Highest Concentration Of Radioactivity Research Articles

Radiosynthesis of 4‐[18F]fluoromethyl‐L‐phenylalanine and [18F]FET via a same strategy and automated synthesis module

AbstractCurrently there is still a need for more potent amino acid analogues as tumour imaging agents for peripheral tumour imaging with PET as it was recently reported that the success of O‐(2′‐[18F]fluoroethyl)‐L‐tyrosine ([18F]FET) is limited to brain, head and neck tumours. As the earlier described 2‐Amino‐3‐(2‐[18F]fluoromethyl‐phenyl)‐propionic acid (2‐[18F]FMP) suffered from intramolecular‐catalysed defluorination, we synthesized 2‐Amino‐3‐(4‐[18F]fluoromethyl‐phenyl)‐propionic acid (4‐[18F]FMP) as an alternative for tumour imaging with PET. Radiosynthesis of 4‐[18F]FMP, based on Br for [18F] aliphatic nucleophilic exchange, was performed with a customized modular Scintomics automatic synthesis hotboxthree system in a high overall yield of 30% and with a radiochemical purity of \gt 99%. 4‐[18F]FMP was found to be stable in its radiopharmaceutical formulation, even at high radioactivity concentrations. Additionally, for a comparative study, [18F]FET was synthesized using the same setup in 40% overall yield, with a radiochemical purity \gt 99%. The described automated radiosynthesis allows the production of two different amino acid analogues with minor alternations to the parameter settings of the automated system, rendering this unit versatile for both research and clinical practice. Copyright © 2009 John Wiley & Sons, Ltd.

Nanocrystalline zirconia: A novel sorbent for the preparation of 188W/ 188Re generator

Nanocrystalline zirconia, a novel high capacity sorbent material was synthesized and tested for its utility in the preparation of 188W/ 188Re generators. The structural investigation of the material was carried out using X-ray diffraction, surface area determination, FTIR and TEM micrograph analysis. Various experimental parameters were optimized to separate 188Re from 188W. The capacity of the material was found to be ∼325 mg W/g at the optimum pH. A chromatographic 188W/ 188Re generator was developed using this material from which >80% of 188Re generated could be eluted with 0.9% saline solution, with high radionuclidic, radiochemical and chemical purity and appreciably high radioactive concentration suitable for radiopharmaceutical applications.

Disposition and Metabolism of a Novel Prostanoid Antiglaucoma Medication, Tafluprost, Following Ocular Administration to Rats

The disposition and metabolism of tafluprost, an ester prodrug of the 15,15-difluoro-prostaglandin F(2alpha) antiglaucoma agent, have been studied in rats after ocular administration. Radioactivity was absorbed very rapidly into the eye and systemic circulation after a single ocular dose of 0.005% [(3)H]tafluprost ophthalmic solution, with maximum levels in plasma and most eye tissues occurring within 15 min. The absorption ratio of radioactivity was approximately 75%, suggesting the high availability of ocular administration of tafluprost. Approximately 10% of the dose was present in cornea at this time, and radioactivity concentrations in this tissue exceeded those in aqueous humor and iris/ciliary body throughout the 24-h study period. After repeated daily ocular doses, radioactivity levels remained greatest in cornea, followed by iris/ciliary body that replaced aqueous humor as the eye tissue containing the second highest radioactivity concentration. In female rats, radioactivity was excreted equally between urine and feces after a single ocular dose, whereas in male rats more was excreted in feces, reflecting the greater biliary excretion in males rats (50% dose) compared with females rats (33% dose). Tafluprost was extensively metabolized in the rat, such that intact prodrug was not detected in plasma, tissues, or excreta by radio-high-performance liquid chromatography. On the other hand, the active moiety, tafluprost acid, was the only noteworthy radioactive component in cornea, aqueous humor, and iris/ciliary body for at least 8 h after the ocular dose, and it was also a major plasma metabolite in early time points. The gender differences in conjugation reactions resulted in the differences in the excretion.

