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1.  ImmunoPET Imaging of Renal Cell Carcinoma with 124I- and 89Zr-Labeled Anti-CAIX Monoclonal Antibody cG250 in Mice 
Abstract
Introduction
Monoclonal antibody (mAb) cG250 recognizes carbonic anhydrase IX (CAIX), overexpressed on clear cell renal cell carcinoma (ccRCC). 124I-cG250 is currently under clinical investigation for the detection of ccRCC. However, the 124I label is rapidly excreted from the tumor cells after internalization of the radiolabeled mAb. We hypothesized that labeling cG250 with the residualizing positron emitter 89Zr would lead to higher tumor uptake and more sensitive detection of ccRCC lesions.
Materials and Methods
Nude mice with CAIX-expressing ccRCC xenografts (SK-RC-52 or NU-12) were i.v. injected with 89Zr-cG250 or 124I-cG250. To determine specificity of 89Zr-cG250 uptake in ccRCC, one control group was i.v. injected with 89Zr-MOPC21 (irrelevant mAb). PET images were acquired using a small animal PET camera and the biodistribution of the radiolabeled mAb was determined.
Results
The ccRCC xenografts were clearly visualized after injection of 89Zr-cG250 and 124I-cG250. Tumor uptake of 89Zr-cG250 was significantly higher compared with 124I-cG250 in the NU-12 tumor model (114.7%±25.2% injected dose per gram (%ID/g) vs. 38.2±18.3%ID/g, p=0.029), but in the SK-RC-52 the difference in tumor uptake was not significant (48.7±15.2%ID/g vs. 32.0±22.9%ID/g, p=0.26). SK-RC-52 tumors were not visualized with 89Zr-MOPC21 (tumor uptake 3.0%ID/g). Intraperitoneal SK-RC-52 lesions as small as 7 mm3 were visualized with 89Zr-cG250 PET.
Conclusion
ImmunoPET imaging with cG250 visualized s.c. and i.p. ccRCC lesions in murine models. This confirms the potential of cG250 immunoPET in the diagnosis and (re)staging of ccRCC. PET imaging of ccRCC tumors with 89Zr-cG250 could be more sensitive than 124I-cG250-PET.
doi:10.1089/cbr.2013.1487
PMCID: PMC3741422  PMID: 23697926
124I; 89Zr; cG250; immunoPET
2.  Dual Contrast Agent for Computed Tomography and Magnetic Resonance Hard Tissue Imaging 
Calcium phosphate cements (CPCs) are commonly used bone substitute materials, which closely resemble the composition of the mineral phase of bone. However, this high similarity to natural bone also results in difficult discrimination from the bone tissue by common imaging modalities, that is, plain X-ray radiography and three-dimensional computed tomography (CT). In addition, new imaging techniques introduced for bone tissue visualization, like magnetic resonance imaging (MRI), face a similar problem. Even at high MRI resolution, the lack of contrast between CPCs and surrounding bone is evident. Therefore, this study aimed to evaluate the feasibility of a dual contrast agent, traceable with both CT and MRI as enhancers of CPC/bone tissue contrast. Our formulation is based on the use of silica beads as vectors, which encapsulate and carry contrast-enhancing nanoparticles, in our case, colloidal Gold and Superparamagnetic Iron oxide particles (SPIO). The bead suspension was incorporated within a calcium phosphate powder. The resultant cements were then tested both in vitro and in vivo in a femoral condyle defect model in rats. Results showed that the mechanical properties of the cement were not significantly affected by the inclusion of the beads. Both in vitro and in vivo data proved the homogeneous incorporation of the contrast within the cement and its visual localization, characterized by a short-term CT contrast enhancement and a long-term MR effect recognizable by the characteristic blooming shape. Finally, no signs of adverse tissue reactions were noticed in vivo. In conclusion, this study proved the feasibility of a multimodal contrast agent as an inert and biocompatible enhancer of CaP cement versus bone tissue contrast.
