Preparation,radiolabeling and biodistribution of a new class of bisaminothiol (BAT) ligands as possible imaging agents

In developing new ligands as potential brain and heart perfusion imaging agents two ligands based upon N₂S₂ donor atoms with the biphenyl backbone were synthesized. Biphenyl-2,2′-bis(N-1-amino-2-methyl-propane-2-thiol) (BP-BAT-TM) and biphenyl-2,2′-bis(N-1-amino-2-ethyl-butane-2-thiol) (BP-BAT-TE) form stable, neutral and lipid soluble complexes with [^99mTc]pertechnetate in the presence of tin(II) tartarate as a reducing agent. The [^99mTc]BP-BAT-TM complex penetrates the blood-brain barrier following i.v. injection into rats. Washout from the brain is fast, indicating no retention. The biodistribution of [^99mTc]BP-BAT-TE in rats showed an intitial heart uptake (0.8% /organ, at 2 min) and a slow washout (0.74% at 15 min). No brain uptake was found (0.05%). Significant uptake and retention in liver was observed. An imaging study of [^99mTc]BP-BAT-TE in a monkey showed no brain uptake and a clear indication of liver uptake and gall bladder clearance. These results indicate that this ligand system may be suitable as the basic core structure for the development of new imaging agents. Further studies with structural variations in the biphenyl backbone are warranted to develop new ^99mTc imaging agents for clinical applications.     

Synthesis,characterization and biodistribution of tris(β-diketonato)technetium(III) complexes

New tris(β-diketonato) complexes of trivalent ⁹⁹Tc/^99mTc with the ligands hexane-2,4-dione, heptane-2,4-dione, heptane-3,5-dione, and octane-3,5-dione were synthesized by reduction of pertechnetate with dithionite in the presence of excess β-diketone. The complexes were purified by HPLC, identified by elemental analysis and FAB mass spectrometry, and characterized by vis./u.v./i.r. spectrophotometry. The hexane-2,4-dionato complex crystallizes in the monoclinic space group P2₁/c, isostructurally with pentane-2,4-dionatotechnetium(III). Biodistribution measurements in mice showed the neutral and lipophilic ^99mTc-diketonato complexes to penetrate the blood-brain barrier. However, increasing lipophilicity decreased the brain uptake except for the heptane-2,4-dionato complex, which displayed the highest uptake of 0.82% injected dose/g.     

Lung scintigraphy with [123I]IMP in patients with pulmonary tuberculosis

Lung scintigraphy using N-isopropyl-p-[¹²³I]iodoamphetamine (IMP) was performed on 26 patients with pulmonary tuberculosis. Early (5 min after injection) and late images (4 h after injection) were obtained with a large-field γ-camera equipped with a digital computer. Lung scintigraphy using [^99mTc]MAA (MAA) was also done. Although early IMP images showed the same findings as [^99mTc]MAA images, a discrepancy between delayed IMP images and [^99mTc]MAA images was seen in some patients. Increment of activities seen in late images was demonstrated in most patients whose chest x-ray findings included exudative inflammatory changes. Uptake and clearance of IMP was considered to be affected by the active phase of pulmonary tuberculosis.     

99mTc- and Re-labeled 6-dialkylamino-2-naphthylethylidene derivatives as imaging probes for β-amyloid plaques

Based on the conjugate strategy, two neutral ^99mTc labeled 2-(1-(6-(dialkylamino)naphthalen-2-yl)ethylidene)malononitrile (DDNP) and 1-(6-(dialkylamino)naphthalen-2-yl)ethanone (ENE) derivatives, and their corresponding rhenium complexes were synthesized. In vitro fluorescent staining indicated that the corresponding rhenium derivatives selectively stained the β-amyloid (Aβ) plaques in the brain sections of AD model mice with low background. Compared with FDDNP and FENE, the affinities of the corresponding rhenium derivatives to Aβ aggregates decreased about 10-14-fold. In vivo biodistribution experiments in normal mice showed that ^99mTc-MAMA-ENE displayed medium initial brain uptake (0.65 %ID/g at 2 min) with a reasonable washout from the brain (0.19 %ID/g at 2 h) while ^99mTc-MAMA-DDNP showed a low brain uptake (0.28 %ID/g at 2 min). Further optimize these ^99mTc-labeled tracers in order to improve their binding affinities to Aβ plaques and diffusion through the blood brain barrier may generate useful imaging agents for SPECT.     