Biodistributions, Myelosuppression, and Toxicities in Mice Treated with an Anti-CD45 Antibody Labeled with the α-Emitting Radionuclides Bismuth-213 or Astatine-211

We previously investigated the potential of targeted radiotherapy using a bismuth-213 ((213)Bi)-labeled anti-CD45 antibody to replace total body irradiation as conditioning for hematopoietic cell transplantation in a canine model. Although this approach allowed sustained marrow engraftment, limited availability, high cost, and short half-life of (213)Bi induced us to investigate an alternative alpha-emitting radionuclide, astatine-211 ((211)At), for the same application. Biodistribution and toxicity studies were conducted with conjugates of the anti-murine CD45 antibody 30F11 with either (213)Bi or (211)At. Mice were injected with 2 to 50 muCi on 10 microg or 20 muCi on 2 or 40 microg of 30F11 conjugate. Biodistribution studies showed that the spleen contained the highest concentration of radioactivity, ranging from 167 +/- 23% to 417 +/- 109% injected dose/gram (% ID/g) after injection of the (211)At conjugate and 45 +/- 9% to 166 +/- 11% ID/g after injection of the (213)Bi conjugate. The higher concentrations observed for (211)At-labeled 30F11 were due to its longer half-life, which permitted better localization of isotope to the spleen before decay. (211)At was more effective at producing myelosuppression for the same quantity of injected radioactivity. All mice injected with 20 or 50 muCi (211)At, but none with the same quantities of (213)Bi, had lethal myeloablation. Severe reversible acute hepatic toxicity occurred with 50 muCi (213)Bi, but not with lower doses of (213)Bi or with any dose of (211)At. No renal toxicity occurred with either radionuclide. The data suggest that smaller quantities of (211)At-labeled anti-CD45 antibody are sufficient to achieve myelosuppression and myeloablation with less nonhematologic toxicity compared with (213)Bi-labeled antibody.

Radiolysis of 2-[ 18F]fluoro-2-deoxy- d-glucose ([ 18F]FDG) and the role of ethanol and radioactive concentration

Radiolysis is the process by which radioactively labeled compounds degrade. Many positron emission tomography (PET) radiopharmaceuticals produced with high radioactive concentrations and specific activities exhibit low radiochemical purity because of radiolysis. Little data exist that describe the radiolytic decomposition of 2-[ 18F]fluoro-2-deoxy- d-glucose ([ 18F]FDG). The objective of our study was to profile the degradation of [ 18F]FDG at various radioactive concentrations by measuring radiochemical purity at different time intervals and to study the effects of ethanol, a well-known reductant stabilizer of [ 18F]FDG preparations.

Evaluation of Toxicity and Tissue Radiation Doses Obtained in Mice with An Anti-CD45 Monoclonal Antibody (mAb) Labeled with the Alpha-Emitting Radionuclides, Astatine-211 or Bismuth-213.

Background: One strategy to decrease toxicity of conditioning regimens for hematopoietic cell transplantation (HCT) has been the use of radiation targeted systemically with radionuclide-labeled mAbs. While mAb labeled with β-emitting radionuclides have shown some efficacy, a more promising alternative is the use of α-particle emitters. In contrast to β-emitting radionuclides, the high linear energy transfer and short particle range of α-particles makes them particularly attractive for killing hematopoietic cells in the blood and marrow. We initially investigated bismuth-213 (213Bi)-labeled anti-CD45 mAb to replace total body irradiation (TBI) as nonmyeloablative conditioning for HCT. This conditioning successfully allowed sustained engraftment of allogeneic marrow in a canine model. However, the limited availability, very short t1/2 of 46 min, and cost to produce 213Bi place limitations in using this for clinical trials. Therefore, in this study we evaluated whether astatine-211 (211At), which has a longer half-life (t1/2 = 7.2 h) than 213Bi, gave comparable results when targeting hematopoietic cells in mice.Methods: After injecting with either 213Bi- or 211At-labeled rat anti-murine CD45 mAb 30F11, we evaluated myelosuppression and non-hematological toxicity with varying quantities of radioactivity (2, 10, 20, and 50 μCi) on 10 μg of 30F11 and 20 μCi of radioactivity on various quantities of 30F11 (2, 10 and 40 μg). We also evaluated biodistribution with 20 μCi on various quantities of 30F11.Results: In the biodistribution studies, the highest concentrations of radioactivity were seen in the spleen. The 211At concentrations ranged from 167–417 % injected dose/gram (% ID/g) at 24 h post injection while the 213Bi concentrations ranged from 45–166 % ID/g at 3 h post injection. This result suggested that the longer half-life of 211At might allow higher quantities of labeled mAb to reach the spleen before decay. Importantly, the longer half-life and higher spleen concentrations of 211At resulted in much higher radiation doses to that tissue (e.g. 29,450 cGy/50 mCi 211At administered vs. 1165 cGy/50 mCi 213Bi when 10 mg of mAb was employed). Significant cytopenias were not observed in any of the 213Bi groups. In contrast, lethal and irreversible myelosuppression was observed in the mice receiving 20 μCi 211At on 40 μg of 30F11 and 50 μCi 211At on 10 μg of 30F11 (minimal WBC counts 0.21 x 103 and 0.12 x 103/mm3, Plt counts 1.2 x 104 and 0.3 x 104/mm3, Hb levels 1.5 and 4.2 g/dl, respectively). In the mice receiving 20 μCi 211At on 10 μg of 30F11, significant but reversible pancytopenia was observed, with a nadir of 2 weeks after injection (minimal WBC count 0.45 x 103/mm3, Plt count 3.3 x 104/mm3, Hb level 9.9 g/dl). The pancytopenia resolved at 3 weeks after injection. The second highest concentrations both in 211At studies (18–50% ID/g) and 213Bi studies (19–33%ID/g) were observed in the liver. Reversible but severe acute hepatic toxicity (maximal AST 1329 IU/L and ALT 928 IU/L) occurred 3h after 50 μCi 213Bi but not after 50 μCi 211At injection. This was surprising given the fact that the estimated radiation dose given to liver after 50 mCi 213Bi injection was ~200 cGy whereas the liver dose ranged from 1350–2600 cGy for 50 mCi 211At (depending on the amount of labeled mAb). No significant renal toxicity was observed with either 211At or 213Bi labeled 30F11 during 8 weeks follow-up period.Conclusion: The study results suggest that we may be able to replace low dose TBI in nonmyeloablative conditioning regimens with much lower (mCi) quantities of 211At-labeled anti-CD45 mAb without major non-hematological toxicities compared to the same mAb labeled with 213Bi.

