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Background: Amino acid positron emission tomography (PET) imaging plays a significant role in the diagnosis of gliomas and in differentiating tumor recurrence from necrosis. In this study, the authors evaluated the diagnostic efficacy of [ 99m Tc]Tc-methionine single-photon emission computed tomography-computed tomography (SPECT-CT) in comparison with [ 11 C]methionine PET-magnetic resonance imaging (MRI) in delineating tumors. Methods: Thirty-one (primary: 16 and postoperative: 15) patients of confirmed (either MRI or histopathological proven) glioma underwent both [ 99m Tc]Tc-methionine SPECT-CT and [ 11 C]methionine PET-MRI. A comparative analysis was performed between SPECT, PET, and MR images to calculate the concordance between the modalities and to evaluate the diagnostic efficacy of the [ 99m Tc]Tc-methionine SPECT. Results: [ 99m Tc]Tc-methionine SPECT showed comparable uptake in the tumor lesions in comparison to [ 11 C]methionine PET. A significant and strong positive correlation was observed between the volume of tumor (Vt) in PET and Vt MR ( p  < 0.004). Likewise, a significant and strong positive correlation was found between Vt SPECT and Vt MR. [ 99m Tc]-methionine has a sensitivity and specificity of 91% and 75%, respectively, compared with 82% and 100% for [ 11 C]methionine in postoperative cases to differentiate the tumor recurrence from necrosis. The sensitivity and specificity of [ 99m Tc]Tc-methionine was 92% and 100%, respectively, compared with 92% and 67% for [ 11 C]methionine in primary tumors. Conclusion: [ 99m Tc]Tc-methionine SPECT-CT is as equally good as [ 11 C]methionine for diagnosing and differentiating it from necrosis especially in high-grade glioma.

Background: The present study evaluated the prognostic value of [ 99m Tc]MDM (bis-methionine-DTPA) follow-up single-photon emission computed tomography (SPECT) imaging for response assessment to chemoradiotherapy in glioma postoperatively. Materials and Methods: One hundred fourteen glioma patients (80 M:34 F) were followed postoperatively by sequential [ 99m Tc]MDM SPECT, dynamic susceptibility contrast-enhanced (DSCE)-MRI, and magnetic resonance spectroscopy (MRS) at baseline, 6, 12, and 22.5 months postchemoradiotherapy. The quantitative imaging results and the clinical outcome were used for response assessment and for the final diagnosis. The quantitative parameter of [ 99m Tc]MDM SPECT were also used for survival analysis. Results: A significantly ( p  = 0.001) lower target to nontarget (T/NT) ratio was observed in responders than in nonresponders. The sensitivity and specificity of [ 99m Tc]MDM-SPECT for identifying tumor recurrence from radiation necrosis at a cutoff ratio of 1.90 were estimated at 97.9% and 92%. Whereas, the sensitivity and specificity of DSCE-MRI with the normalized cerebral blood volume (nCBV) cutoff of 3.32 for this differentiation was found to be 84.6% and 93.0%. MRS intensity ratios of Cho/NAA and Cho/Cr provided comparatively lower sensitivity of 81.0% and 85.3% and specificity of 73.0% and 73.7%. T/NT ratios correlated with nCBV ( r  = 0.775, p  < 0.001) and to a moderate extent with Cho/NAA ratios ( r  = 0.467, p  = 0.001). [ 99m Tc]MDM SPECT and DSCE-MRI provided comparable results for predicting response assessment to chemoradiotherapy. There was a final diagnosis in 72 patients, of which 47 cases were tumor recurrence and 25 were radiation necrosis. The Kaplan-Meier analysis indicated that patients with T/NT ratio <1.9 showed prolonged survival (53.8 months) as compared (37.2 months) with those who demonstrated T/NT ratio >1.9 ( p  = 0.0001). Conclusion: Thus, this low-cost SPECT technique in combination with DSCE-MRI can be used accurately for mapping the disease activity, response assessment, and survival in glioma. [ 99m Tc]MDM SPECT and DSCE-MRI had the same diagnostic efficacy to detect recurrent/residual tumor and radiation necrosis while MRS was inferior to both the techniques.