Impact of functionalized coligands on the pharmacokinetics of 99mTcIII '4+1' mixed-ligand complexes conjugated to bombesin

Bombesins (BN) containing ^99mTc ‘4 + 1’ complexes may be useful to detect tumors expressing the gastrin-releasing peptide receptor (GRPR). Derivatives of the formula [^99mTc(NS₃R)(L2-BN_st)] were synthesized, in which Tc(III) is coordinated by an isocyanide L2-BN_st bearing the peptide (BN_st = βAla-βAla-Gln-Trp-Ala-Val-Gly-His-Cha-Nle-NH₂) and a tetradentate chelator NS₃R. NS₃R consists of 2,2′,2″-nitrilotriethanethiol (NS₃) bearing a crown ether (NS₃crown), an aliphatic amine (NS₃en) and a tricarboxylic acid (NS₃(COOH)₃). Non-radioactive Re compounds were prepared and analysed by electrospray ionization mass spectrometry. The structural similarity to the ^99mTc conjugates was demonstrated by their identical HPLC elution profiles. The lipophilicity of [^99mTc(NS₃R)(L2-BN_st)] decreased depending on the coligands NS₃crown (log D_O/W, pH = 7.4, 0.98 ± 0.11), NS₃en (− 0.49 ± 0.07) and NS₃(COOH)₃ (− 2.01 ± 0.09). Biodistribution in normal rats was characterized by an increasing kidney uptake and a decreasing uptake into the liver corresponding to the reduced lipophilicity of the conjugates. The pancreatic uptake expressed by the organ/blood ratio of standardized uptake values at 60 min p.i. in rats was 8.6 ± 1.2 for [^99mTc(NS₃en)(L2-BN_st)] and higher compared to the other conjugates. The pancreas/liver ratio of the SUV at 60 min p.i. in rats was highest for [^99mTc(NS₃(COOH)₃)(L2-BN_st)] at 8.4 ± 1.3. [^99mTc(NS₃en)(L2-BN_st)] was further studied in tumor-bearing mice and its pancreas/blood and pancreas/liver ratios were lower, however the pancreas/kidney ratios were higher in mice compared to rats. The activity uptake of [^99mTc(NS₃en)(L2-BN_st)] into the PC-3 tumor xenografts was low (%ID/g: 0.83 ± 0.18 at 60 min; SUV: 0.21 ± 0.05 at 60 min) but specific.     

Synthesis,characterization and biodistribution of neutral and lipid-soluble 99mTc-PAT-HM and 99mTc-TMR for brain imaging

Two new ligand systems for complexation with ^99mTc were prepared. The two analogs of bisaminoethanethiol (BAT): N,N′-bis(2-methyl-2-mercaptopropyl)-2,2-dimethylpropylenediamine (PAT-HM) and N,N′-bis[2-(2-ethyl-1-mercaptopropyl)] ethylenediamine (TMR), form neutral and lipid soluble complexes with ^99mTc that readily penetrate the blood-brain barrier following i.v. injection into rats. Although the ^99mTc chelates do not display the prolonged brain retention required for use in single photon emission computed tomographic imaging studies, the fact that each ligand forms a neutral and lipid-soluble complex of high chemical stability when coordinated with ^99mTc warrants further investigation to increase the site- and organ-specificity of these agents.     

