Puja Panwar

Comparative evaluation of F-18 FDOPA, F-18 FDG, and F-18 FLT-PET/CT for metabolic imaging of low grade gliomas.

Introduction: We undertook this prospective study to compare amino acid metabolism, glucose metabolism, and proliferation in primary and recurrent low grade gliomas using positron emission tomography (PET)/computed tomography with F-18 FDOPA, F-18 FDG, and F-18 FLT. Methods: Fifteen patients with newly diagnosed or previously treated low grade gliomas (WHO grade I or II) were subjected to F-18-FDOPA, F-18 FDG, and F-18 FLT PET/computed tomography studies on consecutive days. This included 2 patients in remission as control subjects. Uptake of all the 3 tracers were analyzed visually and quantified using standardized uptake values and tumor to normal (T/N) ratios. The accuracy of all the 3 PET tracers in the detection of newly diagnosed and recurrent low grade gliomas was compared. Results: F-18 FDOPA was positive in all cases of primary and recurrent low grade gliomas and negative in the patients in remission. Tumor was visualized on F-18 FDG in 7 of 13 cases, F-18-FLT was positive in 4 of 13 cases. Average tumor standardized uptake values max for F-18 FDOPA (5.75 ± 4.9) and F-18 FLT (1.8 ± 0.91) was lower than that of F-18 FDG (8.5 ± 4.4). T/N ratios for F-18-FDOPA (2.3 ± 0.51) and F-18 FLT (1.8 ± 0.91) were higher than F-18 FDG (1.03 ± 0.64) providing good image contrast for tumor detection in positive cases. Conclusion: F-18 FDOPA scan is superior to both F-18 FLT and F-18 FDG for visualization of primary and recurrent low grade gliomas. F-18-FLT should not be considered for evaluation of recurrent low grade gliomas.

Radiolabeling and biological evaluation of DOTA-Ph-Al derivative conjugated to anti-EGFR antibody ior egf/r3 for targeted tumor imaging and therapy

An appropriate bifunctional chelating agent namely DOTA-Ph-Al was developed for the conjugation with biological vectors (anti EGFr antibody). We hereby report the synthesis of p-bromoacetamidobenzyl derivative of DOTA and its conjugation to monoclonal antibody anti-EGFR ior egf/r3. Immunoconjugate was prepared by conjugation of p- bromoacetamidobenzyl derivative of DOTA with ior egf/r3. Modified antibody was purified on size exclusion chromatography. DOTA-Ph-Al-ior egf/r3 exhibited quantitative 99mTc labeling (>96%) with specific activity 10-20 mCi/mg of protein and 90Y- labeling with specific activity 2-5 mCi/mg. Immunoreactivity was determined by flow cytometry. Receptor ligand assay on murine cell line EAT and human tumor cell line U- 87MG showed Kd =2.87 nM and 4.86 nM respectively. The stability in serum indicated that 99mTc remained bound to antibodies up to 24h and 98% 90Y was associated with the mAb for 5 days. Biodistribution characteristics of Ab-conjugate radiolabeled to 99mTc and 90Y radionuclide was examined in BALB/c mice grafted with EAT and athymic mice with U-87MG cell line demonstrated high tumor uptake with 5.5 ± 1.3 and 7.85 ± 1.2 %ID/g at 4 and 24 h for 99mTc- DOTA-Ph-Al-ior egf/r3 in EAT tumors after post injection respectively. Maximal radiotracer uptake peaked 17.6 ± 2.5 %ID/g in EAT tumor and 12.89 ± 0.66 % ID/g in U-87MG tumor at 48h for 90Y. The drug excreted through renal routes as the activity in the kidneys was 13.42 ± 0.33 %ID/g at 1h and 4.51± 1.2 %ID/g at 4h for 99mTc- DOTA-Ph-Al-ior egf/r3.

11C-MET PET/CT and advanced MRI in the evaluation of tumor recurrence in high-grade gliomas.