Synthesis of Labeled Compounds Using Recovered Tritium from Expired Beta Light Sources

In this paper, the technological procedures for extracting tritium from beta light source are highlighted. The recovered tritium was used in the synthesis of organically labeled compounds and in the preparation of tritiated water (HTO) with high specific activity. Technological procedures for treatment of beta light sources consist of: envelope breaking into evacuated enclosure, the radioactive gaseous mixture pumping and its storage on metallic sodium.The mixtures of T2 and 3He were used in the synthesis of tritium labeled steroid hormones, nucleosides analogues and for the preparation of HTO with high radioactivity concentrations.

Kinetic brain analysis and whole‐body imaging in monkey of [11C]MNPA: A dopamine agonist radioligand

With a view to future extension of the use of the agonist radioligand [(11)C]MNPA ([O-methyl-(11)C]2-methoxy-N-propylnorapomorphine) from animals to humans, we performed two positron emission tomography (PET) studies in monkeys. First, we assessed the ability to quantify the brain uptake of [(11)C]MNPA with compartmental modeling. Second, we estimated the radiation exposure of [(11)C]MNPA to human subjects based on whole-body imaging in monkeys. Brain PET scans were acquired for 90 min and included concurrent measurements of the plasma concentration of unchanged radioligand. Time-activity data from striatum and cerebellum were quantified with two methods, a reference tissue model and distribution volume. Whole-body PET scans were acquired for 120 min using four bed positions from head to mid thigh. Regions of interest were drawn on compressed planar whole-body images to identify organs with the highest radiation exposures. After injection of [(11)C]MNPA, the highest concentration of radioactivity in brain was in striatum, with lowest levels in cerebellum. Distribution volume was well identified with a two-tissue compartmental model and was quite stable from 60 to 90 min. Whole-body PET scans showed the organ with the highest radiation burden (muSv/MBq) was the urinary bladder wall (26.0), followed by lungs (22.5), gallbladder wall (21.9), and heart wall (16.1). With a 2.4-h voiding interval, the effective dose was 6.4 muSv/MBq (23.5 mrem/mCi). In conclusion, brain uptake of [(11)C]MNPA reflected the density of D(2/3) receptors, quantified relative to serial arterial measurements, and caused moderate to low radiation exposure.