Control of the carcinogenic potential of 99mTechnetium by the immunologic hormone lymphotoxin

Summary Immunologic prevention of the carcinogenicity of the diagnostic gamma-emitting radionuclide ^99mTechnetium (^99mTc) by lymphotoxin was evaluated using an in vivo-in vitro assay of carcinogenesis. Pregnant Syrian golden hamsters received 125–2,300 Ci ^99mTc/kg body weight by injection, and 7 days later colonies of morphologically transformed cells were quantitated in vitro. The transformation frequency increased directly with the radionuclide concentration, and cells derived from transformed colonies produced tumors in athymic nude mice. The total absorbed ^99mTc dose was 0.20 rad following injection of 250 Ci ^99mTc/kg hamster body weight; this compares with an exposure of 0.13 rad following injection of 143 Ci ^99mTc/kg body weight in humans. Intravenous injection of purified hamster lymphotoxin immediately after ^99mTc caused a dose-dependent reduction in the transformation frequency. Transformation was essentially completely prevented (97%) by injection of 8,000 U of lymphotoxin. Thus, the immune system, through the action of lymphotoxin, has the potential to prevent carcinogenesis induced by gamma-radiation from ^99mTc. This emphasizes the importance of considering the recipient's immune and other homeostatic mechanisms as part of a complete diagnostic or therapeutic gamma-radiation regimen.     

Effect of alterations in erythropoiesis on distribution of 99mTc sulfur colloid in the rat

The distribution of ^99mTc sulfur colloid and ⁵⁹Fe was assessed in rats following long or short term stimulation or suppression of erythropoiesis. Acute stimulation of erythropoiesis did not alter ^99mTc sulfur colloid distribution, whereas, long term stimulation resulted in increased marrow colloid uptake. Suppression of erythropoiesis by hypoxia-induced plethora or hypertransfusion did not alter the marrow uptake of ^99mTc sulfur colloid. ^99mTc sulfur colloid blood clearance was not altered by any of the experimental conditions utilized. These observations suggest that marrow RE activity as assessed by ^99mTc sulfur colloid uptake increases with erythropoietic stimulation and varies with the duration and intensity of the stimulus.     

99mTc(Cu)—mannitol complex: a new agent for dynamic renal function studies

Mannitol has been labelled with ^99mTc by using cuprous chloride as a reducing agent. Blood and kidney clearance of ^99mTc(Cu)-mannitol was slightly faster than that of ^99mTc(Sn)-DTPA in rat and maximum radioactivity ratio of kidneys to blood was 84.6 at 5 min. A comparative study of ^99mTc(Cu)-mannitol, ^99mTc(Sn)-DTPA was made in rabbits by taking serial images of kidneys and bladder with a γ camera. Results show superiority of ^99mTc(Cu)-mannitol over other agents for dynamic renal function studies.     

99mTc(N)-DBODC(5), a potential radiolabeled probe for SPECT of multidrug resistance: in vitro study

[^99mTc(N)(DBODC)(PNP5)]⁺ [DBODC is bis(N-ethoxyethyl)dithiocarbamato; PNP5 is bis(dimethoxypropylphosphinoethyl)ethoxyethylamine], abbreviated as ^99mTc(N)-DBODC(5), is a lipophilic cationic mixed compound investigated as a myocardial imaging agent. The findings that this tracer accumulates in mitochondrial structures through a mechanism mediated by the negative mitochondrial membrane potential and that the rapid efflux of ^99mTc(N)-DBODC(5) from nontarget tissues seems to be associated with the multidrug resistance (MDR) P-glycoprotein (P-gp) transport function open up the possibility to extend its clinical applications to tumor imaging and noninvasive MDR studies. The rate of uptake at 4 and 37 °C of ^99mTc(N)-DBODC(5) was evaluated in vitro in selected human cancer cell lines and in the corresponding sublines before and after P-gp and/or MDR-associated protein (MRP) modulator/inhibitor treatment using ^99mTc-sestamibi as a reference. The results indicated that (1) the uptake of both ^99mTc(N)-DBODC(5) and ^99mTc-sestamibi is correlated to metabolic activity of the cells and (2) the cellular accumulation is connected to the level of P-gp/MRP expression; in fact, an enhancement of uptake in resistant cells was observed after treatment with opportune MDR inhibitor/modulator, indicating that the selective blockade of P-gp/MRP prevented efflux of the tracers. This study provides a preliminary indication of the applicability of ^99mTc(N)-DBODC(5) in tumor imaging and in detecting P-gp/MRP-mediated drug resistance in human cancer. In addition, the possibility to control the hydrophobicity and pharmacological activity of this heterocomplex through the variation of the substituents on the ligands backbone without affecting the P₂S₂ coordinating sphere makes ^99mTc(N)-DBODC(5) a suitable scaffold for the preparation of a molecular probe for single photon emission computed tomography of MDR.     