Objectives The purpose of this study was to evaluate the performance of l-[methyl-(11)C]methionine (11C-MET) PET/CT and MRI (with the inclusion of advanced imaging techniques, namely, MR spectroscopy and MR perfusion) in the assessment of tumor recurrence in high-grade gliomas. Patients and Methods Twenty-nine patients with high-grade gliomas who underwent surgical resection, external beam radiation therapy, and standard regimens of chemotherapy were subjected to MRI (conventional, MR perfusion, and MR spectroscopy) and 11C-MET PET/CT scans. A definitive diagnosis was made based on histopathology and/or long-term clinical and radiological follow-up. Several indices were obtained for lesion characterization, namely, SUVmean, SUVmax, and mean lesion-to-normal tissue on PET/CT, as well as relative cerebral blood volume and choline-to-creatine ratio on MRI. Results Histological examination revealed viable tumor cells in 19 cases, whereas the remaining 10 were deemed to be negative based on histology (3 cases) or long-term follow-up (7 cases). All the quantitative indices mentioned previously tended to be higher in patients with tumor recurrence/residual. The sensitivity, specificity, and accuracy of 11C-MET PET/CT in identifying tumor recurrence/residual were 94.7%, 80%, and 89.6%, respectively, whereas that of MRI were 84.2%, 90%, and 86.2%, respectively. Conclusions Both 11C-MET PET/CT and MRI (with the inclusion of advanced MRI techniques) demonstrated a high diagnostic performance in the identification of tumor residual/recurrence in high-grade gliomas posttherapy. Although 11C-MET PET/CT seemed to be more sensitive, whereas advanced MRI seemed more specific, there was no statistically significant difference in the diagnostic performance of either modality in the present study. Further studies with a larger group of patients are warranted.

99mTc-tetraethylenepentamine-folate a new 99mTc based folate derivative for the detection of folate receptor positive tumors: Synthesis and biological evaluation

A new radiopharmaceutical, 99mTc-Tetraethylenepentamine(TEPA)-Folate has been synthesized introducing TEPA (triethylenepenatamine) to the _-carboxyl group of folic acid. This binds with 99mTc high efficiency at ambient temperature. The resulting 99mTc-N5-folate is stable under physiological conditions at least for 24 hr after radiocomplexation. TEPA is a known open chain pentamine (N5) chelator, its four-nitrogen act as the binding site for 99mTc. The folate membrane receptor binding of the 99mTc-TEPA-Folate by established human tumor cell lines (KB, U-87MG and MDA-MB-468) showed KD in _M range in normal DMEM (10% serum, 10 _M folic acid). The blood kinetic studies showed more than 70% clearance within 5 minutes from the circulation. The KB cell line tumors in mice were readily identifiable in the _ images and revealed major accumulation of radiotracer in liver, kidneys and intestines. High tumor uptake was shown in the tumor bearing nude mice; tumor to blood ratios reached 2.68 ± 0.52 and 5.5 ± 1.47 at 1 and 4 h after post injection respectively. Surviving fractions as obtained in clonogenic assay were 1.02 ± 0.07 and 1.03 ± 0.05 in U-87MG and MDA-MB-468 cell lines respectively. The 99mTc-N5-Folate conjugate have promising utility as a receptor specific radiopharmaceutical for imaging neoplastic tissues known to over express folate-binding protein.

Synthesis of novel bifunctional Schiff-base ligands derived from condensation of 1-(p-nitrobenzyl)ethylenediamine and 2-(p-nitrobenzyl)-3-monooxo-1,4,7-triazaheptane with salicylaldehyde

Two potentially tetradentate (N2O2) and pentadentate (N3O3) bifunctional Schiff-base ligands, N,N′-bis(2-hydroxybenzyl)-1-(p-aminobenzyl)ethylenediamine (7) and N,N′-bis(2-hydroxybenzyl)-2-(p-aminobenzyl)-3-monooxo-1,4,7-triazaheptane (5′) have been prepared and characterized by various spectroscopic methods (IR, FAB-MS, NMR). They are derived from the condensation reactions of the C-functionalized diamines 1-(p-nitrobenzyl)ethylenediamine and 2-(p-nitrobenzyl)-3-monooxo-1,4,7-triazaheptane with 2.1 equiv. of salicylaldehyde. The first complexation trials with 99mTc are reported.

