly related to the development of local recurrence. Thus, MET-PET or PET/CT can be useful for predicting or determining the therapeutic efficacy of CIRT.

Purpose: The aim of this study was to investigate the change of 3'-[¹⁸F]fluoro-3'-deoxy-L: -thymidine (¹⁸FLT) uptake in normal bone marrow (BM) after inevitable radiation., Procedures: Twenty-one non-small cell lung cancer patients who received carbon ion radiotherapy (CIRT) were studied with ¹⁸FLT-positron emission tomography/computed tomography (PET/CT) at pre- and post-CIRT. Radiation dose was calculated by radiation planning. Irradiated BM was divided into three groups (<10% of maximum dose, 10-30%, and >30%)., Results: ¹⁸FLT uptake clearly decreased at >10% irradiated areas and mildly decreased at <10% areas. ¹⁸FLT uptake was lowest just after CIRT, somewhat increased at 3 months, and remained unchanged for more than 1 year. There was no significant difference between 10-30% and >30% areas., Conclusion: ¹⁸FLT revealed that BM function decreased by small dose such as <4.2-4.4 GyE/1 fraction of CIRT and is eradicated by >4.2-4.4 GyE/1 fraction.

We describe the synthesis of (11)C-labeled α-aminoisobutyric acid 2 from iodo[(11)C]methane and methyl N-(diphenylmethylen)-d,l-alaniate (5). The tetrabutylammonium fluoride (TBAF)-promoted α-[(11)C]methylation of sterically hindered analog 5 was a key step in our synthesis process. Total radiochemical conversion of 2 was high and a remote-controlled synthesis was carried out. A comparative tumor positron emission tomography (PET) imaging study using the same model mouse showed higher uptake of 2 than with (11)C-labeled methionine and [(18)F] fluorodeoxyglucose (FDG)., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

The use of tumor-suppressor gene p53 as an anticancer therapeutic has been vigorously investigated. However, progress has met with limited success to date. Some major drawbacks are the difficulty in achieving controllable and efficient gene transfer as well as in analyzing the transferred gene expression in real time and the treatment response in a timely manner. Thus, development of novel gene transfer vector with a regulative gene expression system coupled with the reporter gene, by which transgene can be monitored simultaneously, is critical. Moreover, noninvasive imaging-based assessment of the therapeutic response to exogenous wild-type p53 gene transfer is crucial for refining treatment protocols. In this study, as a simple preclinical model, we constructed a doxycycline-regulated bidirectional vector harboring a reporter gene encoding red fluorescence protein and p53. Then, we determined the controllable and simultaneously coordinated expression of both proteins and the p53-mediated anticancer effects in vitro and in vivo. Next, we observed that cells or tumors with induced p53 overexpression exhibited decreased uptake of [(14)C]FDG in cellular assay and [(18)F]FDG in positron emission tomography (PET) imaging. Thus, by coupling with bidirectional vector, controllable p53 transfer was achieved and the capability of fluoro-2-deoxy-D-glucose (FDG)-PET to assess the therapeutic response to p53 gene therapy was evidently confirmed, which may have an impact on the improvement of p53 gene therapy.

Background: Hepatocellular carcinomas (HCCs) accumulate fluorine-18 fluorodeoxyglucose (FDG) to various degrees. The standardized uptake values (SUVs) of FDG-positron emission tomography (PET) in high-grade HCCs are significantly higher than those in low-grade HCCs., Aim: The aim of this study was to evaluate the possible usefulness of FDG-PET in predicting the prognosis of HCC patients after resection. We analyzed the relationship between the tumor to non-tumor SUV ratios (SUV ratio) and surgical outcome in 31 patients., Results: Of the 31 cases of HCC studied, seven (23%) exhibited SUV ratios greater than 2, as the cutoff value. The percentage of patients with poorly differentiated HCC was greater in the higher SUV ratio group (SUV ratio >2) than in the lower SUV ratio group (SUV ratio <2) (57 vs. 32%). The overall survival was significantly longer in the lower SUV ratio group than in the higher SUV ratio group (5-year-survival rate: 63 vs. 29% P = 0.006) (median survival time: 2310 vs.182 days)., Conclusion: The SUV ratio was related significantly to disease-related death as well as other predictive factors, including the number of tumors, the size, stage, and involvement of vessels, and the involvement of the capsule. Consequently, we conclude that the SUV ratio provides information of prognostic relevance in patients with HCC before surgery.