Biodistribution of Radiolabeled Ethanol in Rodents

The biodistribution of [1-(14)C]ethanol in rodents was examined to determine sites of concentration of ethanol or its metabolites that may contribute to its toxicological and pharmacokinetic characteristics. After i.v. administration of [1-(14)C]ethanol in mice, radioactivity showed a widespread distribution among body organs. Determination of the proportion of tissue radioactivity accounted for by volatile [1-(14)C]ethanol versus nonvolatile (14)C metabolites indicated that tissue radioactivity was mostly in the form of the latter, even as early as 5 min after injection, indicating a rapid metabolism of the radiolabeled ethanol to labeled metabolites. In a separate study, radioactivity was imaged using whole-body autoradiography after i.v. administration in rats. High levels of radioactivity were observed in the Harderian gland, preputial gland, and pancreas at 15 and 60 min after injection. High levels of radioactivity were also apparent at the later time point in the intestinal tract, indicating hepatobiliary excretion of radiolabeled metabolites. Moderate levels of radioactivity were present in the liver, lungs, salivary glands, bone marrow, and kidney cortex. In conclusion, after i.v. [(14)C]ethanol administration, radioactivity initially distributes widely among body organs but concentrates in specific tissues at subsequent time points. Especially notable in the current study was the high concentration of radioactivity accumulating in the pancreas. It is thus tempting to speculate that the well documented high incidence of pancreatic disease observed in human chronic alcoholism may be related to a propensity of this organ to accumulate ethanol and/or reactive ethanol metabolites.

Kinetic brain analysis and whole-body imaging in monkey of [ 11C]MNPA, a dopamine agonist radioligand

whole-body biodistribution; kinetic analysis ABSTRACT With a view to future extension of the use of the agonist radioligand ( 11 C)MNPA ((O-methyl- 11 C)2-methoxy-N-propylnorapomorphine) from animals to humans, we performed two positron emission tomography (PET) studies in monkeys. First, we assessed the ability to quantify the brain uptake of ( 11 C)MNPA with com- partmental modeling. Second, we estimated the radiation exposure of ( 11 C)MNPA to human subjects based on whole-body imaging in monkeys. Brain PET scans were acquired for 90 min and included concurrent measurements of the plasma concentra- tion of unchanged radioligand. Time-activity data from striatum and cerebellum were quantified with two methods, a reference tissue model and distribution volume. Whole-body PET scans were acquired for 120 min using four bed positions from head to mid thigh. Regions of interest were drawn on compressed planar whole-body images to identify organs with the highest radiation exposures. After injection of ( 11 C)MNPA, the highest concentration of radioactivity in brain was in striatum, with lowest levels in cerebellum. Distribution volume was well identified with a two-tissue compartmen- tal model and was quite stable from 60 to 90 min. Whole-body PET scans showed the organ with the highest radiation burden (lSv/MBq) was the urinary bladder wall (26.0), followed by lungs (22.5), gallbladder wall (21.9), and heart wall (16.1). With a 2.4-h voiding interval, the effective dose was 6.4 lSv/MBq (23.5 mrem/mCi). In conclu- sion, brain uptake of ( 11 C)MNPA reflected the density of D2/3 receptors, quantified rel- ative to serial arterial measurements, and caused moderate to low radiation exposure.

Absorption, distribution and excretion of the new thienopyridine agent prasugrel in rats

Prasugrel is converted to the pharmacologically active metabolite after oral dosing in vivo. In this study, 14C-prasugrel or prasugrel was administered to rats at a dose of 5 mg kg–1. After oral and intravenous dosing, the values of AUC0–∞ of total radioactivity were 36.2 and 47.1 µg eq. h ml–1, respectively. Oral dosing of unlabeled prasugrel showed the second highest AUC0–8 of the active metabolite of six metabolites analyzed. Quantitative whole body autoradiography showed high radioactivity concentrations in tissues for absorption and excretion at 1 h after oral administration, and were low at 72 h. The excretion of radioactivity in the urine and feces were 20.2% and 78.7%, respectively, after oral dosing. Most radioactivity after oral dosing was excreted in bile (90.1%), which was reabsorbed moderately (62.4%). The results showed that orally administered prasugrel was rapidly and fully absorbed and efficiently converted to the active metabolite with no marked distribution in a particular tissue.