doi:10.1089/ten.tec.2012.0007
PMCID: PMC3629852  PMID: 23259682
3.  Imaging integrin alpha-v-beta-3 expression in tumors with an 18F-labeled dimeric RGD peptide 
Integrin αvβ3 receptors are expressed on activated endothelial cells during neovascularization to maintain tumor growth. Many radiolabeled probes utilize the tight and specific association between the arginine-glycine-aspartatic acid (RGD) peptide and integrin αvβ3, but one main obstacle for any clinical application of these probes is the laborious multistep radiosynthesis of 18F. In this study, the dimeric RGD peptide, E-[c(RGDfK)]2, was conjugated with NODAGA and radiolabeled with 18F in a simple one-pot process with a radiolabeling yield of 20%; the whole process lasting only 45 min. NODAGA-E-[c(RGDfK)]2 labeled with 18F at a specific activity of 1.8 MBq/nmol and a radiochemical purity of 100% could be achieved. Log P value of 18F-labeled NODAGA-E-[c(RGDfK)]2 was −4.26 ± 0.02. In biodistribution studies, 18F-NODAGA-E-[c(RGDfK)]2 cleared rapidly from the blood with 0.03 ± 0.01 %ID/g in the blood at 2 h p.i., mainly via the kidneys and showed good in vivo stability. Tumor uptake of 18F-NODAGA-E-[c(RGDfK)]2 (3.44 ± 0.20 %ID/g, 2 h p.i.) was significantly lower than that of reference compounds 68Ga-labeled NODAGA-E-[c(RGDfK)]2 (6.26 ± 0.76 %ID/g; P <0.001) and 111In-labeled NODAGA-E-[c(RGDfK)]2 (4.99 ± 0.64 %ID/g; P < 0.01). Co-injection of an excess of unlabeled NODAGA-E-[c(RGDfK)]2 along with 18F-NODAGA-E-[c(RGDfK)]2 resulted in significantly reduced radioactivity concentrations in the tumor (0.85 ± 0.13 %ID/g). The αvβ3 integrin-expressing SK-RC-52 tumor could be successfully visualized by microPET with 18F-labeled NODAGA-E-[c(RGDfK)]2. In conclusion, NODAGA-E-[c(RGDfK)]2 could be labeled rapidly with 18F using a direct aqueous, one-pot method and it accumulated specifically in αvβ3 integrin-expressing SK-RC-52 tumors, allowing for visualization by microPET.
doi:10.1002/cmmi.1523
PMCID: PMC4034708  PMID: 23606427
Integrin alpha-v-beta-3; PET; radiofluorination; aluminum fluoride; RGD; NODAGA
4.  68Ga-Triacetylfusarinine C and 68Ga-Ferrioxamine E for Aspergillus Infection Imaging: Uptake Specificity in Various Microorganisms 
Purpose
68Ga-triacetylfusarinine C (68Ga-TAFC) and 68Ga-ferrioxamine E (68Ga-FOXE) showed excellent targeting properties in Aspergillus fumigatus rat infection model. Here, we report on the comparison of specificity towards different microorganisms and human lung cancer cells (H1299).
Procedures
The in vitro uptake of 68Ga-TAFC and 68Ga-FOXE was studied in various fungal, bacterial and yeast cultures as well as in H1299 cells. The in vivo imaging was studied in fungal and bacterial rat infection and inflammation models.
Results
68Ga-TAFC and 68Ga-FOXE showed rapid uptake in A. fumigatus cultures, significantly lower in other fungal species and almost no uptake in other microorganisms and H1299 cells, except for 68Ga-FOXE in Staphylococcus aureus. 68Ga-TAFC and 68Ga-FOXE revealed rapid uptake in the lungs of A. fumigatus-infected rats, low accumulation in sterile inflammation and no uptake in bacterial abscess.
Conclusions
We have shown that 68Ga-FOXE and 68Ga-TAFC have high uptake in A. fumigatus both in vitro and in vivo. 68Ga-TAFC showed higher specificity, while 68Ga-FOXE showed higher sensitivity.
doi:10.1007/s11307-013-0654-7
PMCID: PMC3823598  PMID: 23818006
Siderophores; Gallium-68; Infection imaging; Aspergillus fumigatus; Positron emission tomography
5.  68Ga-Triacetylfusarinine C and 68Ga-Ferrioxamine E for Aspergillus Infection Imaging: Uptake Specificity in Various Microorganisms 
Molecular Imaging and Biology  2013;16(1):102-108.
Purpose
68Ga-triacetylfusarinine C (68Ga-TAFC) and 68Ga-ferrioxamine E (68Ga-FOXE) showed excellent targeting properties in Aspergillus fumigatus rat infection model. Here, we report on the comparison of specificity towards different microorganisms and human lung cancer cells (H1299).