Technetium-99m p-iodophenethyldiaminodithiol (DADT-IPE): Potential brain perfusion imaging agent for SPECT

A new ligand, an N-p-iodophenethyl diaminodithiol (DADT-IPE), an anlog of N-isopropyl-p-iodoamphetamine (IMP), was synthesized and subsequently complexed with ^99mTc, using stannous chloride as a reducing agent. Two complexes (a and b) were separated from ^99mTc-DADT-IPE by high performance liquid chromatography (HPLC). Competitive inhibition studies showed that the IC₅₀ value of DADT-IPE (70 μM) was similar to that of IMP (49 μM). Biodistribution studies of one of the complexes [^99mTc-DADT-IPE(a)] in rats showed that 0.65% of the injected dose of the tracer remained in the brain at 5 min after intravenous injection, with 0.53% of the dose remaining in the brain at 60 min post-injection, whereas the corresponding values for the other complex [^99mTc-DADT-IPE(b)] were 0.34% dose in the brain at 5 min and 0.28% dose in the brain at 60 min post-injection. The half-life for clearance of ^99mTc-DADT-IPE(a) from rat brain was found to be more than 5 h. These results suggested that ^99mTc-DADT-IPE(a) has characteristics which are suitable for cerebral perfusion imaging.     

Synthesis and biological evaluation of a novel 99mTc(CO)3 complex of ciprofloxacin dithiocarbamate as a potential agent to target infection

The ciprofloxacin dithiocarbamate (CPFXDTC) was radiolabeled with [^99mTc(CO)₃(H₂O)₃]⁺ intermediate to form the ^99mTc(CO)₃–CPFXDTC complex in high yield. The ^99mTc(CO)₃–CPFXDTC complex was characterized by HPLC and its stability in serum was studied. Its partition coefficient indicated that it was a lipophilic complex. The bacterial binding efficiency of ^99mTc(CO)₃–CPFXDTC was almost the same as that of ^99mTcN–CPFXDTC, and was higher than that of ^99mTc–ciprofloxacin. Biodistribution results in induced infection mice showed ^99mTc(CO)₃–CPFXDTC had higher uptake at the sites of infection and better abscess/blood and abscess/muscle ratios than those of ^99mTc–ciprofloxacin and ^99mTcN–CPFXDTC. Single photon emission computed tomography (SPECT) static imaging study in infected rabbits demonstrated the uptake in the left thigh infection lesion was observable, while no accumulation in the right thigh muscle was found. These results suggested ^99mTc(CO)₃–CPFXDTC would be a promising candidate for further evaluation as infection imaging agent.     

Synthesis and evaluation of 99mTc–2-[(3-carboxy-1-oxopropyl)amino]-2-deoxy-d-glucose as a potential tumor imaging agent

The 2-[(3-carboxy-1-oxopropyl)amino]-2-deoxy-d-glucose (CPADG) was synthesized and radiolabeled with ^99mTcO₄⁻ to obtain the ^99mTc–CPADG complex in high yield. It was stable over 6 h in saline at room temperature and in serum at 37 °C. The partition coefficient and electrophoresis results indicated that the complex was hydrophilic and cationic. In vitro cell studies showed there was an increase in the uptake of ^99mTc–CPADG as a function of incubation time and ^99mTc–CPADG was possibly transported via the glucose transporters. The biodistribution of ^99mTc–CPADG in mice bearing S 180 tumor showed that the complex accumulated in the tumor with high uptake and good retention. The tumor/blood and tumor/muscle ratios increased with time and reached 1.91 and 5.05 at 4 h post-injection. Single photon emission computed tomography (SPECT) image studies showed there was an obvious accumulation in tumor sites, suggesting ^99mTc–CPADG would be a promising candidate for tumor imaging.     

