Synthesis and evaluation of 99mTc(CO)(3)-DTPA-folate as a folate-receptor-targeted radiopharmaceutical

A folate-receptor-targeted 99mTc-radiopharmaceutical, [99mTc]Tc(CO)(3)DTPA-folate, was prepared by heating [99mTc]Tc(CO)(3)(H(2)O)(3)(+) in an aqueous solution of the previously reported DTPA-folate conjugate. The radiotracer was HPLC purified (> 98% radiochemical purity) and evaluated in vitro and in vivo as an agent for targeting folate-receptor-positive cells. [99mTc]Tc(CO)(3)DTPA-folate experienced high, folate-receptor-specific uptake in human KB tumor cells. Intravenous administration of [99mTc]Tc(CO)(3)DTPA-folate to athymic mice bearing KB cell tumor xenografts resulted in 99mTc tumor uptake of 1.8 +/- 0.5 and 3.3 +/- 0.2%ID/g (n = 3) at 30 minutes and 4 hours post-injection, respectively. Tumor uptake was reduced when folic acid was co-administered with the intravenous [99mTc]Tc(CO)(3)DTPA-folate, consistent with radiopharmaceutical localization being mediated by the folate receptor.     

Preparation of 99mTc(CO)3-Carboxymethylthioethyl iminodiacetic acid and evaluation as a potential renal imaging agent

The ligand, carboxymethylthioethyl iminodiacetic acid (CMT-IDA) has a suitable array of donor atoms for coordination with [99mTc(CO)3]+ core, wherein the resultant complex is expected to possess free carboxylic residues contributing towards hydrophilicity of the complex. The aim of the studies was to study the renal clearance of 99mTc(CO)3- labeled CMT-IDA and determine the potential of the complex towards its use as a renal tubular imaging agent. Methods: CMT-IDA was radiolabeled with the [99mTc(CO)3(H2O)3]+ precursor and was characterized by reverse phase HPLC gradient elution system. Stability, hydrophilicity and plasma protein binding studies were carried out for the complex. Biodistribution studies were carried out in normal male Swiss mice at 10 min.p.i. and 2 h.p.i. The clearance was estimated from the activity observed in the urinary bladder by tying the urethra prior to injection of the complexes under study. Imaging studies were performed with male Swiss mice administered with [99mTc(CO)3(CMT-IDA)]-2 at 30 min. p.i. and blocking studies were carried out by intraperitoneal injection of probenecid 10 min. prior to the injection of the radiotracer. Results: [99mTc(CO)3(CMT-IDA)]-2 could be obtained in > 98% radiochemical purity. The complex showed renal clearance of 71.0? 5.9% ID at 10 min.p.i. which increased to 84.1? 10.6% ID at 2 h.p.i., with no major activity in blood, liver, heart, lungs, stomach and spleen. However, the intestinal uptake was high (10.3? 2.0% ID) at 2 h.p.i. Scintigraphic image of the animal injected with probenecid showed an increase in the activity in kidneys indicating excretion of the [99mTc(CO)3(CMT-IDA)]-2 complex via tubular pathway. Conclusion: The complex, [99mTc(CO)3(CMT-IDA)]-2 has shown excellent renal clearance and thereby can be explored further for potential use as an agent towards assessing effective renal plasma flow.     

Technetium-99m complex ofN-(2-pyridylmethyl)iminodiacetic acid as a new renal radiopharmaceutical

A tetradentate chelating agent constituting of an iminodiacetic acid group and a nitrogen atom of pyridine, N-(2-pyridylmethyl)iminodiacetic acid (PMIDA), was coordinated with 99mTc and evaluated as a renal functional agent. The complex of PMIDA with 99mTc was prepared by using a stannous chloride solution as a reducing agent. The chelating efficiency was analyzed by thin layer chromatography and electrophoresis. Chelation with 99mTc resulted in a single radiochemical product. Biological studies were performed in mice and rats. 99mTc-PMIDA was removed from the circulation solely by the kidneys. Clearance of 99mTc-PMIDA from the blood and the kidneys was as rapid as that of 99mTc-diethylenetriaminepentaacetic acid. The rate of blood clearance was unaffected by the administration of probenecid (a test for tubular secretion by the weak-acid mechanism), so that the glomerular filtration rate could be estimated by measuring its clearance from the blood. The results in animals with myohemoglobinuric acute renal failure suggested that 99mTc-PMIDA might be a useful renal function radiopharmaceutical.     