Procedures
The in vitro uptake of 68Ga-TAFC and 68Ga-FOXE was studied in various fungal, bacterial and yeast cultures as well as in H1299 cells. The in vivo imaging was studied in fungal and bacterial rat infection and inflammation models.
Results
68Ga-TAFC and 68Ga-FOXE showed rapid uptake in A. fumigatus cultures, significantly lower in other fungal species and almost no uptake in other microorganisms and H1299 cells, except for 68Ga-FOXE in Staphylococcus aureus. 68Ga-TAFC and 68Ga-FOXE revealed rapid uptake in the lungs of A. fumigatus-infected rats, low accumulation in sterile inflammation and no uptake in bacterial abscess.
Conclusions
We have shown that 68Ga-FOXE and 68Ga-TAFC have high uptake in A. fumigatus both in vitro and in vivo. 68Ga-TAFC showed higher specificity, while 68Ga-FOXE showed higher sensitivity.
doi:10.1007/s11307-013-0654-7
PMCID: PMC3823598  PMID: 23818006
Siderophores; Gallium-68; Infection imaging; Aspergillus fumigatus; Positron emission tomography
6.  Effects of attenuation map accuracy on attenuation-corrected micro-SPECT images 
EJNMMI Research  2013;3:7.
Background
In single-photon emission computed tomography (SPECT), attenuation of photon flux in tissue affects quantitative accuracy of reconstructed images. Attenuation maps derived from X-ray computed tomography (CT) can be employed for attenuation correction. The attenuation coefficients as well as registration accuracy between SPECT and CT can be influenced by several factors. Here we investigate how such inaccuracies influence micro-SPECT quantification.
Methods
Effects of (1) misalignments between micro-SPECT and micro-CT through shifts and rotation, (2) globally altered attenuation coefficients and (3) combinations of these were evaluated. Tests were performed with a NEMA NU 4–2008 phantom and with rat cadavers containing sources with known activity.
Results
Changes in measured activities within volumes of interest in phantom images ranged from <1.5% (125I) and <0.6% (201Tl, 99mTc and 111In) for 1-mm shifts to <4.5% (125I) and <1.7% (201Tl, 99mTc and 111In) with large misregistration (3 mm). Changes induced by 15° rotation were smaller than those by 3-mm shifts. By significantly altering attenuation coefficients (±10%), activity changes of <5.2% for 125I and <2.7% for 201Tl, 99mTc and 111In were induced. Similar trends were seen in rat studies.
Conclusions
While getting sufficient accuracy of attenuation maps in clinical imaging is highly challenging, our results indicate that micro-SPECT quantification is quite robust to various imperfections of attenuation maps.
doi:10.1186/2191-219X-3-7
PMCID: PMC3579699  PMID: 23369630
Molecular imaging; SPECT; CT; Small animal; Misregistration; Attenuation correction; Quantification
7.  FIAU: From reporter gene imaging to imaging of bacterial proliferation 
The radioiodinated thymidine analogue, FIAU, is a tracer that has been developed for reporter gene, for cells that were transfected with herpes simplex virus thymidine kinase, HSV-TK. FIAU is also a specific substrate of bacterial TK due to the homology between viral and bacterial TK. In this issue of AJNMMI (http://www.ajnmmi.us), Pullamb-hatla et al. reported that the accumulation of 125I-FIAU in pulmonary infectious foci correlated with the bacterial burden in the lungs. 125I-FIAU could be used to monitor the efficacy of anti-microbial therapy in mice. Potentially 124I-FIAU PET could be used to discriminate microbial from sterile inflammation in patients with prosthetic implants.
PMCID: PMC3477741  PMID: 23133817
Infection; inflammation; reporter gene imaging; positron emission tomography (PET)
8.  Preclinical evaluation of two 68Ga-siderophores as potential radiopharmaceuticals for Aspergillus fumigatus infection imaging 
Purpose
Invasive pulmonary aspergillosis is mainly caused by Aspergillus fumigatus, and is one of the major causes of morbidity and mortality in immunocompromised patients. The mortality associated with invasive pulmonary aspergillosis remains high, mainly due to the difficulties and limitations in diagnosis. We have shown that siderophores can be labelled with 68Ga and can be used for PET imaging of A. fumigatus infection in rats. Here we report on the further evaluation of the most promising 68Ga-siderophore candidates, triacetylfusarinine (TAFC) and ferrioxamine E (FOXE).