Synthesis and evaluation of technetium-99m monocationic mixed ligand complexes of phenyl substituted/condensed tetradentate schiff's bases and trimethylphosphine

Tc-99m monocationic mixed ligand complexes of phenyl substituted/condensed Schiff's bases, N,N′-ethylene-bis-(benzoylacetone imine) (L_b) or N,N′-ethylene-bis-(salicylaldehyde imine) (L_c) or N,N′-ethylene-bis-(2-hydroxyacetophenone imine) (L_d) and trimethylphosphine were synthesized to determine the influence of the presence of a phenyl group in these tracers on their heart uptake in rats. A new formulation procedure using aq. β-hydroxypropylcyclodextrin (HPB) solution was developed for intravenous administration of nonpolar ^99mTc complexes. Comparison of biodistribution data for the reference ^99mTc complex from N,N′-ethylene-bis-(acetylacetone imine) and trimethylphosphine using HPB formulation and alternate formulation (0.9% saline) showed the same results. Biodistribution of the title ^99mTc complexes, [^99mTc L_b (PMe₃)₂]⁺, [^99mTc L_c (PMe₃)₂]⁺ and [^99mTc L_d (PMe₃)₂]⁺ showed heart-to-blood activity ratios of 1.7, 2.1 and 1.7, respectively, at 15 min post-injection in rats.     

99mTc-tricarbonyl labeled agents for cell labeling: Development,biodistribution in normal mice and preliminary in vitro evaluation

We have developed four ^99mTc(CO)₃-labeled lipophilic tracers as potential radiolabeling agents for cells based on a hexadecyl tail. ^99mTc(CO)₃-hexadecylamino-N,N′-diacetic acid (negatively charged), ^99mTc(CO)₃-hexadecylamino-N-α-picolyl-N′-acetic acid (uncharged), ^99mTc(CO)₃-N,N′-dipicolylhexadecylamine (positively charged), ^99mTc(CO)₃-N-hexadecylaminoethyl-N′-aminoethylamine (positively charged) were prepared in a radiolabeling yield: >90%. Preliminary cell uptake studies were performed in mixed blood cells with or without plasma and were compared with ^99mTc-d,l-HMPAO and [¹⁸F]FDG. In plasma-free blood cells, maximum uptake (78%) was obtained for ^99mTc(CO)₃-N-hexadecylaminoethyl-N′-aminoethylamine after 60 min incubation (compared to 55% and 23% for ^99mTc-d,l-HMPAO and [¹⁸F]FDG, respectively) while in plasma-rich medium, ^99mTc(CO)₃-N,N′-dipicolylhexadecylamine was best bound (54%, similar to the binding of ^99mTc-d,l-HMPAO). Biodistribution in normal mice showed mainly hepatobiliary clearance of the agents and initial high lung uptake. The radiolabeled compounds showed good blood clearance with maximally 7.9% injected dose per gram at 60 min post injection. While the least lipophilic agent (^99mTc(CO)₃-N,N′-dipicolylhexadecylamine, log P = 1.3) showed the best cell uptake, there appears to be no direct correlation between lipophilicity and tracer uptake in mixed blood cells. In view of its comparable cell uptake to well known cell labeling agent ^99mTc-d,l-HMPAO, ^99mTc(CO)₃-N,N′-dipicolylhexadecylamine merits further evaluation as a potential cell labeling agent.     