Hybrid gold nanoparticles in molecular imaging and radiotherapy

Metallic nanoparticles, because of their size, chemical and physical properties, are particularly attractive as therapeutic probes in treating cancer. Central to any clinical advances in nanoparticulate based therapy will be to produce hybrid nanoparticles that can be targeted to vascular, extracellular or cell surface receptors. Development of hybrid nanoparticles that specifically target cancer vasculature has received considerable attention. Most cancers have leaky vasculature and the defective vascular architecture, created due to the rapid vascularization necessary to serve fast growing cancers, in combination with poor lymphatic drainage allows increased permeation and retention effects. The leaky vasculature, because of higher porosity and permeability, serve as natural high affinity targets to metallic nanoparticles. Another attractive approach toward the application of nanotechnology to nanomedicine is the utility of nanoparticles that display inherent therapeutic properties. For example radioactive gold nanoparticles present attractive prospects in therapy of cancer. The radioactive properties of Au-198 (βmax = 0.96 MeV; t1/2 = 2.7 d) and Au-199 (βmax = 0.46 MeV; t1/2 = 3.14 d) make them ideal candidates for use in radiotherapeutic applications. In addition, they both have imageable gamma emissions for dosimetry and pharmacokinetic studies and Au-199 can be made carrier-free by indirect methods. Gold nanoparticles are of interest for treatment of disease as they can deliver agents directly into cells and cellular components with a higher concentration of radioactivity, e.g. higher dose of radioactivity, to cancerous tumor cells.

In vitro and in vivo characterization of 177Lu-huA33

The humanized monoclonal antibody A33 (huA33) is a potential targeting agent against colorectal carcinoma since the A33 antigen is highly and homogenously expressed in >95% of all colorectal cancers, both primary tumors and metastases. The aim of this study was to determine the biodistribution and tumor-targeting ability of (177)Lu-labeled huA33. huA33 was labeled with the beta-emitting therapeutic nuclide (177)Lu using the chelator CHX-A"-DTPA, and the properties of the (177)Lu-CHX-A"-huA33 ((177)Lu-huA33) conjugate was determined both in vitro and in vivo in a biodistribution study in nude mice xenografted with colorectal SW1222 tumor cells. The (177)Lu-huA33 conjugate bound specifically to colorectal cancer cells in vitro (with a K(D) value of 2.3+/-0.3 nM, determined by a saturation assay) and in vivo. The tumor uptake of (177)Lu-huA33 was very high, peaking at 134+/-21%ID/g 72 h postinjection (pi). Normal tissue uptake was low; radioactivity concentration in blood (which had the second highest radioactivity concentration) was lower than in tumor at all time points studied (8 h to 10 days). The tumor-to-blood ratio increased with time, reaching 70+/-30, 10 days pi. Throughout the study, the uptake of (177)Lu in bone (known to accumulate free (177)Lu) was low, and the fraction of protein-bound (177)Lu in plasma samples was high (95% to 99%). This indicates high stability of the (177)Lu-huA33 conjugate in vivo. The (177)Lu-huA33 conjugate shows a very favorable biodistribution, with an impressively high tumor uptake and high tumor-to-organ ratios, indicating that the conjugate may be suitable for radioimmunotherapy of colorectal cancer.

Level of natural radionuclides in foodstuffs and resultant annual ingestion radiation dose

The natural radioactivities in three major groups of foodstuff widely consumed in Upper Egypt were determined. The specific activities of 226Ra, 232Th, and 40K in cereals, leguminosae, and flour were measured using γ-ray spectroscopy. Another group of hay, water, and soil samples from the same location were also analyzed. Hay samples were found to contain the highest radioactivity concentration among all the samples that were investigated. This increment could be due to the high water content in the shoots which tends to accumulate soluble radionuclides. The average calculated concentrations of soil samples in the present study exhibits the lowest values with respect to those from different countries. In the case of water samples, the average activities of both 232Th and 40K were similar to those for soil while 226Ra was twice that of water sample. The annual ingestion dose from each radionuclide was calculated. The computed annual dose owing to daily intake of radium, thorium, and potassium via wheat flour, lentils, and bean in the present study (214.8 μSv) is ten times lower than the global average annual radiation dose (2400 μSv) from the natural radiation sources as proposed by UNSCEAR. The obtained results show that the dose values are quite low and carry insignificant radiation dose to the public.