Synthesis of a bis-(N-sec-butyl-dithiocarbamato)-nitrido-99mTc complex: a potential new radiopharmaceutical for brain perfusion studies.

A bis-(N-sec-butyl dithiocarbamato) nitrido technetium-99m complex [(99m)TcN(SBDTC)2] (SBDTC: N-sec-butyl dithiocarbamato) was synthesized by the reduction of (99m)TcO4(-) to [(99m)Tc[triple bond]N]2+ with stannous chloride in the presence of succinic dihydrazide and propylenediamine tetraacetic acid, followed by the addition of sodium N-sec-butyl dithiocarbamate dihydrate. The radiochemical purity of the complex was over 90% as measured by thin layer chromatography. It was stable over 6 h at room temperature. Its partition coefficient indicated that it was a good lipophilic complex. The electrophoresis results showed that the complex was neutral. Biodistribution studies in mice demonstrated that the complex accumulated in the brain with high uptake and good retention. The brain uptake (ID%/g) was 3.89, 3.44 and 2.82 and the brain/blood ratio was 1.41, 1.45, 1.00 at 5, 30 and 60 min post-injection respectively. These results suggested the potential usefulness of the complex as a brain perfusion imaging agent.     

99mTc(CO)3-VIP analogues: preparation and evaluation as tumor imaging agent.

Vasoactive intestinal peptide (VIP) receptors are expressed abundantly on many types of tumors and, hence, radiolabeled VIP analogues are being explored for tumor imaging and therapy. Here, we report synthesis of three VIP analogues and their radiolabeling with (99m)Tc via a novel tricarbonyl synthon. The radiolabeled product could be prepared in high yields (>95%) and stability. In vitro studies showed significant uptake of (99m)Tc(CO)((3))-VP05 in human colon carcinoma cells. Biodistribution studies in animal tumor model showed 0.4-1%ID/g tumor uptake.     

Studying the biological feasibility of [99mTc(CO)3]-dextran-cysteine-cysteine-mannose as a potential molecular radiopharmaceutical for sentinel node detection

Objective

The aim of this work was to radiolabel and bioevaluate the technetium-99m labeled dextran dicysteine mannose (DCCM) [^99mTc(CO)₃]-DCCM for sentinel lymph node detection.

Methods

Dextran dicysteine mannose was radiolabeled using the carbonyl method. Various parameters were studied such as in vitro stability at room temperature up to 5 h, protein binding and partition coefficient. Bioevaluation was performed in a rabbit model by developing images under a gamma camera at various time intervals. Biodistribution was performed in Wistar rat models (n = 3) by dissection and measurement of percent injected dose in various body organs, at 60 and 180 min post-injection intervals. Biodistribution was performed in two different groups of animals: in the first group, the radiolabeled compound was injected at a concentration of 200 μg/ml, thus delivering 10 μg radiolabeled compound at the site of injection; in the second group, the radiolabeled compound was injected at a concentration of 50 μg/ml, delivering 2.5 μg radiolabeled compound at the site of injection.

Results

Radiolabeling efficacy was 97.5 ± 1 % which remained quite stable till 5 h. Protein binding data show that 71.1 ± 5 % drug exhibited binding with blood proteins. Partition coefficient results show that our radiopharmaceutical is quite hydrophilic in nature. It can be inferred from the imaging data that sentinel node can be visualized within 30 min post-injection. Rat dissection data showed that when the radiolabeled compound was injected at a concentration of 50 μg/ml, at 60 min post-injection, ~2.85 % of activity was retained in the sentinel node with a significantly less accumulation, e.g., ~0.12 %, in the secondary node, which resulted in very high popliteal extraction (PE) value, e.g., ~98 %. At 180 min post-injection, 2.46 ± 0.29 % was found to be retained in the sentinel node and PE (99.64 ± 0.23 %), thus resulting in almost complete washout from the secondary node (0.05 ± 0.01 %).

Conclusion

The study demonstrates that radiolabeled DCCM might be a successful radiopharmaceutical for sentinel node detection.     