Kinetic Analysis of Leucine-Enkephalin Cellular Uptake at the Luminal Side of the Blood-Brain Barrier of an In Situ Perfused Guinea-Pig Brain

Abstract: The uptake of enkephalin-(5-L-leucine) (Leu-en-kephalin) at the luminal side of the blood-brain barrier was measured by means of an in situ vascular brain perfusion technique in the anaesthetized guinea pig. This method allows measurements of cerebrovascular peptide uptake over periods of up to 20 min, and excludes the solute under study from the general circulation and systemic metabolic influences. A capillary unidirectional transfer constant, K_in, for [tyrosyl-3,5-³H]Leu-enkephalin was estimated graphically from the multiple-time brain uptake data in the presence of different concentrations of unlabelled peptide, and dose-dependent self-inhibition was demonstrated. Analysis of unidirectional influx of blood-borne Leu-en kephalin into the brain revealed Michaelis-Menten saturation kinetics in the parietal cortex, caudate nucleus, and hippocampus, with V_max between 0.14 and 0.16 nmol min^?1 g^?1 and K_m ranging from 34 to 41 μM, for the saturable component, whereas the estimated diffusion constant, K_d, was not significantly different from zero. Entry of [³H]Leu-enkephalin was not inhibited in the presence of either a 5 mM concentration of unlabelled L-tyrosine, tyro-sylglycine, and tyrosylglycylglycine, or aminopeptidase inhibitor, bestatin (0.5 mM), suggesting that the saturable mechanism of the tracer at the luminal side of the blood-brain barrier does not involve uptake of the peptide's N-terminal amino acid and/or its tyrosine-containing fragments. The specific δ-opioid antagonist, allyl²-Tyr-AIB-Phe-OH, and μ-opioid receptor agonist, Tyr-D-Ala-Gly-Me-Phe-NH(CH₂)20H, at concentrations in the perfusate above the K_m value for the saturable transport of Leu-enkephalin, did not affect significantly uptake of [³H]Leu-enkephalin. The present study provides, for the first time, a characterization of the kinetic parameters of the unidirectional uptake of a peptide from the luminal side of the blood-brain barrier     

Technetium-99m in the Diagnosis of Thyrotoxicosis

The thyroid uptake at 20 minutes of intravenously administered Technetium-99^m (^99mTc) was measured in 117 patients with a standard scintillation counter. Patients were divided into three groups on the basis of clinical assessment, four-hour ¹³¹I uptake, triiodothyronine (T-3) resin uptake, and protein-bound iodine measurements.In 31 patients with no evidence of thyroid disease the mean ^99m Tc uptake was 1·8% ±S.D. 1·1%. In 32 patients with thyroid enlargement who were euthyroid the mean uptake was 2·5% ±S.D. 2·2%. In 54 thyrotoxic patients the mean uptake was 17·7% with a range of 4·1 to 44%, all cases having an uptake above the upper limit of normal (4·0%). These results agree closely with reported uptake studies using scanning techniques. In seven patients the extrathyroidal neck activity was measured by using a scanner, and the mean was 6·3% of the extrathyroidal total body radioactivity comparing favourably with an assumed 6% used in our calculations.We have shown that the measurement of the thyroid uptake of ^99mTc with a scintillation counter is of value, and that it is not necessary to use scanning techniques in the diagnosis of thyrotoxicosis. Advantages of ^99m Tc are minimal radiation, reduction in patient and laboratory time, and low cost.     

Tetraamine‐modified octreotide and octreotate: labeling with 99mTc and preclinical comparison in AR4‐2J cells and AR4‐2J tumor‐bearing mice