Objective: To evaluate the diagnostic utility of a single vial ready to label with [99m]Tc kit preparation of DTPA-bis-methionine (DTPA-bis-MET) for the detection of primary breast cancer., Methods: The conjugate (DTPA-bis-MET) was synthesized by covalently conjugating two molecules of methionine to DTPA and formulated as a single vial ready to label with [99m]Tc lyophilized kit preparations. Thirty female patients (mean age=47.5±11.8 years; range=21-69 years) with radiological/clinical evidence of having primary breast carcinoma were subjected to [99m]Tc-methionine scintigraphy. The whole body (anterior and posterior) imaging was performed on all the patients at 5 minutes, 10 minutes, 1 hour, 2 hours, and 4 hours following an intravenous administration of 555-740 MBq radioactivity of [99m]Tc-methionine. In addition, scintimammography (static images; 256×256 matrix) at 1, 2, and 4 hours was also performed on all the patients., Results: The resultant radiolabel, that is, [99m]Tc-DTPA-bis-MET, yielded high radiolabeling efficiency (>97.0%), radiochemical purity (166-296 MBq/μmol), and shelf life (>3 months). The radiotracer primarily gets excreted through the kidneys and localizes in the breast cancer lesions with high target-to-nontarget ratios. The mean±SD ratios on the scan-positive lesions acquired at 1, 2, and 4 hours postinjection were 3.6±0.48, 3.10±0.24, and 2.5±0.4, respectively. [99m]Tc-methionine scintimammography demonstrated an excellent sensitivity and positive predictive value of 96.0% each for the detection of primary breast cancer., Conclusion: Ready to label single vial kit formulations of DTPA-bis-MET can be easily synthesized as in-house production and conveniently used for the scintigraphic detection of breast cancer and other methionine-dependent tumors expressing the L-type amino acid transporter-1 receptor. The imaging technique thus could be a potential substitute for the conventional single-photon emission computed tomography (SPECT)-based tumor imaging agents, especially for tracers with nonspecific mitochondrial uptake. However, the diagnostic efficacy of [99m]Tc-methionine needs to be evaluated in a large cohort of patients through further multicentric trials.

Abstract Early and specific tumor detection and also therapy selection and response evaluation are some challenges of personalized medicine. This calls for high sensitive and specific molecular imaging such as positron emission tomography (PET). The use of peptides for PET molecular imaging has undeniable advantages: possibility of targeting through peptide-receptor interaction, small size and low-molecular weight conferring good penetration in the tissue or at cellular level, low toxicity, no antigenicity, and possibility of wide choice for radiolabeling. Among β(+)-emitter radioelements, Gallium-68 is a very attractive positron-emitter compared with carbon-11 or fluorine-18 taking into account its easy production via a (68)Ge/(68)Ga generator and well established radiochemistry. Gallium-68 chemistry is based on well-defined coordination complexes with macrocycle or chelates having strong binding properties, particularly suitable for linking peptides that allow resistance to in vivo transchelation of the metal ion. Understanding specific and nonspecific molecular mechanisms involved in oncogenesis is one major key to develop new molecular imaging tools. The present review focuses on peptide signaling involved in different oncogenic pathways. This peptide signalization might be common for tumoral and non-tumoral processes or could be specific of an oncological process. This review describes gallium chemistry and different (68)Ga-radiolabeled peptides already in use or under development aiming at developing molecular PET imaging of different oncological processes.

Background: The currently available radiopharmaceuticals are not specific for tumor imaging., Purpose: The present study was conducted to radiolabel doxorubicin with Technetium-99m ([99m]Tc) as a scintigraphic marker of high DNA turnover/intercalation in malignant cells., Methods: Labeling was done by direct method and the developed radiotracer was subjected to quality control tests. The blood kinetics, scintigraphy of tumor-bearing mice, and biodistribution were studied after intravenous injection of about 7.4 MBq of [99m]Tc-doxorubicin. The isotime (5 minutes) anterior images were acquired at different time intervals of 1.5, 3, and 4 hours., Results: The labeling efficiency of [99m]Tc-doxorubicin was estimated to be more than 95%. The protein-binding efficiency was greater than 88% and in vitro stability was up to 24 hours. The biodistribution data support the clearance of the radioligand by dual (renal and hepatic) pathways. A semiquantitative data analysis of the anterior images indicated that a focal concentration of the radiotracer was seen in the tumor at 1.5 hours, which persisted in 3-hour and 4-hour images, respectively., Conclusions: This scintigraphic approach, therefore, could be a powerful tool for cancer detection at early stage. The technique, however, needs further validation through animal experimentation and clinical studies.

Positron emission tomography is a highly specialized imaging technique using short-lived radiolabel substances to produce extremely high resolution images of the body's biological function. The (18)F(-) ion is produced via the (18)O(p,n)(18)F reaction using a silver target cell filled with 1.4 mL of enriched [(18)O] water. On a typical run, the target is irradiated for 45 minutes with 16.5 MeV protons (on target) and an average beam current of 5-45 mA. When the same reaction takes place with [(16)O] water [(13)N] Ammonia is produced as the primary product by the abstraction of hydrogen from water. This study investigated the physical parameters of medical cyclotron during the radiochemical process with induced radioactivity flux and mutual correlation of physical parameters for 16.5 MeV medical cyclotron at the INMAS Delhi, India. It is observed that by getting farther from the target, the relative number of low-energy neutrons increases while the overall flux of neutrons decreases. This is due to multiple scattering of high-energy neutrons in the walls and eventually absorption of low-energy neutrons. The other parameters are also linked with each other which are correlatable.