Purpose: The aim of this study was to evaluate the relationships among [18F]fluorodeoxyglucose ([18F]-FDG) uptake, Glut-1 and HK-II expressions, and grade of inflammation in resected lung lesions., Materials and Methods: Sixty patients had undergone preoperative 18F-FDG-PET imaging and thoracotomy. For semiquantitative analysis of 18F-FDG uptake, partial volume effect corrected maximum standardized uptake values (pSUVs) were calculated. Immunohistochemical staining was performed in resected specimens using anti-Glut-1, anti-HK-II, and anti-proliferative cellular nuclear antigen (PCNA) antibodies, and immunoreactivities were scored as G-, H-, and P-indexes on a five-point scale (0: 0%; 1: 20%, 2: 40%; 3: 60%; 4: 80%, and 5: 100% percentages of strongly immunoreactive cells).Grade of inflammation was also evaluated., Results: The malignant lesions had higher pSUV and higher G- and H- than nonmalignant lesions. pSUVs correlated with the G- (p < .001), H- (p < .01), and P-indexes (p < .01) in malignant lesions. In adenocarcinomas, cancers with lower differentiation showed higher expression of Glut-1 and HK-II than those with higher differentiation. A positive linear regression was observed between pSUVs and the grading of inflammation in nonmalignant lesions (p < .05)., Conclusions: Our study indicates that 18F-FDG uptake in lung cancer correlates well with the Glut-1, HK-II, and PCNA expression. For nonmalignant lesions, the presence of a higher inflammatory process correlated with 18F-FDG uptake.

Unlabelled: The Subcommittee on Survey of Nuclear Medicine Practice in Japan has performed a nationwide survey of nuclear medicine practice every five years since 1982 to provide detailed information on its current status., Methods: Questionnaires were sent to every institution known to the Japan Radioisotope Association to provide nuclear medicine examinations. The questionnaires address the number and kind of nuclear medicine examinations performed as well as the kind and dose of the radiopharmaceuticals used during the month of June 2002. The annual number of total or specific examinations was then estimated., Results: Of the institutions sent questionnaires, 1,204 were for in vivo study, 124 were for in vitro study, and 36 were for positron emission tomography (PET) study. Out of these, 95.8% answered them. A total of 1,697 gamma cameras were installed in 1,160 facilities, of which 50% were dual-head cameras. The estimated total annual number of examinations expressed by the number of administered radiopharmaceuticals was 1.60 million, similar to that of the previous survey (1997). The frequency of study with single photon emission computed tomography (SPECT) increased to 40%, from 30% in the previous survey. The scintigraphy most frequently performed was bone (35%), followed by myocardium (24%) and brain perfusion (12%). All showed a continuous increase over the past 20 years. Tumor imaging, however, fell from third to fourth place. The most commonly used radiopharmaceutical for each scintigraphy was 99mTc-HMDP for bone, 201Tl-chloride for myocardium, 67Ga-citrate for tumor, and 123I-IMP for brain. A total of 29,376 PET studies were performed yearly. Among them, 18F-FDG rapidly increased 3.7-fold. 131I therapy for thyroid cancer and hyperthyroidism was conducted yearly in 1,647 and 3,347 patients, respectively. A total of 31.35 million in vitro radioassays were carried out yearly, the number of which has been decreasing continuously since 1992., Conclusions: It was proved that the content of nuclear medicine practice in Japan has changed in the past five years. This report might be useful for understanding the current trends of nuclear medicine practice in Japan.

Additional phase III multicenter clinical study was performed to investigate the efficacy, safety, and usefulness of somatostatin receptor scintigraphy using 111In-pentetreotide (MP-1727), which binds to somatostatin receptors. Forty patients were included in the study; Group A: 18 patients, gastrointestinal hormone producing tumors had been detected with conventional imaging modalities, Group B: 22 patients, no tumors had been detected with conventional imaging modalities in spite of high serum hormone levels. By comparing the results of the octreotide suppression test, 12/16 cases (75.0%) of Group A and 11/19 cases (57.9%) of Group B were assessed as "effective." By comparing the results of immunohistological examination, 5/9 cases (55.6%) of Group A and 2/4 cases (50.0%) of Group B were assessed as "effective." Severe adverse events were not observed in any of the evaluable 35 cases. MP-1727 was judged as clinically useful in 11/16 cases (68.8%) of Group A and 5/19 cases (26.3%) of group B. These results suggest that MP-1727 scintigraphy is very useful for the diagnosis and decision of the therapeutic strategy of gastrointestinal hormone producing tumors.

