Self-assembling supramolecular dendrimer nanosystem for PET imaging of tumors.

Bioimaging plays an important role in cancer diagnosis and treatment. However, imaging sensitivity and specificity still constitute key challenges. Nanotechnology-based imaging is particularly promising for overcoming these limitations because nanosized imaging agents can specifically home in on tumors via the "enhanced permeation and retention" (EPR) effect, thus resulting in enhanced imaging sensitivity and specificity. Here, we report an original nanosystem for positron emission tomography (PET) imaging based on an amphiphilic dendrimer, which bears multiple PET reporting units at the terminals. This dendrimer is able to self-assemble into small and uniform nanomicelles, which accumulate in tumors for effective PET imaging. Benefiting from the combined dendrimeric multivalence and EPR-mediated passive tumor targeting, this nanosystem demonstrates superior imaging sensitivity and specificity, with up to 14-fold increased PET signal ratios compared with the clinical gold reference 2-fluorodeoxyglucose ([18F]FDG). Most importantly, this dendrimer system can detect imaging-refractory low-glucose-uptake tumors that are otherwise undetectable using [18F]FDG. In addition, it is endowed with an excellent safety profile and favorable pharmacokinetics for PET imaging. Consequently, this dendrimer nanosystem constitutes an effective and promising approach for cancer imaging. Our study also demonstrates that nanotechnology based on self-assembling dendrimers provides a fresh perspective for biomedical imaging and cancer diagnosis.

Experimental Study of the Biodistribution of New Bone-Seeking Compounds Based on Phosphonic Acids and Gallium-68.

We investigate biodistribution of gallium-labeled hydroxyethylidenediphosphonic acid (68Ga-HEDP) and diethylenetriaminepentakis(methylenephosphonic acid) (68Ga-DTPMP) in intact Wistar rats. It was shown that 68Ga-DTPMP accumulated mainly in the bone tissue providing high femur/blood and femur/muscle ratios and had high stability in vivo. In contrast, 68Ga-HEDP was characterized by low stability and high uptake of radioactivity in blood throughout the study. So 68Ga-DTPMP can be considered as a new prospective radiotracer in oncology for imaging bone tissue metastasis by positron emission tomography.

Detecting Vulnerable Atherosclerotic Plaques by 68Ga-Labeled Divalent Cystine Knot Peptide.

Integrin αvß3 has been considered as a promising biomarker for vulnerable atherosclerotic plaques, and it is highly expressed by those instability-associated factors, such as macrophages, vessel endothelial cells, and smooth muscle cells. Our previous study successfully showed that the 64Cu-labeled divalent (containing two RGD motifs) cystine knot peptide, 64Cu-NOTA-3-4A, had high binding affinity and specificity in targeting vulnerable carotid atherosclerotic plaques with increased αvß3 levels. Therefore, considering that 68Ga has excellent nuclear physical properties for positron emission tomography (PET), this study aimed to investigate the feasibility of using 68Ga-NOTA-3-4A for PET study of vulnerable atherosclerotic plaques. The vulnerable carotid atherosclerotic plaques were induced and maintained in ApoE-/- mice through carotid artery ligation and a high-fat diet. Divalent knottin peptide 3-4A was synthesized through solid-phase peptide synthesis chemistry and radiolabeled with 68Ga after being conjugated with 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA). The probe stability was analyzed in phosphate buffered saline (PBS) buffer and mouse serum. ApoE-/- mice with atherosclerotic plaques ( n = 4) were imaged by PET/CT at 1 and 2 h after the tail vein injection of 68Ga-NOTA-3-4A. The targeting specificity was determined by coinjection of 68Ga-NOTA-3-4A and nonradioactive c(RGDyK) peptide. The carotid artery tissues were removed, and immunofluorescent staining was performed to evaluate αvß3 integrin expression. It was found that 68Ga-NOTA-3-4A displayed high stability in both PBS buffer and mouse serum. Small animal PET/CT images and quantification analysis indicated the quick and high plaque uptake of 68Ga-NOTA-3-4A (6.67 ± 1.44 and 2.97 ± 0.46%ID/g at 1 and 2 h, respectively). The plaque-to-normal artery ratio was 15.88 and 9.90 at 1 and 2 h, respectively. Furthermore, the plaque accumulation of 68Ga-NOTA-3-4A was significantly inhibited via coinjection of c(RGDyK). Finally, immunostaining identified integrin αvß3 expressed by macrophages, vessel endothelial cells, and smooth muscle cells. In summary, 68Ga-NOTA-3-4A has high potential to be a promising PET tracer for imaging vulnerable atherosclerotic plaques.