Single-photon emission computed tomography has become a significant imaging modality with huge potential to visualize and provide information of anatomic dysfunctions that are predictive of future diseases. This imaging tool is complimented by radiopharmaceuticals/radiosubstrates that help in imaging specific physiological aspects of the human body. The present study was undertaken to explore the utility of technetium-99m (⁹⁹(m)Tc)-labeled glutamate conjugates for tumor scintigraphy. As part of our efforts to further utilize the application of chelating agents, glutamic acid was conjugated with a multidentate ligand, diethylenetriaminepentaacetic acid (DTPA). The DTPA-glutamate conjugate [DTPA-bis(Glu)] was well characterized by IR, NMR, and mass spectroscopy. The biological activity of glutamic acid was compared with its DTPA conjugate by radiocomplexation with ⁹⁹(m)Tc (labeling efficiency ≥98%). In vivo studies of both the radiolabeled complexes ⁹⁹(m)Tc-Glu and ⁹⁹(m)Tc-DTPA-bis(Glu) were then carried out, followed by gamma scintigraphy in New Zealand albino rabbits. Improved serum stability of ⁹⁹(m)Tc-labeled DTPA conjugate indicated that ⁹⁹(m)Tc remained bound to the conjugate up to 24 hours. Blood clearance showed a relatively slow washout of the DTPA conjugate when compared with the labeled glutamate. Biodistribution characteristics of the conjugate in Balb/c mice revealed that DTPA conjugation of glutamic acid favors less accumulation in the liver and bone and rapid renal clearance. Tumor scintigraphy in mice showed increasing tumor accumulation, stable up to 4 hours. These preliminary studies show that ⁹⁹(m)Tc-DTPA-bis(Glu) can be a useful radiopharmaceutical for diagnostic applications in single-photon emission computed tomography imaging.

Computational chemistry is playing an increasingly important role in drug design and discovery, structural biology, and quantitative structure-activity relationship studies. A series of 4(3H)-quinozolone derivatives were screened for two-dimensional quantitative structure-activity relationship studies and subsequently their absorption, distribution, metabolism, and excretion (ADME) properties with the use of soft modeling techniques after selecting suitable descriptors for molecular structure. Multiple linear regression analysis was performed for this study. The final quantitative structure-property relationship mathematical models were found as follows: Equation [Y= log (1MIC)] [symbol: see the text] pMIC= 1. 0:2165κ(1) - 2.082χ(3) - 0.3235μT - 0.2185μx - 100.6qN - 35.42. 2. 0:2185κ(1) - 2.1575χ(3) - 0.3622μT - 0.2142μx - 100.4qN - 31.25. 3. 0:0015ω - 2.0822χ(3) - 0.1252μT - 0.2180μx - 112.9qN - 36.05. 4. 2:108χ(3) - 0.0035ET - 0.2033μx - 3.489qesp - 92.60qN - 33.20. 5. 0:2140κ(1) - 2.186χ(3) - 0.0036Oxxx - 0.0016Oxyy - 78.02qN - 31.52.

The imaging of the distribution of β-amyloid plaques in the brain is becoming an important diagnostic modality in Alzheimer's disease. The present study reports the synthesis of novel benzothiazole derivatives. The final products were characterized by spectral techniques such as FTIR, (1)H NMR, and electrospray ionization-mass spectrometry. The structure-activity relationship of these benzothiazole derivatives is also reported. The K(i) values of these derivatives were evaluated by competitive binding assay studies. The analogs were labeled with (99m)Tc for the potential diagnostic imaging of Alzheimer's disease using stannous chloride as a reducing agent. The radiochemical stability was found to be ≥ 90% for both the compounds and they were stable for 10-12 hours in human serum. Biodistribution studies of the (99m)Tc complex in normal mice were performed after intravenous injection through the tail vein. The data showed high initial brain uptakes at 2 minutes (2.2% ± 0.1% ID/g), and brain activities washed out to 0.3% ± 0.02% ID/g at 6 hours. In conclusion, benzothiazole derivatives showed excellent binding affinities for β-amyloid aggregates and high initial brain uptakes in normal mice.

The synthesis of eight ligands by using 2-amino benzimidazole with different mono/bis aldehydes is described herein. The final products were characterized by spectral techniques such as FT-IR, (1)H NMR, and EI-Mass. The structure-activity relationships of the benzimidazole derivatives are also reported. Studies on the complexation of the ligands with (99m)Tc were optimized by using stannous tartrate as reducing agent under various reaction conditions. The radiochemical stability was >or=95% for all the complexes, and they were to be stable for 12-14 hours in serum. Most of the ligands showed fast blood clearance. Biodistribution studies of the (99m)Tc complexes of these ligands showed no significant uptake in the brain or in the heart, and the clearance was mainly through the hepatobiliary system. Among the eight compounds evaluated for their antiproliferative activity in vitro, L(8) produced good activity against the cancer cell lines A549 and PC-3.

