Current interest in the regioselective N-functionalization of tetraazacycloalkanes (cyclen and cyclam) stems mainly from their complexes with radioactive metals for applications in diagnostic (64Cu, 111In, 67Ga) and therapeutic (90Y) medicine, and with paramagnetic ions for magnetic resonance imaging (Gd+3). Selective methods for the N-substitution of cyclen and cyclam is a crucial step in most syntheses of cyclen and cyclam-based radiometal complexes and bifunctional chelating agents. In addition, mixing different pendent groups to give hetero-substituted cyclen derivatives would be advantageous in many applications for fine-tuning the compound's physical properties. So far, numerous approaches for the regioselective N-substitution of tetraazacycloalkanes and more specifically cyclen and cyclam are reported. Unfortunately, none of them are general and every strategy has its own strong points and drawbacks. Herein, we categorize numerous regioselective N-alkylation methods into three strategies, such as 1) direct substitution of the macrocycle, 2) introduction of the functional groups prior to cyclization, and 3) protection/functionalization/deprotection. Our discussion is also split into the methods of mono- and tri-functionalization and di-functionalizataion based on number of substituents. At the end, we describe new trials for the new macrocycles which form more stable metal complexes with various radiometals, and briefly mention the commercially available tetraazacycloalkanes which are used for the biconjugation of biomolecules.
Chelating Agents ; Coordination Complexes ; Cyclization ; Ions ; Ligands* ; Magnetic Resonance Imaging ; Metals

PURPOSE: The estrogen receptor (ER), which is over-expressed in ER-positive breast tumors, has been imaged by positron emission tomography (PET) using [18F] labeled estrogen ligands, especially [18F]FES. However, [18F] has relatively short-lived half-life (t1/2=1.8 h) and the labeling yield of radio-fluorination is usually low compared with 64Cu (t1/2=12.7 h). 1,4,7,10-tetraazacyclododecane (cyclen) is used to form stable metal complexes with copper, indium, gallium, and gadolinium. With these in mind, we prepared cyclen-based Cu complexes which mimic estradiol in aspect of two hydroxyl groups. MATERIALS AND METHODS: 1,7-Protected cyclen, 1,7-bis (benzyloxycarbonyl)-cyclen was synthesized according to the reported procedure. After introducing two 4-benzyloxybenzyl groups at 4,10-positions, the benzyloxycarbonyl and benzyl groups were removed at the same time by hydrogenation on Pd/C to give 1,7-bis(4-hydroxybenzyl)-1,4,7,10-tetraazacyclododecane (1). RESULTS: The prepared ligand 1 was fully characterized by 1H, 13C NMR, and mass spectrometer. The synthesized ligand was reacted with copper chloride and copper perchlorate to give copper complexes [Cu(1)]2+2(ClO4-) and [Cu(1)Cl]+Cl- which were confirmed by high-resolution mass (FAB). CONCLUSION: We successfully synthesized a cyclen derivative of which two phenol groups are located on trans position of N-atoms. And, two Cu(II) complexes of +2 and +1 overall charge, were prepared as a potential PET tracers for ER imaging.
Breast Neoplasms ; Coordination Complexes ; Copper* ; Estradiol ; Estrogens* ; Gadolinium ; Gallium ; Half-Life ; Hydrogen ; Hydrogenation ; Indium ; Ligands ; Phenol ; Positron-Emission Tomography

PURPOSE: Adenosine myocardial perfusion SPECT has proven to be useful in the detection of coronary artery disease, in the follow up the success of various therapeutic regimens and in assessing the prognosis of coronary artery disease. The purpose of this study is to define the reproducibility of myocardial perfusion SPECT using adenosine stress testing between two consecutive Tc-99m sestaMIBI (MIBI) SPECT studies in the same subjects. METHODS: Thirty patients suspected of coronary artery disease in stable condition underwent sequential Tc-99m MIBI SPECT studies using intravenous adenosine. Gamma camera, acquisition and processing protocols used for the two tests were identical and no invasive procedures were performed between two tests. Mean interval between two tests were 4.1 days (range: 2-11 days). The left ventricular wall was divided into 18 segments and the degree of myocardial tracer uptake was graded with four-point scoring system by visual analysis. Images were interpretated by two independent nuclear medicine physicians and consensus was taken for final decision, if segmental score was not agreeable. RESULTS: Hemodynamic responses to adenosine were not different between two consecutive studies. There were no serious side effects to stop infusion of adenosine and side effects profile was not different. When myocardial uptake was divided into normal and abnormal uptake, 481 of 540 segments were concordant (agreement rate 89%, Kappa index 0.74). With four-grade scoring system, exact agreement was 81.3% (439 of 540 segments, tau b=0.73). One and two-grade differences were observed in 97 segments (18%) and 4 segments (0.7%) respectively, but three-grade difference was not observed in any segment. Extent and severity scores were not different between two studies. The extent and severity scores of the perfusion defect revealed excellent positive correlation between two test (r value for percentage extent and severity score is 0.982 and 0.965, p< 0.001) CONCLUSION: Hemodynamic responses and side effects profile were not different between two consecutive adenosine stress tests in the same subjects. Adenosine Tc-99m sestaMIBI SPECT is highly reproducible, and could be used to assess temporal changes in myocardial perfusion in individual patients.
Adenosine* ; Consensus ; Coronary Artery Disease* ; Coronary Vessels* ; Diagnosis* ; Exercise Test ; Follow-Up Studies ; Gamma Cameras ; Hemodynamics ; Humans ; Nuclear Medicine ; Perfusion ; Prognosis ; Tomography, Emission-Computed, Single-Photon*