H2CHXdedpa and H4CHXoctapa-chiral acyclic chelating ligands for (67/68)Ga and (111)In radiopharmaceuticals.

The chiral acyclic ligands H2CHXdedpa (N4O2), H2CHXdedpa-bb (N4O2), and H4CHXoctapa (N4O4) (CHX = cyclohexyl/cyclohexane, H2dedpa = 1,2-[[6-carboxy-pyridin-2-yl]-methylamino]ethane, bb = N,N'-dibenzylated, H4octapa = N,N'-bis(6-carboxy-2-pyridylmethyl)-ethylenediamine-N,N'-diacetic acid) were synthesized, complexed with Ga(III) and/or In(III), and evaluated for their potential as chelating agents in radiopharmaceutical applications. The ligands were compared to the previously studied hexadentate H2dedpa and octadentate H4octapa ligands to determine the effect adding a chiral 1R,2R-trans-cyclohexane to replace the ethylenediamine backbone would have on metal complex stability and radiolabeling kinetics. It was found that [Ga(CHXdedpa)](+) showed very similar properties to those of [Ga(dedpa)](+), with only one isomer in solution observed by NMR spectroscopy, and minimal structural changes in the solid-state X-ray structure. Like [Ga(dedpa)](+), [Ga(CHXdedpa)](+) exhibited exceptionally high thermodynamic stability constants (log KML = 28.11(8)), and the chelate retained the ability to label (67)Ga quantitatively in 10 min at room temperature at ligand concentrations of 1 × 10(-5) M. In vitro kinetic inertness assays demonstrated the [(67)Ga(CHXdedpa)](+) complex to be more stable than [(67)Ga(dedpa)](+) in a human serum competition, with 90.5% and 77.8% of (67)Ga remaining chelate-bound after 2 h, respectively. Preliminary coordination studies of H4CHXoctapa with In(III) demonstrated [In(CHXoctapa)](-) to have an equivalently high thermodynamically stable constant as [In(octapa)](-), with log KML values of 27.16(9) and 26.76(14), respectively. The [(111)In(CHXoctapa)](-) complex showed exceptionally high in vitro kinetic inertness over 120 h in human serum, comparing well with previously reported [(111)In(octapa)](-) values, and an improved stability compared to the current industry "gold standards" 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) and diethylenetriaminepentaacetic acid (DTPA). Initial investigations reveal that the chiral acyclic hexadentate H2CHXdedpa and octadentate H4CHXoctapa ligands are ideal candidates for radiopharmaceutical elaboration of gallium or indium isotopes, respectively.

(68)Ga/DOTA- and (64)Cu/NOTA-phthalocyanine conjugates as fluorescent/PET bimodal imaging probes.

In this paper, we describe the synthesis and characterization of a series of new bimodal probes combining water-soluble sulfonated zinc phthalocyanine (ZnPc) as a fluorescence imaging unit and either (68)Ga/1,4,7,10-tetraazocyclododecane-N,N'N″,N'″-tetraacetic acid (DOTA) or (64)Cu/1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA) for PET imaging. The two moieties were linked through aliphatic chains of different lengths to modulate amphiphilicity. Labeling of DOTA- or NOTA-ZnPc conjugates with (68)Ga (t1/2 = 68 min) and (64)Cu (t1/2 = 12.7 h) was performed at 100 °C for 15 min with >90% efficiency for all conjugates. In vitro plasma stability assays demonstrated high stability of the (64)Cu/NOTA-ZnPc conjugate, which remained intact over a 24 h time period, and reasonably high stability of the (68)Ga/DOTA-ZnPc conjugate, which released up to 7% of free (68)Ga over a 3 h period. Based on in vitro plasma stability results, we performed biodistribution studies on two (64)Cu-labeled derivatives, which allowed us to select a single candidate for preliminary in vivo experiments. Fluorescence and PET imaging confirmed the potential of these novel conjugates to act as bimodal probes.

In vivo evaluation of a radiogallium-labeled bifunctional radiopharmaceutical, Ga-DOTA-MN2, for hypoxic tumor imaging.