Two somatostatin analogues, [^99mTc]Demotide and [^99mTc]Demotate 4, were compared with [^99mTc]Demotate 1, a previously reported somatostatin receptor subtype 2 (sst₂) targeting tracer. Conjugates were prepared by coupling an open‐chain tetraamine chelator to D ‐Phe¹ of [Tyr³]‐octreotide or [Tyr³]‐octreotate, respectively, via a p‐benzylaminodiglycolic acid spacer adopting solid‐phase peptide synthesis techniques. Peptide conjugates were collected in a highly pure form after chromatographic purification. Eventually, [^99mTc]Demotide and [^99mTc]Demotate 4 were obtained in ～1 Ci/µmol specific activity and >96% purity after labeling under alkaline conditions. Demotide and Demotate 4 exhibited similar high binding affinities for the sst₂ expressed in AR4‐2J cells with IC₅₀ values 0.16 and 0.10 nM, respectively. The (radio)metallated analogues [^99mTc]Demotide and [^99mTc]Demotate 4 showed equally high affinities to the sst₂ during saturation binding assays in AR4‐2J cell membranes (K_ds 0.08 and 0.07 nM, respectively). During incubation at 37 °C with AR4‐2J cells, the radiopeptides internalized effectively via a receptor‐mediated process, with [^99mTc]Demotate 4 exhibiting a faster internalization rate than [^99mTc]Demotide. After injection in athymic mice bearing sst₂‐expressing AR4‐2J tumors, the radiotracers showed high and specific uptake in the tumor (>25%ID/g at 1 h) and in the sst₂–positive organs. However, both [^99mTc]Demotide and [^99mTc]Demotate 4 showed unfavorably higher background activity, especially in the abdomen, in comparison to [^99mTc]Demotate 1 and are, therefore, less suited than [^99mTc]Demotate 1 for sst₂‐targeted tumor imaging in man. Copyright © 2005 European Peptide Society and John Wiley & Sons, Ltd.     

Metastatic melanoma imaging using a novel Tc-99m-labeled lactam-cyclized alpha-MSH peptide

The purpose of this study was to determine the metastatic melanoma imaging property of ^99mTc(EDDA)-HYNIC-Aoc-Nle-CycMSH_hex {hydrazinonicotinamide-8-aminooctanoic acid-Nle-c[Asp-His-DPhe-Arg-Trp-Lys]-CONH₂}. HYNIC-Aoc-Nle-CycMSH_hex was synthesized using fluorenylmethyloxy carbonyl (Fmoc) chemistry. The IC₅₀ value of HYNIC-Aoc-Nle-CycMSH_hex was 0.78?±?0.13?nM for B16/F10 melanoma cells. ^99mTc(EDDA)-HYNIC-Aoc-Nle-CycMSH_hex displayed significantly higher uptake (14.26?±?2.74 and 10.45?±?2.31%?ID/g) in B16/F10 metastatic melanoma-bearing lung than that in normal lung (0.90?±?0.15 and 0.53?±?0.14%?ID/g) at 2 and 4?h post-injection, respectively. B16/F10 pulmonary metastatic melanoma lesions were clearly visualized by SPECT/CT using ^99mTc(EDDA)-HYNIC-Aoc-Nle-CycMSH_hex as an imaging probe at 2?h post-injection, underscoring its potential as an imaging probe for metastatic melanoma detection.     

Synthesis and biological evaluation of novel technetium-99m labeled phenylbenzoxazole derivatives as potential imaging probes for β-amyloid plaques in brain

Two uncharged (99m)Tc-labeled phenylbenzoxazole derivatives were biologically evaluated as potential imaging probes for β-amyloid plaques. The (99m)Tc and corresponding rhenium complexes were synthesized by coupling monoamine-monoamide dithiol (MAMA) and bis(aminoethanethiol) (BAT) chelating ligand via a pentyloxy spacer to phenylbenzoxazole. The fluorescent rhenium complexes 6 and 9 selectively stainined the β-amyloid plaques on the sections of transgenic mouse, and showed high affinity for Aβ((1-42)) aggregates (K(i)=11.1 nM and 14.3 nM, respectively). Autoradiography in vitro indicated that [(99m)Tc]6 clearly labeled β-amyloid plaques on the sections of transgenic mouse. Biodistribution experiments in normal mice revealed that [(99m)Tc]6 displayed moderate initial brain uptake (0.81% ID/g at 2 min), and quickly washed out from the brain (0.25% ID/g at 60 min). The preliminary results indicate that the properties of [(99m)Tc]6 are promising, although additional refinements are needed to improve the ability to cross the blood-brain barrier.