Effects of Cell-Permeating Peptide Binding on the Distribution of 125I-Labeled Fab Fragment in Rats

The peptides comprising the sequence of HIV-1 Tat protein (positions 48-60), Antennapedia (positions 43-58), and HIV-1 Rev protein (positions 34-50) are known to be cell-permeating. In this study, we examined how the distribution of Fab fragments in rats is affected by conjugation with these peptides. Fab fragment was iodinated by a chloramine-T method and then chemically conjugated with cell-permeating peptide. The complex of 125I-Fab and cell-permeating peptide was administered to male rats intravenously at a dose of 1 mg/kg, and whole-body autoradiography was performed at 4 and 24 h after administration. The patterns of distribution of 125I-Fab exhibited remarkable variation depending on the cell-permeating peptide used. In particular, at 4 h, high concentrations of radioactivity were observed in the spleen, adrenal gland, renal medulla, and liver with Rev peptide-Fab complex, in the liver and spleen with Tat peptide-Fab complex, and in the spleen, adrenal gland, and liver with Antennapedia peptide-Fab complex. Even at 24 h, high concentrations of radioactivity were still observed in the spleen and renal medulla of rat with Rev peptide-Fab complex, and in the spleen and renal cortex of rat with Antennapedia peptide-Fab complex. These findings demonstrate that the patterns of distribution of peptide-125I-Fab complexes can be modulated by selection of cell-penetrating peptides. Moreover, the patterns of retention of peptide-125I-Fab complexes in internal organs also differed at 24 h after administration. These findings provide valuable information for the development of novel antibody pharmaceuticals and therapeutic systems.

Metabolism and disposition of juglone in male F344 rats

The metabolism and disposition of 14C-labelled juglone in male F344 rats following oral, intravenous and dermal administration were studied. Approximately 40–50% of an oral dose (0.1 to 10 mg kg−1) and less than 20% of the dermal dose (4 mg kg−1) were absorbed within 24 h. Most of the oral dose was excreted in faeces and urine within 24 h and only 1–3% remained in the tissues. High concentrations of juglone-derived radioactivity were found in kidney for all three dosing routes. The accumulation in kidney can be attributed to covalent binding of juglone and/or metabolites to cytosolic protein. Five metabolites were identified in the urine of rats treated with an oral dose: 1,4,5-trihydroxynaphthalene di-glucuronide, 1,4,5-trihydroxynaphthalene mono-glucuronide mono-sulfate, 2-sulfo-2,3-dihydrojuglone, 4,8-dihydroxy-1-tetralone mono-glucuronide and 1,4,5-trihydroxynaphthalene mono-glucuronide. Liver microsomal incubations of juglone in the presence of NAD(P)H and UDP-glucuronic acid gave rise to two 1,4,5-trihydroxynaphthalene mono-glucuronides.

NC100668, A NEW TRACER FOR IMAGING OF VENOUS THROMBOEMBOLISM: DISPOSITION AND METABOLISM IN RATS

The 99mTc-complex of NC100668 [Acetyl-Asn-Gln-Glu-Gln-Val-Ser-Pro-Tyr(3-iodo)-Thr-Leu-Leu-Lys-Gly-NC100194] is being evaluated for nuclear medical imaging of venous thromboembolism. NC100668 is a 13-amino acid peptide with a Tc-binding chelator [NC100194; -NH-CH2-CH2-N(CH2-CH2-NH-C(CH3)2-C(CH3)=N-OH)2] linked to the C-terminal end. Following injection in rats of [Asn-U-14C]NC100668 (labeling of the N-terminal amino acid), approximately 70% of the radioactivity was recovered in urine within 3 days. Following injection of [Lys-U-14C]NC100668 (labeling close to the C-terminal amino acid), radioactivity was cleared more slowly, with only 8% recovered in urine and approximately 80% of the radioactivity present in the body after 3 days. The highest concentration of radioactivity in the body following injection of [Lys-U-14C]NC100668 was observed in the kidney inner cortex; this probably represents 14C-labeled Lys, which is reabsorbed in the kidney tubules and incorporated into protein metabolism. Metabolite profiling by high-performance liquid chromatography with radiochemical detection revealed that following injection of [Asn-U-14C]NC100668, there is a rapid appearance in blood of one peak containing radioactive metabolite(s) originating from the N-terminal part of the molecule. In urine samples, only this radioactive peak was observed with no intact NC100668 remaining; this very hydrophilic N-terminal metabolite was probably either the N-terminal amino acid or a very short peptide. Liquid chromatography-mass spectrometry analyses of rat urine samples obtained after injection of nonlabeled NC100668 confirmed the identity of two metabolites generated from the C-terminal end of the molecule; Gly-NC100194 was identified as the major of these metabolites and NC100194 as a minor metabolite present at approximately one-tenth the amount of Gly-NC100194. No other metabolites were identified.