On the basis of the findings obtained by X-ray crystallography of Ga-DOTA chelates and the drug design concept of bifunctional radiopharmaceuticals, we previously designed and synthesized a radiogallium-labeled DOTA chelate containing two metronidazole moieties, (67)Ga-DOTA-MN2, for hypoxic tumor imaging. As expected, (67)Ga-DOTA-MN2 exhibited high in vivo stability, although two carboxyl groups in the DOTA skeleton were conjugated with metronidazole moieties. In this study, we evaluated (67/68)Ga-DOTA-MN2 as a nuclear imaging agent for hypoxic tumors. (67)Ga-labeling of DOTA-MN2 with (67)GaCl(3) was achieved with high radiochemical yield (>85%) by 1-min of microwave irradiation (50 W). The pharmacokinetics of (67)Ga-DOTA-MN2 were examined in FM3A tumor-bearing mice, and compared with those of (67)Ga-DOTA-MN1 containing one metronidazole unit and (67)Ga-DOTA. Upon administration, (67)Ga-DOTA-MN2 exhibited higher accumulation in the implanted tumors than (67)Ga-DOTA. Tumor-to-blood ratios of (67)Ga-DOTA-MN2 were about two-fold higher than those of (67)Ga-DOTA-MN1. Autoradiographic analysis showed the heterogeneous localization of (67)Ga-DOTA-MN2 in the tumors, which corresponds to hypoxic regions suggested by well-established hypoxia marker drug, pimonidazole. Furthermore, in positron emission tomography (PET) study, the tumors of mice administered (68)Ga-labeled DOTA-MN2 were clearly imaged by small-animal PET at 1 h after administration. This study demonstrates the potential usefulness of (67/68)Ga-DOTA-MN2 as a nuclear imaging agent for hypoxic tumors and suggests that two functional moieties, such as metronidazole, can be conjugated to radiogallium-DOTA chelate without reducing the complex stability. The present findings provide useful information about the chemical design of radiogallium-labeled radiopharmaceuticals for PET and single photon emission computed tomography (SPECT) studies.

Stabilities of 67ga- and 111In-labeled transferrin in vitro.

We attempted to develop a stable radiolabeled transferrin (Tf) useful in experimental studies related to Tf receptor. 67Ga and 111In were used as labeling radioisotopes. The results from gel chromatography, dialysis, and electrophoresis showed that 111In-DTPA-Tf was the most stable among the radiolabeled Tfs examined in the present study. 111In-DTPA-Tf was also the most stable radiolabeled transferrin in the blood.

68Ga-Sienna+ for PET-MRI Guided Sentinel Lymph Node Biopsy: Synthesis and Preclinical Evaluation in a Metastatic Breast Cancer Model.

Sentinel lymph node biopsy (SLNB) is commonly performed in cancers that metastasise via the lymphatic system. It involves excision and histology of sentinel lymph nodes (SLNs) and presents two main challenges: (i) sensitive whole-body localisation of SLNs, and (ii) lack of pre-operative knowledge of their metastatic status, resulting in a high number (>70%) of healthy SLN excisions. To improve SLNB, whole-body imaging could improve detection and potentially prevent unnecessary surgery by identifying healthy and metastatic SLNs. In this context, radiolabelled SPIOs and PET-MRI could find applications to locate SLNs with high sensitivity at the whole-body level (using PET) and guide high-resolution MRI to evaluate their metastatic status. Here we evaluate this approach by synthesising a GMP-compatible 68Ga-SPIO (68Ga-Sienna+) followed by PET-MR imaging and histology studies in a metastatic breast cancer mouse model. Methods. A clinically approved SPIO for SLN localisation (Sienna+) was radiolabelled with 68Ga without a chelator. Radiochemical stability was tested in human serum. In vitro cell uptake was compared between 3E.Δ.NT breast cancer cells, expressing the hNIS reporter gene, and macrophage cell lines (J774A.1; RAW264.7.GFP). NSG-mice were inoculated with 3E.Δ.NT cells. Left axillary SLN metastasis was monitored by hNIS/SPECT-CT and compared to the healthy right axillary SLN. 68Ga-Sienna+ was injected into front paws and followed by PET-MRI. Imaging results were confirmed by histology. Results.68Ga-Sienna+ was produced in high radiochemical purity (>93%) without the need for purification and was stable in vitro. In vitro uptake of 68Ga-Sienna+ in macrophage cells (J774A.1) was significantly higher (12 ± 1%) than in cancer cells (2.0 ± 0.1%; P < 0.001). SPECT-CT confirmed metastasis in the left axillary SLNs of tumour mice. In PET, significantly higher 68Ga-Sienna+ uptake was measured in healthy axillary SLNs (2.2 ± 0.9 %ID/mL), than in metastatic SLNs (1.1 ± 0.2 %ID/mL; P = 0.006). In MRI, 68Ga-Sienna+ uptake in healthy SLNs was observed by decreased MR signal in T2/T2*-weighted sequences, whereas fully metastatic SLNs appeared unchanged. Conclusion.68Ga-Sienna+ in combination with PET-MRI can locate and distinguish healthy from metastatic SLNs and could be a useful preoperative imaging tool to guide SLN biopsy and prevent unnecessary excisions.