Preparation and characterization of 99mTc(CO)3-BPy-RGD complex as alphav beta3 integrin receptor-targeted imaging agent.

The aim of this study is to develop a novel arginine-glycine-aspartic acid (RGD) peptide-containing ligand for (99m)Tc labeling as alpha(v)beta(3) integrin receptor-targeted imaging agent. BPy-RGD conjugate was successfully synthesized by coupling of 5-carboxylate-2,2'-bipyridine and c(RGDyK) peptide through EDC/SNHS in aqueous solution and was characterized by MADLI-TOF-MS (m/z=802.72, C(38)H(48)N(11)O(9)). (99m)Tc(CO)(3)-BPy-RGD was prepared by exchange reaction between [(99m)Tc(H(2)O)(3)(CO)(3)](+) and BPy-RGD. Final product was purified by HPLC and tested for octanol/water partition coefficient. Cell-binding assays of BPy-RGD and unmodified c(RGDyK) were tested in MDA-MB-435 cells ((125)I-echistatin as radioligand). Preliminary biodistribution of the (99m)Tc(I)-labeled radiotracer in orthotopic MDA-MB-435 breast tumor xenograft model was also evaluated. The BPy-RGD conjugate had good integrin-binding affinity (50% inhibitory concentration (IC(50))=92.51+/-22.69 nM), slightly lower than unmodified c(RGDyK) (IC(50)=59.07+/-11.03 nM). The hydrophilic radiotracer also had receptor-mediated activity accumulation in MDA-MB-435 tumor (1.45+/-0.25 percentage of injected dose per gram (%ID/g) at 1.5h postinjection (p.i.)), which is known to be integrin positive. After blocking with c(RGDyK), the tumor uptake was reduced from 0.71+/-0.01%ID/g to 0.33+/-0.18%ID/g at 4h p.i. (99m)Tc(I) tricarbonyl complex of cyclic RGD peptide is a promising strategy for integrin targeting. Further modification of the bipyridine-conjugated RGD peptide by using more potent RGD peptides and fine tuning of the tether group between the RGD moiety and (99m)Tc(CO)(3)(+) core to improve the tumor targeting efficacy and in vivo kinetic profiles is currently in progress.     

Initial evaluation of new 99mTc(CO)3 renal imaging agents having carboxyl-rich thioether ligands and chemical characterization of ReCO3 analogues

INTRODUCTION: The first human studies of a characterized radiopharmaceutical containing a {(99m)Tc(CO)(3)}(+) core, Na[(99m)Tc(CO)(3)(LAN)], demonstrated that Na[(99m)Tc(CO)(3)(LAN)] was an excellent renal imaging agent; however, its clearance was less than that of (131)I-orthoiodohippurate ((131)I-OIH), and it did not provide a direct measure of effective renal plasma flow. In order to develop a (99m)Tc renal agent with pharmacokinetic properties equivalent to those of (131)I-OIH, we investigated the (99m)Tc(CO)(3)/Re(CO)(3) complexes formed from carboxymethylmercaptosuccinic acid (CMSAH(3)) and thiodisuccinic acid (TDSAH(4)). Once the ligand is bound to (99m)Tc(CO)(3) through a thioether and two carboxyl groups, the complexes have at least one unbound carboxyl group, essential for the interaction with the renal tubular transporter. METHODS: X-ray crystal structural analysis of [NMe(4)][Re(CO)(3)(CMSAH)] was performed to interpret the nature of (99m)Tc tracers. CMSAH(3) and TDSAH(4) were radiolabeled by incubating each ligand and the precursor [(99m)Tc(CO)(3)(H(2)O)(3)](+) at 70 degrees C (pH 7) for 30 min. The products were purified by reversed-phase high-performance liquid chromatography, and biodistribution studies were performed in Sprague-Dawley rats, with (131)I-OIH as an internal control at 10 and 60 min. RESULTS: Radiolabeling CMSAH(3) and TDSAH(4) with the [(99m)Tc(CO)(3)(H(2)O)(3)](+) precursor gave products quantitatively. Analysis of the Re(CO)(3) complexes with the CMSAH(3) and TDSAH(4) ligands demonstrates that ligands are bound in (99m)Tc/Re(CO)(3) complexes through a thioether and two deprotonated carboxyl groups (forming tridentate dianionic moieties, generally with two 5-membered chelate rings). Renal excretion at 60 min (activity in the urine as a percentage of (131)I-OIH) was 68+/-1% for Na(3)[(99m)Tc(CO)(3)(TDSA)] but was 98+/-1% for Na(2)[(99m)Tc(CO)(3)(CMSA)]. CONCLUSION: In rats, Na(2)[(99m)Tc(CO)(3)(CMSA)] is extracted by the kidneys and eliminated in the urine almost as rapidly as (131)I-OIH; consequently, Na(2)[(99m)Tc(CO)(3)(CMSA)] may provide a direct measure of effective renal plasma flow, and further evaluation in humans is warranted.     