Purpose: To study the contribution of immunologic background to the uptake of fluorine-18-fluorodeoxyglucose ((18)F-FDG) by the tumor tissues., Methods: The uptakes of (18)F-FDG to the same experimental tumor model (SCCVII) xenografted into immunocompetent and immunodeficient (athymic) mice were compared. In addition, the immunomodifying effect of steroid on the uptake of (18)F-FDG by these tumors was investigated., Results: The uptake of (18)F-FDG by the tumors in immunocompetent mice was significantly higher than that in immunodeficient (athymic) mice. Although steroid pretreatment had no effect on the tumor uptake in immunodeficient mice, it significantly decreased the tumor uptake in immunocompetent mice., Conclusion: The higher tumor uptake of (18)F-FDG observed in immunocompetent mice, modulated by steroid pretreatment, was contributed by the host immune reaction, probably cellular immunity employed by T-lymphocytes. These findings can clinically conclude that the intense accumulation of (18)F-FDG in the metastatic lymph nodes, which contain only a small number of cancer cells, was caused by the enhanced uptake of (18)F-FDG by activated T-lymphocytes due to host immunity against cancer cells present in metastatic lymph nodes.

An enhancement of the target/nontarget ratio of radioactivity levels enables reliable diagnosis and therapy using polypeptide radiopharmaceuticals in nuclear medicine. In the present study, we investigated the effects of the physicochemical properties of radiometabolites on the radioactivity pharmacokinetics after administration of 99mTc-labeled polypeptides using 6-hydrazinopyridine-3-carboxylic acid (HYNIC). Four ternary ligands (L) [3-benzoylpyridine (BP), 3-acetylpyridine (AP), 3-nicotinic acid (NIC), pyridine (PY)] with different lipophilicity were selected as coligands for the preparation of 99mTc-HYNIC-polypeptides. Each of the ternary ligands tested provided 99mTc-HYNIC-labeled galactosyl-neoalbumin (NGA) and Fab fragments of high stability with high radiochemical purity. Moreover, after administration of each 99mTc-HYNIC-labeled NGA into normal mice, the respective ternary ligand [99mTc](HYNIC-lysine)(tricine)(L) complexes were generated as final radiometabolites in the hepatic lysosome. The partition coefficients of [99mTc](HYNIC-lysine)(tricine)(BP), [99mTc](HYNIC-lysine)(tricine)(AP), [99mTc](HYNIC-lysine)(tricine)(NIC), and [99mTc](HYNIC-lysine)(tricine)(PY) were determined to be -2.21, -2.37, -2.93, and -2.73, respectively. Elimination rates of these radiometabolites from the lysosome were enhanced in the order of increasing lipophilicity of the radiometabolites. After injection of the four 99mTc-HYNIC-labeled Fab fragments into normal mice, blood clearances of radioactivity were similar while radioactivity elimination rates from the kidney were enhanced in the order of increasing lipophilicity of the radiometabolites. The present study indicated that the lipophilicity of the radiometabolites constitutes one important factor affecting their elimination rates from the tissues. Thus, as ternary ligands facilitate alteration of the physicochemical properties of radiometabolites, the use of ternary ligand complexes might be applicable for controlling the pharmacokinetics of 99mTc-labeled polypeptides.

The rapid blood flow and perfusion of macromolecules in the inflammatory breast cancer xenograft (WIBC-9), which exhibits a "vasculogenic mimicry" type of angiogenesis without the participation of endothelial cells and expresses high levels of the HER-2/neu antigen, was evaluated in mice using 3D-micro-MR angiography using a novel macromolecular MR contrast agent [G6-(1B4M-Gd)(256)]. Herceptin, which recognizes the HER-2/neu antigen and has similar size (10 nm) to G6-(1B4M-Gd)(256), accumulated and internalized in the WIBC-9 tumors more quickly than in the control MC-5 tumors that progress with normal angiogenesis. Three dimensional micro-MRI with the G6-(1B4M-Gd)(256) macromolecular MRI contrast agent distinguishes between the different types of angiogenesis and is predictive of the rapid accumulation and internalization of Herceptin in the WIBC-9 inflammatory breast cancer xenograft.