PURPOSE: To investigate the feasibility of Tl-201 SPECT with intracoronary injection (IC-I) in the detection of viable myocardium, we have performed SPECT imaging after direct intracoronary injection of Tl-201 and images were compared with those of stress-reinjection (Re-I) SPECT. METHODS: Fourteen coronary artery disease patients (male 11, mean age 54 years) who had myocardial infarction or demonstrated left ventricular wall motion abnormality on echocardiography were enrolled. Three mCi of Tl-201 was injected into both coronary arteries during angiography and images were acquired between 6- and 24-hour after injection. Reinjection imaging with 1 mCi of Tl-201 was performed at 4-hour after adenosine stress imaging with 3 mCi of Tl-201. Images were interpreted according to 4-grade visual scoring system (grade 0-3). Segments with mild to moderated uptake (< or=grade 1), and upgraded more than one score with reinjection, and were defined as viable myocardium. RESULTS: Image quality was poor in two cases with IC-I. Numbers of non-viable segments were 60 (23.8%) with IC-I, and 38 (15.1%) with Re-I, respectively. Overall agreement for perfusion grade per myocardial segment in each IC-I and Re-I was 76.5%. Overall agreement for viable segment between IC-I and Re-I was 90.5%. Only one out of 38 segments interpreted as non-viable with Re-I were interpretated as viable with IC-I. And 23 out of 214 segments interpreted as viable with Re-I were interpreted as non-viable with IC-I. CONCLUSION: Intracoronary Tl-201 SPECT seemed to be not advantageous over stress-rest reinjection imaging in the assessment of myocardial viability, mainly due to low count statistics at 6-hour or 24-hour delayed time points. The feasibility of intracoronary Tl-201 SPECT is considered to be limited.
Adenosine ; Angiography ; Coronary Artery Disease ; Coronary Vessels ; Echocardiography ; Humans ; Myocardial Infarction ; Myocardium ; Perfusion ; Tomography, Emission-Computed, Single-Photon*

PURPOSE: To investigate the feasibility of Tl-201 SPECT with intracoronary injection (IC-I) in the detection of viable myocardium, we have performed SPECT imaging after direct intracoronary injection of Tl-201 and images were compared with those of stress-reinjection (Re-I) SPECT. METHODS: Fourteen coronary artery disease patients (male 11, mean age 54 years) who had myocardial infarction or demonstrated left ventricular wall motion abnormality on echocardiography were enrolled. Three mCi of Tl-201 was injected into both coronary arteries during angiography and images were acquired between 6- and 24-hour after injection. Reinjection imaging with 1 mCi of Tl-201 was performed at 4-hour after adenosine stress imaging with 3 mCi of Tl-201. Images were interpreted according to 4-grade visual scoring system (grade 0-3). Segments with mild to moderated uptake (< or=grade 1), and upgraded more than one score with reinjection, and were defined as viable myocardium. RESULTS: Image quality was poor in two cases with IC-I. Numbers of non-viable segments were 60 (23.8%) with IC-I, and 38 (15.1%) with Re-I, respectively. Overall agreement for perfusion grade per myocardial segment in each IC-I and Re-I was 76.5%. Overall agreement for viable segment between IC-I and Re-I was 90.5%. Only one out of 38 segments interpreted as non-viable with Re-I were interpretated as viable with IC-I. And 23 out of 214 segments interpreted as viable with Re-I were interpreted as non-viable with IC-I. CONCLUSION: Intracoronary Tl-201 SPECT seemed to be not advantageous over stress-rest reinjection imaging in the assessment of myocardial viability, mainly due to low count statistics at 6-hour or 24-hour delayed time points. The feasibility of intracoronary Tl-201 SPECT is considered to be limited.
Adenosine ; Angiography ; Coronary Artery Disease ; Coronary Vessels ; Echocardiography ; Humans ; Myocardial Infarction ; Myocardium ; Perfusion ; Tomography, Emission-Computed, Single-Photon*