Technetium-99m (99mTc) mercaptoacetyltriglycine: update on the new 99mTc renal tubular function agent.

Technetium-99m (99mTc) mercaptoacetyltriglycine (MAG3) is a new renal radiopharmaceutical that was recently introduced as a 99mTc-labeled replacement for iodine-131 (131I) o-iodohippurate (OIH). Since its introduction, a wide variety of in vitro and in vivo studies have been performed to characterize the high-performance liquid chromatography (HPLC)-purified complex and kit formulations. [99mTc]MAG3 has a slower plasma clearance, a higher plasma protein binding, less red blood cell (RBC) penetration, a lower extraction ratio, and a smaller volume of distribution than OIH. Because of the slower plasma clearance, [99mTc] MAG3 cannot be used as a direct measurement of effective renal plasma flow. Simplified methods have been developed to calculate [99mTc]MAG3 clearances, as well as regression equations to convert these clearances to an equivalent OIH value. The image quality of [99mTc]MAG3 is superior to [131I]OIH; the renogram curves and the fraction of the dose of the two agents that appears in the urine are almost identical, even though the plasma clearance of [99mTc]MAG3 is only 50% to 65% that of OIH. [99mTc]MAG3 compares favorably with OIH in patients with a wide range of clinical problems. The radiation dose to a patient with normal renal function using standard imaging doses is higher for [99mTc]MAG3 than for [131I]OIH, but in patients with impaired renal function, the radiation dose from [131I]OIH is much higher than [99mTc]MAG3. [99mTc]MAG3 also provides superior image quality compared with [99mTc]diethylenetriaminepentaacetic acid (DTPA) in patients with impaired renal function, but it is important to note that [99mTc]MAG3 cannot be used to measure the glomerular filtration rate (GFR). [99mTc]MAG3 is the most promising 99mTc tubular function agent to date, and it has replaced OIH and [99mTc]DPTA in a number of institutions. However, there are physiologic differences between these three agents and, therefore, they should not be expected to behave identically in all clinical conditions.     

Breast tumor targeting with (99m)Tc-HYNIC-PR81 complex as a new biologic radiopharmaceutical

Human epithelial mucin, MUC1, is commonly overexpressed in adenocarcinoma that includes more than 80% of breast cancers. The PR81 is a murine anti-MUC1 monoclonal antibody (MAb) that was prepared against the human breast cancer. We developed an indirect method for labeling of this antibody with (99m)Tc in order to use the new preparation in immunoscintigraphy studies of BALB/c mice bearing breast tumors. The (99m)Tc-PR81 complex was prepared using the HYNIC as a chelator and tricine as a coligand. The labeling efficiency determined by instant thin-layer chromatography (ITLC) was 89.2%+/-4.7%, and radiocolloides measured by cellulose nitrate electrophoresis were 3.4%+/-0.9%. The in vitro stability of labeled product was determined at room temperature by ITLC and in human serum by gel filtration chromatography - 88.3%+/-4.6% and 79.8%+/-5.7% over 24 h, respectively. The integrity of labeled MAb was checked by means of sodium dodecyl sulfate polyacrylamide gel electrophoresis, and no significant fragmentation was seen. The results of cell binding studies showed that both labeled and unlabeled PR81 were able to compete for binding to MCF 7 cells. Biodistribution studies performed in female BALB/c mice with breast tumor xenografts at 4, 16 and 24 h after the (99m)Tc-HYNIC-PR81 injection demonstrated a specific localization of the compound at the site of tumors and minimum accumulation in non target organs. The tumor imaging was performed in BALB/c mice with breast xenograft tumors at 4, 8, 12, 16, 20, 24, 28, 32 and 36 h after the complex injection. The tumors were visualized with high sensitivity after 8 h. The findings showed that the new radiopharmaceutical is a promising candidate for radioimmunoscintigraphy of the human breast cancer.     