Unlabelled: Recently, some studies have shown that delayed scanning with (18)F-FDG PET may help to differentiate malignant from benign pancreatic lesions. However, no study has evaluated the relationship between temporal changes in (18)F-FDG uptake and expression of hexokinase or glucose transporter., Methods: Twenty-one consecutive patients with pancreatic cancer were studied preoperatively by dual-phase (18)F-FDG PET, performed 1 and 2 h after injection of (18)F-FDG. The standardized uptake value (SUV) of the pancreatic cancer was determined, and the retention index (RI) (%) was calculated by subtracting the SUV at 1 h (SUV1) from the SUV at 2 h (SUV2) and dividing by SUV1. The percentages of cells strongly expressing hexokinase type-II (HK-II) and glucose transporter-1 (GLUT-1) were scored on a 5-point scale (1 = 0%-20%, 2 = 20%-40%, 3 = 40%-60%, 4 = 60%-80%, 5 = 80%-100%) by visual analysis of immunohistochemical staining of paraffin sections from the tumor specimens using anti-HK-II and anti-GLUT-1 antibody (HK-index and G-index, respectively)., Results: SUV2 (mean +/- SD, 5.7 +/- 2.6) was higher than SUV1 (5.1 +/- 2.1), with an RI of 8.5 +/- 11.0. Four cases of cancer, in which SUV2 showed a decline from SUV1, showed a low HK-index (1.8 +/- 1.1), whereas 4 cases with an RI of > or =20 and 13 cases with an intermediate RI (0-20) showed significantly higher HK-indices (4.3 +/- 0.7 and 3.1 +/- 1.5, respectively; P < 0.05). RI showed a positive correlation with HK-index, with an R(2) of 0.27 (P < 0.05), but no significant correlation with the G-index. SUV1 showed no relationship with the HK-index but showed a weak positive correlation with the G-index, with an R(2) of 0.05 (P = 0.055)., Conclusion: These preliminary findings suggest that the RI obtained from dual-phase (18)F-FDG PET can predict HK-II expression and that the SUV (at 1 h) has a positive correlation with GLUT-1 expression but not with HK-II expression.

Unlabelled: The aim of the study was to investigate the increase in myocardial (99m)Tc-methoxyisobutylisonitrile (sestamibi) retention in humans during pharmacologic vasodilation., Methods: For calculation of the increase in (99m)Tc-sestamibi retention during hyperemia, baseline and adenosine triphosphate (ATP)-induced hyperemic stress sestamibi studies were performed using a same-day rest-stress protocol. On the injection of sestamibi, left ventricular dynamic data were obtained for 90 s. The increase in sestamibi retention from baseline to hyperemia was calculated by the formula [abstract: see text] where Cm(h)(t) and Cm(b)(t) are myocardial counts on the tomographic image, and Cb(b)(tau) and Cb(h)(tau) are the left ventricular blood-pool counts during the first transit of sestamibi at baseline and during hyperemia, respectively. Coronary flow increase during intravenous ATP stress was measured using intracoronary Doppler flow guide wire and compared with the scintigraphic results of 28 measurements in 22 patients., Results: Sestamibi retention increased as coronary flow velocity increased but plateaued at >2.5-3 times baseline flow velocity. The relationship between the increase in sestamibi retention (Y) and the increase in flow (X) is expressed as follows: Y = 0.44 + 0.60X - 0.068X(2) (r = 0.82)., Conclusion: In humans, the increase in (99m)Tc-sestamibi myocardial retention underestimates coronary flow reserve, particularly at high flow rates. Knowledge of these tracer retention characteristics will contribute to a more comprehensive understanding of the manner and interpretation of stress sestamibi imaging.