Methods
Siderophores were labelled with 68Ga using acetate buffer. Log P, protein binding and stability values were determined. Uptake by A. fumigatus was studied in vitro in cultures with high and low iron loads. In vivo biodistribution was determined in normal mice and an infection model was established using neutropenic rats inoculated with A. fumigatus. Static and dynamic μPET imaging was performed and correlated with CT images, and lung infection was evaluated ex vivo.
Results
68Ga-siderophores were labelled with high radiochemical purity and specific activity. 68Ga-TAFC and 68Ga-FOXE showed high uptake by A. fumigatus in iron-deficient cultures. In normal mice, 68Ga-TAFC and 68Ga-FOXE showed rapid renal excretion with high metabolic stability. In the rat infection model focal lung uptake was detected by μPET with both compounds and increased with severity of the infection, correlating with abnormal CT images.
Conclusion
68Ga-TAFC and 68Ga-FOXE displayed excellent in vitro stability and high uptake by A. fumigatus. Both compounds showed excellent pharmacokinetics, highly selective accumulation in infected lung tissue and good correlation with severity of disease in a rat infection model, which makes them promising agents for A. fumigatus infection imaging.
Electronic supplementary material
The online version of this article (doi:10.1007/s00259-012-2110-3) contains supplementary material, which is available to authorized users.
doi:10.1007/s00259-012-2110-3
PMCID: PMC3369139  PMID: 22526953
68Ga-siderophores; Aspergillus fumigatus; Invasive aspergillosis; Infection imaging
9.  Radiolabelled peptides for oncological diagnosis 
Radiolabelled receptor-binding peptides targeting receptors (over)expressed on tumour cells are widely under investigation for tumour diagnosis and therapy. The concept of using radiolabelled receptor-binding peptides to target receptor-expressing tissues in vivo has stimulated a large body of research in nuclear medicine. The 111In-labelled somatostatin analogue octreotide (OctreoScan™) is the most successful radiopeptide for tumour imaging, and was the first to be approved for diagnostic use. Based on the success of these studies, other receptor-targeting peptides such as cholecystokinin/gastrin analogues, glucagon-like peptide-1, bombesin (BN), chemokine receptor CXCR4 targeting peptides, and RGD peptides are currently under development or undergoing clinical trials. In this review, we discuss some of these peptides and their analogues, with regard to their potential for radionuclide imaging of tumours.
doi:10.1007/s00259-011-2014-7
PMCID: PMC3304069  PMID: 22388627
Radiolabelled receptor-binding peptides; Gastrin; CXCR4; Bombesin; GLP-1
10.  Pretargeted immuno-PET of CEA-expressing intraperitoneal human colonic tumor xenografts: a new sensitive detection method 
EJNMMI Research  2012;2:5.
Background
In this study, pretargeted immuno-positron-emission tomography [PET] with a bispecific monoclonal anti-carcinoembryonic antigen [CEA] (CEACAM5) × anti-hapten antibody (bispecific monoclonal antibody [bsmAb]) and a small (1.5 kD) peptide labeled with 68Ga was compared to fludeoxyglucose [18F-FDG]-PET for detecting intraperitoneal [i.p.] CEA-expressing human colonic tumor xenografts in nude mice.
Methods
Two groups of female BALB/c nude mice were inoculated with LS174T human colonic tumor cells i.p. One group received 5 MBq 18F-FDG, and the other received intravenous injections of the bsmAb, followed 16 h later with 5 MBq of 68Ga-labeled peptide. One hour after the radiolabeled peptide or FDG was given, micro-PET/computed tomography images were acquired. Thereafter, the uptake of the 68Ga or 18F in dissected tissue was determined.
Results
Within 1 h, high uptake of the 68Ga-labeled peptide in the tumor lesions (23.4 ± 7.2% ID/g) and low background activity levels were observed (e.g., tumor-to-intestine ratio, 58 ± 22). This resulted in a clear visualization of all intra-abdominal tumor lesions ≥ 10 μL and even some tumors as small as 5 μL (2 mm diameter). 18F-FDG efficiently localized in the tumors (8.7 ± 3.1% ID/g) but also showed physiological uptake in various normal tissues (e.g., tumor-to-intestine ratio, 3.9 ± 1.1).