PURPOSE: Multidrug resistance (MDR) of the cancer cells related to mdr1 gene expression can be effectively treated by selective short hairpin RNA for mdr1 gene (shMDR). Sodium/iodide symporter (NIS) gene is well known to have both reporter and therapeutic gene characteristics. We have co-transfected both shMDR and NIS gene into colon cancer cells (HCT15 cell) expressing MDR and Tc-99m sestamibi and I-125 uptake were measured. In addition, cytotoxic effects of doxorubicin and I-131 therapy were also assessed after transfection. MATERIAL AND METHODS: At first, shMDR was transfected with liposome reagent into human embryonic kidney cells (HEK293) and HCT cells. shMDR transfection was confirmed by RT-PCR and western blot analysis. Adenovirus expressing NIS (Ad-NIS) gene and shMDR (Ad-shMDR) were co-transfected with Ad-NIS into HCT15 cells. Forty-eight hours after infection, inhibition of P-gycoprotein (Pgp) function by shMDR was analyzed by a change of Tc-99m sestamibi uptake and doxorubicin cytotoxicity, and functional activity of induced NIS gene expression was assessed with I-125 uptake assay. RESULTS: In HEK293 cells transfected with shMDR, mdr1 mRNA and Pgp protein expressions were down regulated. HCT15 cells infected with 20 MOI of Ad-NIS was higher NIS protein expression than control cells. After transfection of 300 MOI of Ad-shMDR either with or without 10 MOI of Ad-NIS, uptake of Tc-99m sestamibi increased up to 1.5-fold than control cells. HCT15 cells infected with 10 MOI of Ad-NIS showed approximately 25-fold higher I-125 uptake than control cells. Cotransfection of Ad-shMDR and Ad-NIS resulted in enhanced cytotoxic by doxorubicin in HCT15 cells. I-131 treatment on HCT15 cells infected with 20 MOI of Ad-NIS revealed increased cytotoxic effect. CONCLUSION: Suppression of mdr1 gene expression, retention of Tc-99m sestamibi, enhanced doxorubicin cytotoxicity and increases in I-125 uptake were achieved in MDR expressing cancer cell by co-transfection of shMDR and NIS gene. Dual therapy with doxorubicin and radioiodine after cotransfection shMDR and NIS gene can be used to overcome MDR.
Adenoviridae ; Blotting, Western ; Colonic Neoplasms ; Doxorubicin* ; Drug Resistance, Multiple* ; Gene Expression ; HEK293 Cells ; Humans ; Ion Transport* ; Kidney ; Liposomes ; RNA, Messenger ; RNA, Small Interfering ; Transfection

PURPOSE: We have evaluated characteristics of adrenal masses incidentally observed in nonenhanced F-18 FDG PET/CT of the oncologic patients and the diagnostic ability of F-18 FDG PET/CT to differentiate malignant from benign adrenal masses. MATERIALS AND METHODS: Between Mar 2005 and Aug 2008, 75 oncologic patients (46 men, 29 women; mean age, 60.8+/-10.2 years; range, 35-87 years) with 89 adrenal masses incidentally found in PET/CT were enrolled in this study. For quantitative analysis, size (cm), Hounsfield unit (HU), maximum standardized uptake value (SUVmax), SUVratio of all 89 adrenal masses were measured. SUVmax of the adrenal mass divided by SUVliver, which is SUVmax of the segment 8, was defined as SUVratio. The final diagnosis of adrenal masses was based on pathologic confirmation, radiologic evaluation (HU<0 : benign), and clinical decision. RESULTS: Size, HU, SUVmax, and SUVratio were all significantly different between benign and malignant adrenal masses.(P < 0.05) And, SUVratio was the most accurate parameter. A cut-off value of 1.0 for SUVratio provided 90.9% sensitivity and 75.6% specificity. In small adrenal masses (1.5 cm or less), only SUVratio had statistically significant difference between benign and malignant adrenal masses. Similarly a cut-off value of 1.0 for SUVratio provided 80.0% sensitivity and 86.4% specificity. CONCLUSION: F-18 FDG PET/CT can offer more accurate information with quantitative analysis in differentiating malignant from benign adrenal masses incidentally observed in oncologic patients, compared to nonenhanced CT.
Adrenal Gland Neoplasms ; Diagnosis, Differential ; Humans ; Male ; Neoplasm Metastasis ; Sensitivity and Specificity