Objective: Recurrence is often a major problem for patients who have undergone surgery for ovarian cancer. This prospective study was undertaken to evaluate the clinical contribution of positron emission tomography (PET) using (18)F-fluorodeoxyglucose (FDG) for recurrent ovarian cancer., Subjects and Methods: Twenty-four women who had undergone surgery or chemoradiotherapy for histopathologically proven ovarian cancer were enrolled in this study. Ovarian cancer was thought to have recurred in 12 of these women because of evidence on conventional imaging modalities or tumor marker measurements (group A). Clinical findings for the remaining 12 women showed them to be disease-free (group B). PET findings for the women were compared with the final diagnoses obtained by histopathology or by clinical follow-up. The clinical contribution of PET was assessed by evaluating whether PET yielded information complementing the findings of conventional modalities and by examining its impact on treatment., Results: PET gave valuable information for seven of 12 patients in group A in addition to the information obtained from findings on conventional imaging, and treatment was affected in five patients. On the other hand, in group B, additional information was obtained in only three of 12 patients, and treatment of only one patient was affected. Overall sensitivity, specificity, and accuracy of conventional imaging modalities were 72.7%, 75.0%, and 73.3%, respectively, and these rates improved to 92.3%, 100.0%, and 94.4%, respectively, by considering both conventional imaging modalities and PET findings., Conclusion: Our preliminary data suggest that whole-body PET with FDG can be a complementary modality for following up patients who have had ovarian cancer, especially patients believed to be at risk for recurrence.

6-Hydrazinopyridine-3-carboxylic acid (HYNIC) is a representative agent used to prepare technetium-99m ((99m)Tc)-labeled polypeptides with tricine as a coligand. However, (99m)Tc-HYNIC-labeled polypeptides show delayed elimination rates of the radioactivity not only from the blood but also from nontarget tissues such as the liver and kidney. In this study, a preformed chelate of tetrafluorophenol (TFP) active ester of [(99m)Tc](HYNIC)(tricine)(benzoylpyridine: BP) ternary complex was synthesized to prepare (99m)Tc-labeled polypeptides with higher stability against exchange reactions with proteins in plasma and lysosomes using the Fab fragment of a monoclonal antibody and galactosyl-neoglycoalbumin (NGA) as model polypeptides. When incubated in plasma, [(99m)Tc](HYNIC-Fab)(tricine)(BP) showed significant reduction of the radioactivity in high molecular weight fractions compared with [(99m)Tc](HYNIC-Fab)(tricine)(2.) When injected into mice, [(99m)Tc](HYNIC-NGA)(tricine)(BP) was metabolized to [(99m)Tc](HYNIC-lysine)(tricine)(BP) in the liver with no radioactivity detected in protein-bound fractions in contrast to the observations with [(99m)Tc](HYNIC-NGA)(tricine)(2.) In addition, [(99m)Tc](HYNIC-NGA)(tricine)(BP) showed significantly faster elimination rates of the radioactivity from the liver as compared with [(99m)Tc](HYNIC-NGA)(tricine)(2.) Similar results were observed with (99m)Tc-labeled Fab fragments where [(99m)Tc](HYNIC-Fab)(tricine)(BP) exhibited significantly faster elimination rates of the radioactivity not only from the blood but also from the kidney. These findings indicated that conjugation of [(99m)Tc](HYNIC)(tricine)(BP) ternary ligand complex to polypeptides accelerated elimination rates of the radioactivity from the blood and nontarget tissues due to low binding of the [(99m)Tc](HYNIC)(tricine)(BP) complex with proteins in the blood and in the lysosomes. Such characteristics would render the TFP active ester of [(99m)Tc](HYNIC)(tricine)(BP) complex attractive as a radiolabeling reagent for targeted imaging.