Chemical and biological characterization of new Re(CO)3/[99mTc](CO)3 bombesin analogues

INTRODUCTION: Bombesin, a neuropeptide with potential for breast and prostate tumor targeting, is rapidly metabolized in vivo, and as a result, uptake in tumor xenografts in mice is poor. An improvement can be expected from the introduction of nonnatural amino acids and spacers. Leu13 was replaced by cyclohexylalanine and Met14 by norleucine. Two spacers, -betaAla-betaAla- and 3,6-dioxa-8-aminooctanoic acid, were inserted between the receptor-binding amino acid sequence (7-14) of bombesin (BBS) and the retroN(alpha)-carboxymethyl histidine chelator used for labeling with the [99mTc](CO)3 core and the rhenium (Re) congener. METHODS: The biological characterization of the new compounds was performed both in vitro on prostate carcinoma PC-3 cells (binding affinity, internalization/externalization) and in vivo (biodistribution in nude mice with tumor xenografts). The stability was also investigated in human plasma. The Re analogues were prepared for chemical characterization. RESULTS: The nonnatural amino acids led to markedly slower degradation in human plasma and PC-3 cell cultures. The receptor affinity of the new technetium 99m ([99mTc])-labeled BBS analogues was similar to the unmodified compound with Kd<1 nM. Uptake in the pancreas and in PC-3 tumor xenografts in nude mice was blocked by unlabeled BBS. The best target-to-nontarget uptake ratio was clearly due to the presence of the more polar spacer, -betaAla-betaAla-. CONCLUSIONS: The different spacers did not have a significant effect on stability or receptor affinity but had a clear influence on the uptake in healthy organs and tumors. Uptake in the kidneys was lower than in the liver, which is likely to be due to the lipophilicity of the compounds. A specific, high uptake was also observed in the gastrin-releasing peptide receptor-rich pancreas. Thus, with the introduction of spacers the in vivo properties of the compounds can be improved while leaving the affinity unaffected.     

Initial Evaluation of 99mTc(CO)3(ASMA) as a Renal Tracer in Healthy Human Volunteers

Purpose

Preclinical studies in rats showed that two of ^99mTc(CO)₃(ASMA) isomers (rac- and L-ASMA) had pharmacokinetic properties equivalent to that of ¹³¹I-OIH, the radiopharmaceutical standard for the measurement of effective renal plasma flow. The aim of this study was to evaluate the pharmacokinetics of ^99mTc(CO)₃(ASMA) isomers in healthy human subjects.

Methods

Three ASMA ligands (rac-, L- and D-ASMA) were labeled with ^99mTc(CO)₃ using an IsoLink kit (Covidien), and each formed ^99mTc(CO)₃(ASMA) tracer was co-injected with ¹³¹I-OIH into healthy human subjects followed by sequential imaging, plasma clearance measurements and timed urine collection. Plasma protein binding, red cell uptake and percent injected dose in the urine were determined. Urine from each group of volunteers was analyzed for metabolites by HPLC.

Results

Image quality was excellent with all three agents. Each ^99mTc(CO)₃(ASMA) preparation was excreted unchanged in the urine. The plasma clearance ratio (^99mTc(CO)₃(ASMA)/¹³¹I-OIH) was 81 ± 3 % for D-ASMA compared to only 20 ± 4 % for L-ASMA and 37 ± 7 % for rac-ASMA; the 81 % clearance ratio for D-ASMA isomer is still ∼ 30 % higher than the ^99mTc-MAG3/¹³¹I-OIH clearance ratio (∼50-60 %). Red cell uptake was similar for all three tracers (6-9 %), and all tracers had a relatively rapid renal excretion; at 3 h, the ^99mTc(CO)₃(ASMA)/¹³¹I-OIH urine ratio was 100 ± 3 % for D-ASMA, 80 ± 2 % for L-ASMA and 88 ± 1 % for rac-ASMA.