Synthesis of 99mTc-DOTMP and Its Preclinical Evaluation as a Multidentate Imaging Agent for Skeletal Metastases

The convenient synthetic methodology and in vivo stability of the bone-seeking gamma-radiation-emitting compound, (99m)Tc-DOTMP are described in this paper. The radiolabeling efficiency was found to be >97%, and the stability in serum indicated that (99m)Tc remained bound to the chelate, DOTMP, for up to 24 hours. Blood clearance showed a quick washout from the circulation, and biologic half-life was found to be t(1/2)(F) = 25 min; t(1/2)(S) = 6 hours 5 minutes. The LD(50) was found to be 70 mg/kg, as determined by toxicity studies in BALB/c mice. Biodistribution characteristics of (99m)Tc-DOTMP were examined in BALB/c mice. The drug was excreted mainly through renal routes and the accumulation of (99m)Tc-DOTMP in bone was 9.06 +/- 0.75 percent injected dose per gram at 1 hour. Visual image analysis of (99m)Tc-DOTMP was clinically comparable to the interpretation of imaging studies with conventional (99m)Tc-MDP and other phosphonate derivatives. (99m)Tc-DOTMP injected into Balb/c mice showed prominent bone localization and rapid clearance from blood and other organs, thereby making it a promising candidate as a diagnostic pharmaceutical of bone metastases.

A New Bifunctional Chelating Agent Conjugated with Monoclonal Antibody and Labelled with Technetium-99m for Targeted Scintigraphy: 6-(4-isothiocyanatobenzyl)-5, 7-dioxo-1,11-(carboxymethyl)-1,4,8,11-tetraazacyclotridecane

Objective: The purpose of this study was to obtain the convenient, synthetically useful bifunctional chelating agent, 6-(4-isothiocyanatobenzyl)-5,7-dioxo-1,11-(carboxymethyl)-1,4,8,11-tetraazacyclotridecane, and to apply it to stable 99mTc-labelling of monoclonal antibodies (mAbs). Methods: The chelate was synthesised by reaction of nitrobenzyl malonate and triethylenetetramine followed by alkylation by reacting with bromoacetic acid at pH 10. The amino group was converted to isothiocyanato derivative by reacting with thiophosgene at pH 2.0. Conjugation with mAbs [(anti-carcinoembryonic antigen (CEA) and anti-epidermal growth factor receptor (EGFr)] was performed at pH 8.4 using trisodium phosphate solution by incubating at 37°C for 1 h and subjected to purification on size exclusion chromatography. Results: When radioimmunoconjugates were labelled with 99mTc, the specific activity of immunoconjugates was 20–30 mCi/mg of protein and their immunoreactivity exceeded 80%. The stability in serum indicated that the metal remained bound to antibodies. Biodistribution studies in athymic mice grafted with U-87 human glioblastoma multiforme and MDA-MB-468 human breast carcinoma tumours revealed significant localisation of 99mTc-labelled antibodies in tumours and reduced accumulation in normal organs. Conclusion: This bifunctional chelating agent is promising for immunoscintigraphy because of good tumour-to-normal organ contrast.

Utility of intrastriatal ratios of FDOPA to differentiate idiopathic Parkinson's disease from atypical parkinsonian disorders.