Copper(II) bis(thiosemicarbazone) are very useful for blood flow and hypoxic imaging. The aim of this study was to identify structure-activity relationships (SARs) within a series of analogues with different substitution patterns in the ligands, in order to design improved hypoxia imaging agents and elucidate hypoxia selectivity mechanisms. Genetic algorithms (GAs) were used to develop specific copper metal-ligand force field parameters for the MM3 force-field calculations. These new parameters produced results in good agreement with experiment and previously reported copper metal-ligand parameters. A successful quantitative SAR (QSAR) for predicting the several classes of Cu(II)-chelating ligands was built using a training set of 21 Cu(II) complexes. The QSAR exhibited a correlation between the predicted and experimental test set. The QSAR preformed with great accuracy; r(2) = 0.95 and q(2) = 0.90 utilizing a leave-one-out cross-validation with multiple linear regression analysis to find correlation between different calculated molecular descriptors of these complexes. The final QSAR mathematical models were found as the following: Log P = {3.01698 (+/-0.0590)} - LUMO {0.1248 (+/-0.068)} + MR {0.3219 (+/-0.086)} n = 21 |r| = 0.972 s = 0.188 F = 98.102 The resulting models could act as an efficient strategy for estimating the hypoxic conditions through imaging and provide some insights into the structural features related to the biological activity of these compounds.

(99m)Tc-DTPA-bis(His) conjugate has been synthesized and evaluated as a potential radiopharmaceutical for tumor imaging. The compound was synthesized by the covalent coupling of DTPA bis(anhydride) with L-histidine and was characterized on the basis of infrared, nuclear magnetic resonance, and mass spectroscopy. (99m)Tc-labeled compound was found stable for about 24 hour under physiologic conditions with a more than 96% radiolabeling yield. A blood kinetic study of this complex showed a biexponential pattern as well as quick washout from the blood circulation. The biologic t(1/2)(F) and t(1/2)(S) was found to be 45 +/- 0.041 minutes and 6.5 hours +/- 0.039 minutes, respectively. Imaging and biodistribution studies were performed in mice bearing Ehrlich ascites tumor (EAT) tumors in the right thigh. The EAT tumors in the mice were readily visible in the gamma-images and showed major accumulation of the radiotracer in the kidney. Biodistribution studies revealed a high accumulation at the tumor site. Tumor-to-muscle ratios were 5.07 +/- 0.08 and 4.2 +/- 0.01 at 1 and 4 hours, respectively. The receptor binding of the (99m)Tc-DTPA-bis(His) by an established human tumor cell line (U87-MG) showed K(D) = 1.08 nM. The preliminary studies of the (99m)Tc-DTPA-bis(His) are encouraging to carrying out further in vivo experiments for targeted tumor imaging.

Indole-based alendronate (AI) was derived from the condensation reaction of indole 3-carboxaldehyde with sodium alendronate (ALN) and was characterized by various spectroscopic methods (e.g., ultraviolet, fourier-transform-infrared, and liquid chromatography mass spectrometry). The AI was labeled with (99m)Tc and radiochemical purity was above 97%, which was ascertained by instant thin-layer chromatography, using different solvent conditions, with a specific activity 2-5 mCi/mg. The receptor ligand assay on human bone cell line Soas-2 showed K(D) = 0.55 nM. The derivative (AI) was stable, which was determined under physiologic conditions up to 24 hours The blood kinetic study showed a biexponential pattern as well as quick wash-out from the circulation with varying biologic t(1/2)(F) and t(1/2)(S). Excellent-quality radio images were recorded of bone, showing a rapid clearance of background activity, at an early visualization at 1.5 hours. The excretory pathway of the derivative was through the kidneys, which was evidenced by biodistribution studies. Thus, the newly synthesized derivative can be considered as a specific bone-seeking agent.

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.

Polyethylene glycols (PEGs) are potential drug carriers for humanizing the therapeutic index of anti-cancer agents. In this paper, we report on the modification of the anticancer drugs, methotrexate (MTX) and melphalan (L-PAM), covalently linked to PEGs for drug delivery. Conjugates of MTX and L-PAM were analyzed through different spectroscopic techniques. Both conjugates were labeled with (99m)Tc by the classical way, using reducing agents at a physiologic pH. Blood kinetic data revealed the biphasic pattern of clearance. Evaluation of the in vitro cytotoxicity of the drug polymer conjugates on the U87MG human glioma cell line revealed that the conjugates showed enhanced dose-dependent cytotoxicity.