6-Hydrazinopyridine-3-carboxylic acid (HYNIC) constitutes one of the most attractive reagents to prepare (99m)Tc-labeled polypeptides and peptides of various molecular weights in combination with two tricine molecules as coligands. Indeed, (99m)Tc-HYNIC-conjugated IgG showed biodistribution of radioactivity similar to that of (111)In-DTPA-conjugated IgG. However, recent studies indicated significant plasma protein binding when the (99m)Tc labeling procedure was expanded to low molecular weight peptides. In this study, pharmacokinetics of (99m)Tc-HYNIC-conjugated IgG, Fab and RC160 using tricine were compared with their radioiodinated counterparts to evaluate this (99m)Tc-labeling method. In mice, [(99m)Tc](HYNIC-IgG)(tricine)(2) and [(99m)Tc](HYNIC-Fab)(tricine)(2) showed persistent localization of radioactivity in tissues when compared with their (125)I-labeled counterparts. [(99m)Tc](HYNIC-IgG)(tricine)(2) eliminated from the blood at a rate similar to that of (125)I-labeled IgG, while [(99m)Tc](HYNIC-Fab)(tricine)(2) showed significantly slower clearance of the radioactivity than (125)I-labeled Fab. On size-exclusion HPLC analyses, little changes were observed in radiochromatograms after incubation of [(99m)Tc](HYNIC-IgG)(tricine)(2) in murine plasma. However, [(99m)Tc](HYNIC-Fab)(tricine)(2) and [(99m)Tc](HYNIC-RC160)(tricine)(2) demonstrated significant increases in the radioactivity in higher molecular weight fractions in plasma. Formation of higher molecular weight species was reduced when [(99m)Tc](HYNIC-RC160)(tricine)(2) was stabilized with nicotinic acid (NIC) to generate [(99m)Tc](HYNIC-RC160)(tricine)(NIC). [(99m)Tc](HYNIC-RC160)(tricine)(NIC) also demonstrated significantly faster clearance of the radioactivity from the blood than [(99m)Tc](HYNIC-RC160)(tricine)(2). These findings suggested that one of the tricine coligands in (99m)Tc-HYNIC-labeled (poly)peptides would be replaced with plasma proteins to generate higher molecular weight species that exhibit slow blood clearance. In addition, the molecular sizes of parental peptides played an important role in the progression of the exchange reaction of one of the tricine coligands with plasma proteins.

The purpose of this retrospective study was to elucidate the fluorine-18 fluorodeoxyglucose positron emission tomography (FDG-PET) findings in autoimmune-related pancreatitis (AIP), which is a reversible chronic pancreatitis with an autoimmune cause. The study group comprised six patients with clinically diagnosed AIP. After 370 MBq (10 mCi) of FDG had been injected intravenously, the abdomen and/or the whole body was scanned at 1 h post injection in all patients, and scanning was repeated at 2 h in four patients. PET findings were evaluated visually and/or semiquantitatively using the standardized uptake value (SUV). In four of the six patients, PET demonstrated intense uptake in the whole pancreas, which appeared swollen on computed tomography, and the accumulation increased with time in three patients. In one patient, intense focal uptake in the pancreatic head was observed, and the accumulation decreased over time. In the remaining patient, no abnormal accumulation in the pancreas was observed. Follow-up PET scanning after steroid therapy was performed in three patients, and intense FDG uptake was no longer observed. Our preliminary data show that AIP can cause intense FDG uptake in the pancreas. This fact, and the benign status of the condition, should be kept in mind when making a diagnosis with FDG-PET in patients with pancreatic disorders.

Unlabelled: The purpose of this study was to evaluate asialoglycoprotein receptor scintigraphy in the post-transplant monitoring of liver graft and native liver functions in recipients of auxiliary partial orthotopic liver transplantation (APOLT) from living donors., Methods: We performed 36 asialoglycoprotein receptor scintigraphies on 13 patients who had undergone APOLT for noncirrhotic metabolic liver diseases or for small-for-size grafts. The portal vein of the native liver was separated in 12 patients. Anterior dynamic images including the heart and both livers were obtained for 16 min after intravenous injection of 99mTc-diethylenetriamine pentaacetic acid-galactosyl human serum albumin (GSA), and thereafter static SPECT images of both livers were obtained. Uptake rates from the blood to the graft and to the native liver were determined separately by Patlak plot graphical analysis. Relative uptake of GSA by the graft was calculated from transverse SPECT images. The relative volume of the graft liver was determined by CT., Results: The relative uptake of GSA by the graft was higher or increased more rapidly than the relative volume of the graft in 8 of 11 patients with no severe complications concerning the graft. The relative uptake by severely damaged graft liver in 2 patients was much lower than the relative volume. The uptake rate of GSA by the graft was low in these 2 patients. The uptake rate by the native liver decreased when the portal vein was separated., Conclusion: The relative uptake of GSA was a better indicator of graft liver function than was anatomic volume. The uptake rate provided additional independent information of each liver. Asialoglycoprotein receptor scintigraphy is useful for distinguishing and monitoring the graft and native liver functions in patients who had undergone APOLT.