Conclusions
Pretargeted immuno-PET with bsmAb and a 68Ga-labeled peptide could be a very sensitive imaging method for imaging colonic cancer, disclosing occult lesions.
doi:10.1186/2191-219X-2-5
PMCID: PMC3298693  PMID: 22284761
colorectal cancer; carcinoembryonic antigen; imaging; PET; pretargeting; bispecific antibodies
11.  Optimized labeling of NOTA-conjugated octreotide with F-18 
Tumour Biology  2011;33(2):427-434.
We recently reported a facile method based on the chelation of [18F]aluminum fluoride (Al18F) by NOTA (1,4,7-triazacyclononane-1,4,7-triacetic acid). Here, we present a further optimization of the 18F labeling of NOTA-octreotide (IMP466). Octreotide was conjugated with the NOTA chelate and was labeled with 18F in a two-step, one-pot method. The labeling procedure was optimized with regard to the labeling buffer, ionic strength, peptide concentration, and temperature. Radiochemical yield, specific activity, in vitro stability, and receptor affinity were determined. Biodistribution of 18F-IMP466 was studied in AR42J tumor-bearing mice. In addition, microPET/CT images were acquired. IMP466 was labeled with Al18F in a single step with 97% yield in the presence of 80% (v/v) acetonitrile or ethanol. The labeled product was purified by HPLC to remove unlabeled peptide and unbound Al18F. The radiolabeling, including purification, was performed for 45 min. Specific activities of 48,000 GBq/mmol could be obtained. 18F-IMP466 showed a high tumor uptake and excellent tumor-to-blood ratios at 2 h post-injection. In addition, the low bone uptake indicated that the Al18F–NOTA complex was stable in vivo. PET/CT scans revealed excellent tumor delineation and specific accumulation in the tumor. Uptake in receptor-negative organs was low. NOTA-octreotide could be labeled with 18F in quantitative yields using a rapid two-step, one-pot, method. The compound was stable in vivo and showed rapid accretion in SSTR2-receptor-expressing AR42J tumors in nude mice. This method can be used to label other NOTA-conjugated compounds such as RGD peptides, GRPR-binding peptides, and Affibody molecules with 18F.
doi:10.1007/s13277-011-0250-x
PMCID: PMC3296034  PMID: 22009690
Octreotide; Radiofluorination; NOTA; Peptide; PET; Aluminum fluoride
12.  Preclinical Evaluation of 68Ga-DOTA-Minigastrin for the Detection of Cholecystokinin-2/Gastrin Receptor–Positive Tumors 
Molecular imaging  2011;10(2):144-152.
In comparison to somatostatin receptor scintigraphy, gastrin receptor scintigraphy using 111In-DTPA-minigastrin (MG0) showed added value in diagnosing neuroendocrine tumors. We investigated whether the 68Ga-labeled gastrin analogue DOTA-MG0 is suited for positron emission tomography (PET), which could improve image quality. Targeting of cholecystokinin-2 (CCK2)/gastrin receptor–positive tumor cells with DOTA-MG0 labeled with either 111In or 68Ga in vitro was investigated using the AR42J rat tumor cell line. Biodistribution was examined in BALB/c nude mice with a subcutaneous AR42J tumor. In vivo PET imaging was performed using a preclinical PET–computed tomographic scanner. DOTA-MG0 showed high receptor affinity in vitro. Biodistribution studies revealed high tumor uptake of 68Ga-DOTA-MG0: 4.4 ± 1.3 %ID/g at 1 hour postinjection. Coadministration of an excess unlabeled peptide blocked the tumor uptake (0.7 ± 0.1 %ID/g), indicating CCK2/gastrin receptor–mediated uptake (p = .0005). The biodistribution of 68Ga-DOTA-MG0 was similar to that of 111In-DOTA-MG0. Subcutaneous and intraperitoneal tumors were clearly visualized by small-animal PET imaging with 5 MBq 68Ga-DOTA-MG0. 111In- and 68Ga-labeled DOTA-MG0 specifically accumulate in CCK2/gastrin receptor–positive AR42J tumors with similar biodistribution apart from the kidneys. AR42J tumors were clearly visualized by microPET. Therefore, 68Ga-DOTA-MG0 is a promising tracer for PET imaging of CCK2/gastrin receptor–positive tumors in humans.