Evaluation of a Flexible NOTA-RGD Kit Solution Using Gallium-68 from Different 68Ge/68Ga-Generators: Pharmacokinetics and Biodistribution in Nonhuman Primates and Demonstration of Solitary Pulmonary Nodule Imaging in Humans.

PURPOSE: Radiopharmaceuticals containing the motive tripeptide arginyl-glycyl-asparatic acid (RGD) are known to target ανß3 integrins during tumor angiogenesis. A more generic kit radiolabeling procedure accommodating Ga-68 from different generators was developed for NOTA-RGD and evaluated for its versatile use and safety in subsequent in vivo applications. The [68Ga]NOTA-RGD kit was further verified for its expected biodistribution and pharmacokinetics in nonhuman primates and its clinical sensitivity to detect solitary pulmonary nodules (SPN) in cancer patients. PROCEDURES: Single vial kits containing 28-56 nmol of NOTA-cyclo-Arg-Gly-Asp-d-Tyr-Lys (NOTA-RGD) and sodium acetate trihydrate buffer were formulated. Versatility of the NOTA-RGD radiolabeling performance and adaption to a TiO2- and a SnO2-based generator type, characterization and long-term storage stability of the kits were carried out. The blood clearance and urine recovery kinetics as well as the image-guided biodistribution of [68Ga]NOTA-RGD was studied in a vervet monkey model. [68Ga]NOTA-RGD kits were further tested clinically to target solitary pulmonary nodules. RESULTS: The kits could be successfully formulated warranting integrity over 3-4 months with a good [68Ga]NOTA-RGD radiolabeling performance (radiochemical purity >95 %, decay corrected yield 76-94 %, specific activity of 8.8-37.9 GBq/µmol) The kits met all quality requirements to be further tested in vivo. [68Ga]NOTA-RGD cleared rapidly from blood and was majorly excreted via the renal route. The liver, spleen, heart and intestines showed initial uptake with steadily declining tissue activity concentration over time. In addition, the [68Ga]NOTA-RGD kit allowed for delineation of SPN from non-malignant lung tissue in humans. CONCLUSIONS: A more versatile radiolabeling procedure using kit-formulated NOTA-RGD and different generator types was achieved. The uncompromised in vivo behavior and efficient targeting of SPN warrants further investigations on the clinical relevance of [68Ga]NOTA-RGD derivatives to implement initial guidelines and management of patients, with regard to integrin targeted imaging.

68Ga-radiolabeled AGuIX nanoparticles as dual-modality imaging agents for PET/MRI-guided radiation therapy.

AIM: The aim of this study was to develop a dual-modality positron emission tomography/magnetic resonance (PET/MR) imaging probe by radiolabeling gadolinium-containing AGuIX derivatives with the positron-emitter Gallium-68 (68Ga). MATERIALS & METHODS: AGuIX@NODAGA nanoparticles were labeled with 68Ga at high efficiency. Tumor accumulation in an appropriate disease model was assessed by ex vivo biodistribution and in vivo PET/MR imaging. RESULTS:  68Ga-AGuIX@NODAGA was proven to passively accumulate in U87MG human glioblastoma tumor xenografts. Metabolite assessment in serum, urine and tumor samples showed that 68Ga-AGuIX@NODAGA remains unmetabolized up to at least 60 min postinjection. CONCLUSION: This study demonstrates that 68Ga-AGuIX@NODAGA can be used as a dual-modality PET/MR imaging agent with passive accumulation in the diseased area, thus showing great potential for PET/MR image-guided radiation therapy.

In vivo radioimaging of bradykinin receptor b1, a widely overexpressed molecule in human cancer.