Carbidopa pretreatment improves image interpretation and visualisation of carcinoid tumours with 11C-5-hydroxytryptophan positron emission tomography

Positron emission tomography (PET) with 11C-5-hydroxytryptophan (5-HTP) as tracer is a promising imaging instrument in the management of patients with neuroendocrine tumours (NETs). However, high radioactivity concentrations in the urinary collecting system sometimes produce image reconstruction artefacts that can make detection of small NETs difficult. As a means to decrease urinary excretion of radioactivity and thereby improve image quality, we examined the effect of pretreatment with carbidopa (CD), a peripheral inhibitor of aromatic amino acid decarboxylase (AADC), which converts 5-HTP to serotonin (5-hydroxytryptamine, 5-HT). Six patients with midgut carcinoid metastases were examined with 11C-5-HTP PET before and 1 h after oral administration of 100 or 200 mg of CD. There was a fourfold significant reduction of tracer uptake in the urinary collecting system after CD administration (p=0.0277, n=6), with a mean standard uptake value (SUV) of 155+/-195 before CD and 39+/-14 after CD. In tumour lesions there was a significant increase in SUV after CD administration (p<0. 0001, n=18), with a mean SUV of 11+/-3 before CD and 14+/-3 after CD. There was no difference between the doses (100 and 200 mg) of CD in this respect. In all patients, image interpretation and tumour detection were markedly improved after CD administration. We conclude that CD premedication improves 11C-5-HTP PET image quality and facilitates detection of NET lesions. Because of the similarity of metabolic pathways, this method could probably be applied to improve PET imaging using other tracers like 18F-DOPA and 11C-DOPA.

Conjugation to Polyethylene Glycol Polymer Promotes Aptamer Biodistribution to Healthy and Inflamed Tissues

Here, we examine biodistribution of radiolabeled aptamers and assess the relative ability of different stabilized aptamer compositions (mixed 2'-F/2'-O-Me; fully 2'-O-Me modified) to access inflamed tissues in a murine inflammation model. Biodistribution of 3H-labeled aptamers, including pegylated and unpegylated compositions, was assessed 3 hours postadministration using quantitative whole body autoradiography (QWBA). Aptamer penetration of cells in kidney and liver was also examined at a qualitative level by microautoradiography. To evaluate aptamer distribution to diseased tissues, inflammation was induced locally in animal hind limbs by treatment with carrageenan just prior to aptamer dosing. Aptamer compositions examined exhibited significant variation in distribution levels among organs and tissues. Highest concentrations of radioactivity in whole body tissues for all animals were observed in the kidney and urinary bladder contents. Relatively little radioactivity was associated with brain, spinal cord, and adipose tissue. Overall, the total level of radioactivity in whole body tissues was significantly higher for a 20-kDa PEG conjugate than for other aptamers. Comparatively high levels of the 20-kDa conjugate were seen in well-perfused organs and tissues, including liver, lungs, spleen, bone marrow, and myocardium. A fully 2'-O-Me composition aptamer had the lowest level of radioactivity in whole body tissues but distributed to higher concentrations in the gastrointestinal tract contents relative to other aptamers. Interestingly, the 20-kDa PEG-conjugated aptamer showed significantly higher levels of distribution to inflamed paw tissues than did either unconjugated or fully 2'-O-Me-modified aptamers.

Synthesis, in vitro binding and biodistribution in B16 melanoma-bearing mice of new iodine-125 spermidine benzamide derivatives

In the course of our investigations aimed at improving the biological characteristics of iodobenzamides for melanoma therapeutic applications, four new derivatives containing a spermidine chain have been prepared and radiolabeled with 125I. In vitro studies showed that all compounds displayed high affinity for melanin superior to the reference compound BZA, thus validating our experimental approach. In vivo biodistribution was investigated in B16 melanoma-bearing mice. All four compounds, particularly benzamide 3, showed accumulation in the tumor, but lower, however, than that of BZA. Moreover, high concentrations of radioactivity in other organs, namely, the liver and lung, demonstrated nonspecific tumoral uptake. In view of these results, compounds 1 2 3 4 do not appear to be suitable radiopharmaceuticals for melanoma radionuclide therapy.