PMCID: PMC3123532  PMID: 21439259
13.  Comparative biodistribution of 12 111In-labelled gastrin/CCK2 receptor-targeting peptides 
Purpose
Cholecystokinin 2 (CCK-2) receptor overexpression has been demonstrated in various tumours such as medullary thyroid carcinomas and small-cell lung cancers. Due to this high expression, CCK-2 receptors might be suitable targets for radionuclide imaging and/or radionuclide therapy. Several CCK-2 receptor-binding radiopeptides have been developed and some have been tested in patients. Here we aimed to compare the in vivo tumour targeting properties of 12 111In-labelled 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)-conjugated gastrin/CCK2 receptor-binding peptides.
Methods
Two CCK8-based peptides and ten gastrin-based peptide analogues were tested. All peptides were conjugated with DOTA and labelled with 111In. Biodistribution studies were performed in mice with subcutaneous CCK2/gastrin receptor-expressing tumours and with receptor-negative tumours contralaterally. Biodistribution was studied by counting dissected tissues at 1 and 4 h after injection.
Results
Both the CCK analogues displayed relatively low tumour uptake (approximately 2.5%ID/g) as compared to minigastrin analogues. Two linear minigastrin peptides (MG0 and sargastrin) displayed moderate tumour uptake at both 1 and 4 h after injection, but also very high kidney uptake (both higher than 48%ID/g). The linear MG11, lacking the penta-Glu sequence, showed lower tumour uptake and also low kidney uptake. Varying the N-terminal Glu residues in the minigastrin analogues led to improved tumour targeting properties, with PP-F11 displaying the optimal biodistribution. Besides the monomeric linear peptides, a cyclized peptide and a divalent peptide were tested.
Conclusion
Based on these studies, optimal peptides for peptide receptor radionuclide targeting of CCK2/gastrin receptor-expressing tumours were the linear minigastrin analogue with six D-Glu residues (PP-F11), the divalent analogue MGD5 and the cyclic peptide cyclo-MG1. These peptides combined high tumour uptake with low kidney retention, and may therefore be good candidates for future clinical studies.
doi:10.1007/s00259-011-1806-0
PMCID: PMC3127012  PMID: 21461732
Gastrin; Cholecystokinin; Tumour; DOTA
14.  Pretargeted ImmunoPET Imaging of CEA-expressing Tumors with a Bispecific Antibody and a 68Ga- and 18F-labeled Hapten-peptide in Mice with Human Tumor Xenografts 
Molecular cancer therapeutics  2010;9(4):1019-1027.
18F-Fluorodeoxyglucose (18F-FDG) is the most common molecular imaging agent in oncology, with a high sensitivity and specificity for detecting a number of cancers. Antibodies could enhance specificity; therefore, procedures were developed for radiolabeling a small (∼1.5 kD) hapten-peptide with 68Ga or 18F to compare their specificity to 18F-FDG for detecting tumors using a pretargeting procedure. Mice were implanted with carcinoembryonic (CEA; CEACAM5)-expressing LS174T human colonic tumors, a CEA-negative tumor, or an inflammation was induced in thigh muscle. A bispecific monoclonal (bsMAb) anti-CEA × anti-hapten antibody was given to mice, and 16 h later, 5 MBq of 68Ga- or 18F-labeled hapten-peptides were administered intravenously. Within 1 h, tissues showed high and specific targeting of the 68Ga-IMP-288, with 10.7 ± 3.6% ID/g uptake in the tumor and very low uptake in normal tissues (e.g., tumor/blood 69.9 ± 32.3), in a CEA-negative tumor (0.35 ± 0.35% ID/g), and inflamed muscle (0.72 ± 0.20% ID/g). 18F-FDG localized efficiently in the tumor (7.42 ± 0.20% ID/g), but also in the inflamed muscle (4.07 ± 1.13% ID/g) and in a number of normal tissues; thus, pretargeted 68Ga-IMP-288 provided better specificity and sensitivity. PET/CT images reinforced the improved specificity of the pretargeting method. 18F-labeled IMP-449 distributed similarly in the tumor and normal tissues as the 68Ga-labeled IMP-288, indicating that either radiolabeled hapten-peptide could be used. Thus, pretargeted immunoPET performs exceptionally well with short-lived radionuclides, and is a highly sensitive procedure that is more specific than 18F-FDG-PET.