AimThe striatal-to-occipital ratio (SOR) is commonly used as an analytical parameter in L-3,4-dihydroxy-6-18F-fluorophenylalanine (FDOPA) PET studies. It has been shown to be useful in differentiating idiopathic Parkinson’s disease (IPD) patients from healthy individuals. We assessed the performance of SORs and subregional ratio of striatal-to-occipital ratios (RSORs) in the clinical assessment of nigrostriatal dopaminergic function for differentiating typical IPD from atypical parkinsonian disorders (APD). Materials and methodsA total of 117 patients referred from movement disorder clinics in speciality neurology centres underwent an FDOPA PET study and were kept under follow-up for at least 2 years. Sixty-five patients (43 IPD and 22 APD) completed the 2-year follow-up and were included in the final analysis. Their PET images were spatially normalized to occipital counts and analysed with three striatal subregional regions of interest (caudate, anterior putamen and posterior putamen) and two occipital regions of interest. The RSORs of the caudate and posterior putamen, the caudate and anterior putamen, the caudate and whole putamen and the anterior putamen and posterior putamen were also calculated and compared between the IPD and APD groups using the t-test. ResultsThe P values for these SORs were found to be insignificant between IPD and APD patients (caudate: 0.1325; anterior putamem: 0.5469; and posterior putamen: 0.9835). However, the RSORs of the caudate and posterior putamen showed significant differences between these two populations of patients. ConclusionThe SOR method is already known to be a good diagnostic tool to differentiate between IPD patients and the normal population. SOR, however, fails to distinguish IPD from APD patients, and hence the RSOR of the caudate and posterior putamen can be utilized to differentiate between them.

99mTc-methionine scintimammography in the evaluation of breast cancer.

ObjectiveThe diagnostic utility of a 11C-methionine scan has been established in breast cancer. We were able to radiolabel methionine with 99mTc at our institute. Thus, we undertook clinical trials to determine the role of 99mTc-methionine scans in the detection of breast cancer. MethodsScintimammography was performed in 47 female (median age 44 years, range 28–68 years) patients having palpable breast masses. All of them underwent ultrasound, mammography, fine-needle aspiration cytology, and 99mTc-methionine scintimammography before surgery. The final diagnosis was made after histopathological examination. 99mTc-methionine scintimammography was done after injecting 555 MBq of radiotracer intravenously. The results of scintimammography were compared with histopathology. ResultsThe histopathological findings were malignant in 33 (70%) and benign in 14 (30%) cases. Scintimammography showed true-positive findings in 29 patients out of 33 cases of breast cancer. True-negative findings were found in 13 out of 14 patients having benign breast lesions. The sensitivity, specificity, and positive predictive value were found to be 87.8, 92.8, and 96.6% respectively. Conclusion99mTc-methionine imaging can provide useful information with reasonably high sensitivity and specificity in evaluating patients having breast masses.

Metabolic assessment of intracranial tuberculomas using 11C-methionine and 18F-FDG PET/CT.

Background18F-fluorodeoxyglucose (18F-FDG) has limited specificity in the evaluation of intracranial lesions as it is taken up by inflammatory and granulomatous lesions as well. 11C-methionine is known to have a higher specificity in tumor detection, delineation, and differentiation of benign from malignant lesions. However, its uptake in granulomatous lesions remains unclarified. ObjectiveThe aim of this study was to explore the value of 11C-methionine PET/CT and 18F-FDG in the evaluation of intracranial tuberculomas. Methods11C-methionine PET/CT followed by 18F-FDG PET/CT study was performed on 12 patients with intracranial tuberculomas. The diagnosis was confirmed for all cases on histopathological evaluation and/or follow-up. Quantitative analysis was performed for all cases by measuring the lesion-to-normal gray matter uptake ratio. ResultsA high lesion-to-normal gray matter uptake ratio was observed on both 11C-methionine (1.8±0.38) and 18F-FDG scans (1.64±0.26) in all newly diagnosed cases. Lesion detection and delineation was superior on 11C-methionine PET/CT. In addition, 11C-methionine appeared to be a more sensitive indicator for assessing early therapeutic response and incomplete therapeutic response in intracranial tuberculomas. There was complete concordance in the number and sites of lesions detected on 11C-methionine PET/CT and radiological imaging modalities (namely, CT and MRI). ConclusionThis preliminary study suggests that in newly diagnosed, untreated intracranial tuberculomas, 11C-methionine, like 18F-FDG, may have limited specificity in distinguishing it from a neoplastic lesion. However, it may play an important role in assessing the response to antitubercular treatment. Further studies are warranted to explore the potential of 11C-methionine in this regard.