A 68-year-old man suffering from chronic heart failure due to coronary artery disease (CAD) underwent rest technetium-99m (99mTc)-tetrofosmin and thallium-201 (201Tl) with reinjection studies, but died thereafter. The heart was removed and sectioned into short-axis slices and examined by gross and microscopic pathologic methods. A close correlation between the amount of residual cardiomyocytes and the level of regional tracer activity in the left ventricular wall was obtained for redistribution 201Tl, reinjection 201Tl and rest 99mTc tetrofosmin images. The correlation coefficients were r=0.901 for the 201Tl redistribution images, r=0.913 for the 201Tl reinjection images and r=0.917 for the rest 99mTc-tetrofosmin images. This case report provides further evidence of the validity of SPECT tetrofosmin imaging for the determination of myocardial viability in CAD.

99mTc labeled galactosyl serum albumin (GSA) has been used clinically as a receptor-binding agent for the assessment of liver function. The aim of this study was to investigate the usefulness of 99mTc-GSA in intraperitoneal (i.p.) tumor imaging. A tumor model was established by i.p. inoculating nude mice with human ovarian cancer cell SHIN-3, or colon cancer cell LS 180. Radiolabels were i.p. injected into the tumor-bearing mice and the biodistribution of radioactivity was examined. After administration, 99mTc-GSA rapidly accumulated in the tumor. The tumor uptake was 5.82-8.46 %ID/g from 30 min to 6 h after the injection. Radioactivity in the blood was very low, less than 0.3 %ID/g, resulting in high tumor-to-blood ratio. Tumors could be clearly seen by scintigraphic imaging. Accumulation of i.p.-injected 99mTc labeled human serum albumin (HSA) in i.p. tumors was similar to that of 99mTc-GSA, but radioactivity of 99mTc-HSA in the circulation was high, resulting in a significantly lower tumor-to-blood ratio. In conclusion, 99mTc-GSA, when i.p. injected, accumulated in i.p. tumors and cleared from circulation rapidly, which would make it useful for the imaging of i.p. tumors.

Technetium-99m (V)-dimercaptosuccinic acid (DMSA) is a tumour-imaging agent which has been used to evaluate medullary thyroid cancer and soft tissue tumours. Physiological uptake has been demonstrated in the kidneys, nasal mucosa and blood pool. In addition to positive accumulation in these sites, uptake in the breasts has been noted. The purpose of this retrospective study was to evaluate the accumulation of 99mTc (V)-DMSA in the normal breasts of 83 patients. There was no accumulation in male breasts. On the other hand, 24 of 51 female patients showed bilateral symmetrical accumulation in the breasts. Positive uptake was seen in 16 of 23 patients (70%) between 15 and 50 years old, but in only 7 of 25 (28%) above 50 years old. One out of three patients (33%) under 15 years old showed positive breast uptake. In conclusion, the female breasts should be included in the description of a pattern of normal biodistribution of 99mTc (V)-DMSA.

In order to label avidin with Tc-99m, we took advantage of the high affinity binding of biotin to avidin; we radiolabeled a biotin derivative with Tc-99m and then bound this Tc-99m labeled biotin derivative to avidin. For our labeling approach, N epsilon-biotinyl-L-lysine (Biocytin) was reacted with the N-hydroxy-succinimide ester of benzoylmercaptoacetyltriglycine (Bz-MAG3). The resulting Bz-MAG3-Biocytin was labeled with Tc-99m using Tc-99m glucarate as a Tc-99m transchelating agent and mixed with avidin at a 1:1 molar ratio resulting in almost a quantitative labeling yield. Tc-99m-MAG3-Biocytin/Avidin was stable in serum at 37 degrees C with 97 and 95% of the total Tc-99m activity still bound to avidin at 2 and 24 h, respectively. The biodistribution of Tc-99m-MAG3-Biocytin/Avidin in normal Balb/c mice showed a high liver and kidney uptake with 56.6 and 28.9%, respectively at 10 min. We attempted to lower the liver and the kidney activities by reducing the isoelectric point (pI) of avidin by conjugating succinic acid moieties at lysine residues of avidin (pI 10). The kidney uptake decreased to 19.0, 3.1 and 1.7% when the pI of avidin was reduced to 7.0-9.3, 5.5-6.2 and 4.0-4.8, respectively. The lowering of the pI, however, did not change the liver activity appreciably.