Conclusions

The renal excretion characteristics of ^99mTc(CO)₃(D-ASMA) in humans are superior to those of the other two ^99mTc(CO)₃(ASMA) isomers studied, but are still inferior to ¹³¹I-OIH, even though there was no difference in the clearance of two of ^99mTc(CO)₃(ASMA) isomers and ¹³¹I-OIH in rats. The work described here demonstrates the sensitivity in in vivo biological behavior of ^99mTc(CO)₃(ASMA) isomers to their subtle structural differences.     

A new neutral-lipophilic 99mTc complex with a bis-hydrazide-phosphine (BHP) ligand

A new bis-hydrazide-phosphine (BHP) ligand was synthesized, characterized and complexed with ^99mTc. ^99mTc phenyl-BHP (PBHP) was shown to form a neutral-lipophilic chelate with ^99mTc, in high yields, that is stable over a wide pH range. Results with ^99mTc-PBHP indicate that the BHP chelating moiety is attractive for use in designing new ^99mTc-imaging agents.     

On the structural modification of 2-nitroimidazole-99mTc(CO)3 complex,a hypoxia marker,for improving in vivo pharmacokinetics

IntroductionA 2-nitroimidazole-^99mTc(CO)₃ complex reported earlier showed promise with respect to its uptake and retention in hypoxic tumor. However, significant uptake and slow clearance from liver imposed severe limitations towards advocating its possible practical utility. In an attempt to improving its liver clearance, an ether linkage, which is known to help in liver clearance, was introduced in the molecule.MethodsThe 2-nitroimidazole iminodiacetic acid (IDA) derivative containing an ether linkage was synthesized in a five step procedure from 2-nitroimidazole. This derivative was radiolabeled using [^99mTc(CO)₃(H₂O)₃]⁺ precursor complex. The corresponding Re(CO)₃ analogue was also synthesized in the macroscopic level for structural characterization. The ^99mTc(CO)₃ complex was evaluated in an animal model bearing fibrosarcoma tumor.ResultsThe in vivo evaluation of the complex indicated that, as envisaged, introduction of the ether linkage has improved clearance from the liver. The complex also showed higher retention in tumor compared to the 2-nitroimidazole-IDA-^99mTc(CO)₃ complex reported earlier. Though the tumor to muscle ratio improved with time, the tumor to blood ratio did not show any significant improvement. Despite improved liver clearance, there was significant liver activity present even at 3 h p.i. attributable to gradual accumulation of activity cleared from muscle and blood.ConclusionsThough the introduction of ether linkage improved liver clearance of the modified 2-nitroimidazole complex, it was found that a single ether linkage was not sufficient to achieve the desirable level of clearance. Probably, a linker with multiple ether groups, such as a di- or tri-ethylene glycol spacer, may be a possible solution to this issue.     

Evaluation of 99mTc(CO)5I as a potential lung perfusion agent

IntroductionThe use of ^99mTc-macroggregated albumin for lung perfusion imaging is well established in nuclear medicine. However, there have been safety concerns over the use of blood-derived products because of potential contamination by infective agents, for example, Variant Creutzfeldt Jakob Disease. Preliminary work has indicated that Tc(CO)₅I is primarily taken up in the lungs following intravenous administration. The aim of this study was to evaluate the biodistribution and pharmacokinetics of ^99mTc(CO)₅I and its potential as a lung perfusion agent.Methods^99mTc(CO)₅I was synthesized by carbonylation of ^99mTcO_4? at 160 atm of CO at 170°C in the presence of HI for 40 min. Radiochemical purity was determined by HPLC using ⁹⁹Tc(CO)₅I as a reference. ^99mTc(CO)₅I was administered by ear-vein injection to three chinchilla rabbits, and dynamic images were acquired using a gamma camera (Siemens E-cam) over 20 min. Imaging studies were also performed with ^99mTc-labeled macroaggregated albumin (^99mTc-MAA) and ^99mTcO_4? for comparison. ^99mTc(CO)₅I was administered intravenously to Sprague–Dawley rats, and tissue distribution studies were obtained at 15 min and 1 h postinjection. Comparative studies were performed using ^99mTc-MAA.ResultsRadiochemical purity, assessed by HPLC, was 98%. The retention time was similar to that of ⁹⁹Tc(CO)₅I. The dynamic images showed that 70% of ^99mTc(CO)₅I appeared promptly in the lungs and remained constant for at least 20 min. In contrast, ^99mTcO_4? rapidly washed out of the lungs after administration. As expected ^99mTc-MAA showed 90% lung accumulation. The percentage of injected dose per gram of organ ±S.D. at 1 h for ^99mTc(CO)₅I was as follows: blood, 0.22±0.02; lung, 12.8±2.87; liver, 0.8±0.15; heart, 0.15±0.01; kidney, 0.47±0.08. The percentage of injected dose per organ ±S.D. at 1 h was as follows: lung, 22.47±2.31; liver, 10.53±1.8; heart, 0.18±0.01; kidney, 1.2±0.17. Tissue distribution studies with ^99mTc-MAA showed 100% lung uptake.Conclusion^99mTc(CO)₅I was synthesized with a high radiochemical purity and showed a high accumulation in the lungs. Further work on the mechanism and optimization of lung uptake of ^99mTc-pentacarbonyl complexes is warranted.     