doi:10.1158/1535-7163.MCT-09-0862
PMCID: PMC2852483  PMID: 20354120
PET; pretargeting; bispecific antibody; gallium-68; fluorine-18; colorectal neoplasms; mice
15.  A novel facile method of labeling octreotide with 18F-fluorine 
Several methods have been developed to label peptides with fluorine-18. However, in general these are laborious and require a multistep synthesis. We present a facile method based on the chelation of [18F]aluminum fluoride (“Al18F”) by NOTA (1,4,7-triazacyclononane-1,4,7-triacetic acid). The method is characterized by labeling NOTA-octreotide (IMP466) with 18F.
Methods
Octreotide was conjugated with the NOTA chelate and was labeled with 18F in a two-step, one-pot method. The labeling procedure was optimized with regard to the labeling buffer, peptide, and aluminum concentration. Radiochemical yield, specific activity, in vitro stability, and receptor affinity were determined. Biodistribution of 18F-IMP466 was studied in AR42J tumor-bearing mice and compared to that of 68Ga-labeled IMP466. In addition, microPET/CT images were acquired.
Results
IMP466 was labeled with “Al18F” in a single step with 50% yield. The labeled product was purified by HPLC to remove unbound “Al18F” and unlabeled peptide. The radiolabeling, including purification, was performed in 45 min. The specific activity was 45,000 GBq/mmol and the peptide was stable in serum for 4 h at 37° C. Labeling was performed at pH 4.1 in sodium citrate, sodium acetate, HEPES and MES buffer and was optimal in sodium acetate buffer. The apparent IC50 of the 19F-labeled IMP466 determined on AR42J cells was 3.6 nM. Biodistribution studies at 2 h p.i. showed a high tumor uptake of 18F-IMP466 (28.3 ± 5.2 %ID/g, tumor-to-blood ratio: 300 ± 90), which could be blocked by an excess of unlabeled peptide (8.6 ± 0.7%ID/g), indicating that the accumulation in the tumor was receptor-mediated. Biodistribution of 68Ga-IMP466 was similar to that of 18F-IMP466. 18F-IMP466 was stable in vivo, since bone uptake was only 0.4 ± 0.2 %ID/g, whereas free “Al18F” accumulated rapidly in the bone (36.9 ± 5.0 %ID/g at 2 h p.i.). MicroPET/CT scans showed excellent tumor delineation and high preferential accumulation in the tumor.
Conclusions
NOTA-octreotide could be labeled rapidly and efficiently with 18F using a two-step, one-pot, method. The compound was stable in vivo and showed rapid accretion in SSTR2-receptor expressing AR42J tumors in nude mice. This method can be used to label other NOTA-conjugated compounds with 18F.
doi:10.2967/jnumed.109.066902
PMCID: PMC2908260  PMID: 20150268
octreotide; radiofluorination; NOTA; peptide; PET; aluminum fluoride
16.  Radiolabeled CCK/gastrin peptides for imaging and therapy of CCK2 receptor-expressing tumors 
Amino Acids  2010;41(5):1049-1058.
Cholecystokinin (CCK) receptors are overexpressed in numerous human cancers, like medullary thyroid carcinomas, small cell lung cancers and stromal ovarian cancers. The specific receptor-binding property of the endogenous ligands for these receptors can be exploited by labeling peptides with a radionuclide and using these as carriers to guide the radioactivity to the tissues that express the receptors. In this way, tumors can be visualized using positron emission tomography and single photon emission computed tomography imaging. A variety of radiolabeled CCK/gastrin-related peptides has been synthesized and characterized for imaging. All peptides have the C-terminal CCK receptor-binding tetrapeptide sequence Trp-Met-Asp-Phe-NH2 in common or derivatives thereof. This review focuses on the development and application of radiolabeled CCK/gastrin peptides for radionuclide imaging and radionuclide therapy of tumors expressing CCK receptors. We discuss both preclinical studies as well as clinical studies with CCK and gastrin peptides.
doi:10.1007/s00726-010-0501-y
PMCID: PMC3205271  PMID: 20198494
Cholecystokinin-2 receptors; Peptides; Minigastrin; CCK8; Medullary thyroid carcinoma

Results 1-16 (16)