PURPOSE: To determine optimal imaging time for diagnostic I-123 whole body scan in the follow-up of patients with differentiated thyroid cancer (DTC), we compared the image quality of 6- and 24-hour images of the same subjects. MATERIALS AND METHODS: Four hundred ninety-eight patients (M:F=55:443, Age 47.6+/-12.9 years) with DTC who had undergone total thyroidectomy and I-131 ablation therapy underwent diagnostic whole body scanning 6 hour and 24 hour after oral ingestion of 185 MBq (5 mCi) of I-123. Serum thyroglobulin measurement and ultrasonography of the neck were performed at the time of imaging. In 40 patients underwent additional I-131 therapy, post-therapy I-131 images were obtained and compared with diagnostic I-123 images. RESULTS: In 440 patients (88.4%), 6- and 24-hour diagnostic I-123 images were concordant, and 58 patients (11.6%) showed discordant findings. Among 58 discordant patients, 31 patients showed abnormal tracer uptake on only 6-hour image, which turned out false-positive findings in all cases. In 12 patients with positive findings on only 24-hour image, remnant thyroid tissue (4 patients) and cervical lymph node metastasis (3 patients) were presented. Among 40 patients underwent additional I-131 therapy, 6-hour and 24-hour images were discordant in 13 patients. All 5 patients with abnormal uptake on only 6-hour image revealed false-positive results, whereas most of 24-hour images were concordant with post-therapy I-131 images. CONCLUSION: I-123 imaging at 24-hour could reduce false-positive findings and improve diagnostic accuracy, compared with 6-hour image in the follow-up of patient with DTC.
Eating ; Follow-Up Studies ; Humans ; Lymph Nodes ; Neck ; Neoplasm Metastasis ; Thyroglobulin ; Thyroid Gland ; Thyroid Neoplasms ; Thyroidectomy ; Whole Body Imaging

PURPOSE: Early detection of recurrence is an important factor for long term survival of patients with colorectal cancer. Measurement of serum levels of CEA, CA 19-9, CT and PET/CT has been commonly used in the postoperative surveillance of colorectal cancer. The purpose of this study was to compare the diagnostic ability of PET/CT, tumor marker and CT for recurrence in colorectal cancer patients after treatment. MATERIALS AND METHODS: F-18 FDG PET/CT imaging was performed in 189 colorectal cancer patients who underwent curative surgical resection and/or chemotherapy. Measurement of serum levels of CEA, CA 19-9 and CT imaging were performed within 2 months of PET/CT examination. Final diagnosis of recurrence was made by biopsy, radiologic studies or clinical follow-up for 6 months after each study. RESULTS: Overall sensitivity, specificity of PET/CT was 94.7%, 91.1%, while those of serum CEA were 44.7% and 97.3%, respectively. Sensitivity and specificity were 94.2%, 90.4% for PET/CT and better than those of combined CEA and CA 19-9 measurement (52.1%, 88.5%) in 174 patients measured available both CEA and CA 19-9 data. In 115 patients with both tumor markers and CT images available, PET/CT showed similar sensitivity but higher specificity (92.9%, 91.3%) compared to combination of tumor markers and CT images (92.9%, 74.1%). CONCLUSION: PET/CT was superior for detection of recurred colorectal cancer patients compared with both CEA, CA 19-9, and even with combination of both tumor markers and CT. Therefore PET/CT could be used as a routine surveillance examination to detect recurrence or metastasis of colorectal cancer.
Biopsy ; Carcinoembryonic Antigen ; Colorectal Neoplasms ; Follow-Up Studies ; Humans ; Neoplasm Metastasis ; Recurrence ; Sensitivity and Specificity ; Biomarkers, Tumor

PURPOSE: Thyroglobulin (Tg) is a valuable and sensitive tool as a marker for diagnosis and follow-up for several thyroid disorders, especially, in the follow-up of patients with differentiated thyroid cancer (DTC). Often, clinical decisions rely entirely on the serum Tg concentration. But the Tg assay is one of the most challenging laboratory measurements to perform accurately owing to antithyroglobulin antibody (Anti-Tg). In this study, we have compared the degree of Anti-Tg effects on the measurement of Tg between availale Tg measuring kits. MATERIALS AND METHODS: Measurement of Tg levels for standard Tg solution was performed with two different kits commercially available (A/B kits) using immunoradiometric assay technique either with absence or presence of three different concentrations of Anti-Tg. Measurement of Tg for patient's serum was also performed with the same kits. Patient's serum samples were prepared with mixtures of a serum containing high Tg levels and a serum containg high Anti-Tg concentrations. RESULTS: In the measurements of standard Tg solution, presence of Anti-Tg resulted in falsely lower Tg level by both A and B kits. Degree of Tg underestimation by A kit was more prominent than B kit. The degree of underestimation by B kit was trivial therefore clinically insignificant, but statistically significant. Addition of Anti-Tg to patient serum resulted in falsely lower Tg levels with only A kit. CONCLUSION: Tg level could be underestimated in the presence of anti-Tg. Anti-Tg effect on Tg measurement was variable according to assay kit used. Therefore, accuracy test must be performed for individual Tg-assay kit.
Diagnosis ; Follow-Up Studies ; Humans ; Immunoradiometric Assay* ; Thyroglobulin* ; Thyroid Gland ; Thyroid Neoplasms