Synthesis and evaluation of a technetium-99m-labeled diethylenetriaminepentaacetate-deoxyglucose complex ([99mTc]-DTPA-DG) as a potential imaging modality for tumors.

This study describes the radiolabeling and preliminary biologic testing of diethylenetriaminepentaacetic acid (DTPA)-deoxyglucose (DG) labeled with (99m)Tc. A one-step [(99m)Tc]-DTPA-DG kit was prepared using the stannous chloride reduction method. When (99m)TcO(4)(-) was added to the DTPA-DG kit at room temperature the radiochemical purity 30 min later was 99.2%, and it remained >98.6% for 6 h. Rapid blood clearance of [(99m)Tc]-DTPA-DG was observed in in vivo biodistribution, the main route of clearance was via the kidneys. No significant accumulation in any other organs was seen. The tumor-to-brain and tumor-to-muscle concentration ratios for [(99m)Tc]-DTPA-DG uptake were higher than those for fluorine-18-flurodeoxyglucose ((18)F-FDG). Scintigraphic results demonstrated the feasibility of [(99m)Tc]-DTPA-DG imaging tumors. The [(99m)Tc]-DTPA-DG complex is a potential imaging agent due to the ideal physical characteristics of the radionuclide, ease of preparation, low cost, early accumulation and the preference for the renal route of excretion.     

Synthesis of 99mTc(CO)3-deoxyuridine derivatives as potential HSV1-tk gene expression imaging agents.

In this study, we synthesized (99m)Tc(CO)(3)-2'-aminomethylpyridyl-2'-deoxyuridine ((99m)Tc(CO)(3)-AMPDU) and (99m)Tc(CO)(3)-aminoethylpyridyl-2'-deoxyuridine ((99m)Tc(CO)(3)-AEPDU) as potential agents for imaging the expression of the non-invasive herpes simplex virus type-1 thymidine kinase. AMPDU and AEPDU were synthesized from uridine in five chemical steps and then labeled with [(99m)Tc(CO)(3)(H(2)O)(3)](+) (370MBq/0.5 mL) at 100 degrees C for 10 min. Under optimal conditions (0.5 and 1.0mg for AMPDU and AEPDU and heating for 10 min), the labeling efficiency was 95.3+/-2.8% for AMPDU and 94.2+/-5.1% for AEPDU. To validate the chemical structure of (99m)Tc(CO)(3)-labeled compounds, we also synthesized ReBr(CO)(3)-AMPDU and ReBr(CO)(3)-AEPDU by reacting [Et(4)N][ReBr(3)(CO)(3)] and AMPDU or AEPDU in methanol at 25 degrees C for 6h. (99m)Tc(CO)(3)-AMPDU and (99m)Tc(CO)(3)-AEPDU had the same retention time on HPLC analysis as ReBr(CO)(3)-AMPDU and ReBr(CO)(3)-AEPDU. (99m)Tc(CO)(3)-AMPDU and (99m)Tc(CO)(3)-AEPDU had high radiochemical stabilities of 98.1+/-1.5% and 98.0+/-1.7% for 6h, respectively.