The bradykinin receptor B1R is overexpressed in many human cancers where it might be used as a general target for cancer imaging. In this study, we evaluated the feasibility of using radiolabeled kallidin derivatives to visualize B1R expression in a preclinical model of B1R-positive tumors. Three synthetic derivatives were evaluated in vitro and in vivo for receptor binding and their ability to visualize tumors by PET. Enalaprilat and phosphoramidon were used to evaluate the impact of peptidases on tumor visualization. While we found that radiolabeled peptides based on the native kallidin sequence were ineffective at visualizing B1R-positive tumors, peptidase inhibition with phosphoramidon greatly enhanced B1R visualization in vivo. Two stabilized derivatives incorporating unnatural amino acids ((68)Ga-SH01078 and (68)Ga-P03034) maintained receptor-binding affinities that were effective, allowing excellent tumor visualization, minimal accumulation in normal tissues, and rapid renal clearance. Tumor uptake was blocked in the presence of excess competitor, confirming that the specificity of tumor accumulation was receptor mediated. Our results offer a preclinical proof of concept for noninvasive B1R detection by PET imaging as a general tool to visualize many human cancers.

The source of gallium-67 in gastrointestinal contents: concise communication.

The sources of Ga-67 in gastrointestinal (GI) contents, and factors affecting its secretion were studied in rats. To prevent loss of fecal Ga-67, the anus was sutured before intravenous injection of Ga-67 citrate. Secretion of Ga-67 into the contents of the GI tract was rapid, 3, 6, and 9% of the injected dose were secreted at 1, 6, and 24 hr after injection, respectively. In contrast, Ga-67 concentration in the GI tissues remained relatively constant throughout this period. Analysis of Ga-67 contents of various parts of the GI trace revealed that small intestine is its major source, contributing 60% while the bile contributes 20%, large intestine 10%, GI contents. In contrast, the serum unbound iron-binding capacity (UIBC) played an important role in the Gl secretion of Ga-67 reducing the serum UIBC reduced the Ga-67 secretion into GI contents.

Mechanism of gallium-67 accumulation in tumors.

Neoplasms are characterized by increased perfusion, increased permeability of their capillary beds to macromolecules, and a delay in new lymphatic vessel growth. These lead to the increased entry and residency time of macromolecules in the interstitial space of tumors. Multiple factors contribute to the localization of 67Ga in tumors. Adequate blood supply is essential; at areas with no blood supply such as the necrotic center of a large tumor, there is no 67Ga accumulation. Gallium-67, mainly in the form of transferrin-67Ga complex, is delivered to the tumor through capillaries with increased permeability. In tumors, some 67Ga is taken up by tumor cells; some may also be taken up by inflammatory cells when they are present. Gallium-67 binding proteins, such as lactoferrin or ferritin, may also contribute to the accumulation and retention of 67Ga in tumors; however, their roles are less clear. The intensity of these various factors determine their relative contribution and the degree of 67Ga accumulation in tumors.

Studies on gallium accumulation in inflammatory lesions: I. Gallium uptake by human polymorphonuclear leukocytes.

The mechanism of ionic gallium-67 localization in inflammatory lesions was studied. Human polymorphonuclear leukocytes (PMN) had higher Ga-67 uptake than lymphocytes, whereas red blood cells had no affinity for Ga-67. Uptake by PMN showed temperature dependence, was independent of Ga-67 concentrations, and was not inhibited by metabolic inhibitors. However, its binding to PMN could be removed by trypsin but not by neuraminidase. These results are consistent with the hypothesis that the plasma membrane serves as a diffusion barrier and Ga-67 only binds to the surface of the PMN plasma membrane. When this membrane's permeability barrier was disrupted, as in heat-killed PMN, Ga-67 uptake increased markedly. Experimental abscesses were induced with E. coli or turpentine in rabbits. Twenty-four hours after i.v. injection, only 20% of Ga-67 in abscesses was in fractions containing intact PMN, cell debris or bacteria; the remainder was in a soluble, non-cellular fraction (2,500-g supernatant).

67Gallium-labeled liposomes with prolonged circulation: preparation and potential as nuclear imaging agents.

A method is described for 67Ga-labeling liposomes containing a polyethylene glycol coating which exhibit prolonged blood circulation, reduced liver and spleen uptake and accumulation in tumors. Applications as agents for diagnostic imaging and delivery of therapeutic agents are considered. Previous methods were adapted to compensate for the presence of low temperature phase transition phospholipids resulting in consistent loading with low levels of residual unentrapped label.

Plasma aluminum is bound to transferrin.

Aluminum ion is bound to at least one of the two specific iron binding sites of serum transferrin and also to serum albumin, as shown by in vivo competition studies with 67-Ga, gel filtration chromatography and ultraviolet difference spectroscopy. Binding of aluminum to transferrin requires CO2 and therefore involves a specific iron site. Samples of commercial transferrin contained large amounts of aluminum. Aluminum may cause anemia by entering pathways of iron distribution and metabolism.

67Gallium kinetics in the blood of patients with malignant tumors.

67Gallium was injected into 60 patients with malignant tumors and into 42 patients in whom malignant tumors had been excluded by clinical investigation. 67Ga kinetics in blood were evaluated by non-linear least square regression computer analysis according to an open 2-compartment model where elimination proceeds from the peripheral compartment. Parameters of 67Ga kinetics in tumor patients showed a bimodal distribution, as was also the case in patients without tumors. No difference could be demonstrated between kinetic parameters of tumor patients and patients without tumors. In 4 patients, 67Ga kinetics could be evaluated before and after treatment of their malignant tumors, but a decrease in the volume of distribution was the single alteration of kinetic parameters occurring after treatment. This decrease may be explained by a smaller peripheral compartment resulting from the loss of tumor mass after treatment. Nevertheless, we conclude that the evaluation of 67Ga kinetics in blood will provide only limited information about the presence, size and growth rate of malignant tumors in man.

Retention and subcellular distribution of 67Ga in normal organs.

Using normal rats, retention values and subcellular distribution of 67Ga in each organ were investigated. At 10 min after administration of 67Ga-citrate the retention value of 67Ga in blood was 6.77% dose/g, and this value decreased with time. The values for skeletal muscle, lung, pancreas, adrenal, heart muscle, brain, small intestine, large intestine and spinal cord were the highest at 10 min after administration, and they decreased with time. Conversely, this value in bone increased until 10 days after injection. But in the liver, kidney, and stomach, these values increased with time after administration and were highest 24 h or 48 h after injection. After that, they decreased with time. The value in spleen reached a plateau 48 h after administration, and hardly varied for 10 days. From the results of subcellular fractionation, it was deduced that lysosome plays quite an important role in the concentration of 67Ga in small intestine, stomach, lung, kidney and pancreas; a lesser role in its concentration in heart muscle, and hardly any role in the 67Ga accumulation in skeletal muscle. In spleen, the contents in nuclear, mitochondrial, microsomal, and supernatant fractions all contributed to the accumulation of 67Ga.

67Ga-9N3 uptake by xenografts of human melanotic melanoma in mice.

Tumour uptake of the inert, neutral complex 67Ga-9N3 and the tumour:blood concentration ratio (1,4,7,triazacyclononane-1,4,7, triacetic acid) were measured in mice bearing xenografts of the human melanotic melanoma HX118. Between 1 and 4 h after the injection the tumour:blood ratio increased from 3.5 to 21 and the concentration of 67Ga-9N3 in the tumour decreased from 0.43 to 0.13% g-1. During the first 24 h the concentration of 67Ga-9N3 in the tumour exceeded that in all other tissues except the liver and kidneys. The tumour:blood ratio and tissue distribution of 67Ga-9N3 at 4 h were compared with those of four other complexes. The results indicated that of the five complexes 67Ga-9N3 would be the most suitable for tumour imaging at early times after administration. Imaging would not be restricted to gamma emitting 67Ga as there is also the possibility of using the 9N3 ligand to bind 111In for single photon emission computed tomography (SPECT), 68Ga for positron emission tomography (PET) or even stable Ga for direct in vivo nuclear magnetic resonance (NMR) detection.

Platelet labeling with 67Ga chelates.

68Ga-labeled platelets could be useful for positron emission tomographic (PET) studies. In order to identify the optimal chelate for radiolabeling of platelets with 68Ga, we investigated the platelet uptake of 67Ga-oxine, -tropolone and -MPO. The platelet uptake of 67Ga-oxine and -tropolone is very low (< 5%). The platelet uptake of 67Ga-MPO, in contrast, increases with platelet density (highest at 10(9) platelets/ml) up to 18%. Our data provide evidence that only 68Ga-MPO could be useful for PET-studies.