scholarly journals Radiosynthesis and Preliminary Biological Evaluation of 18F-Fluoropropionyl-Chlorotoxin as a Potential PET Tracer for Glioma Imaging

2018 ◽  
Vol 2018 ◽  
pp. 1-9 ◽  
Author(s):  
Jing Zhao ◽  
Yu-liang Wang ◽  
Xin-bei Li ◽  
Si-yuan Gao ◽  
Shao-yu Liu ◽  
...  
Keyword(s):  
Pet Imaging ◽  
Biological Evaluation ◽  
Brain Parenchyma ◽  
C6 Glioma ◽  
Small Animal Pet ◽  
Matrix Metalloproteinase 2 ◽  
Normal Brain ◽  
High Accumulation ◽  
Pet Tracer

Purposes. Chlorotoxin can specifically bind to matrix metalloproteinase 2 (MMP-2), which are overexpressed in the glioma. In this work, radiosynthesis of [18F]-fluoropropionyl-chlorotoxin ([18F]-FP-chlorotoxin) as a novel PET tracer was investigated, and biodistribution in vivo and PET imaging were performed in the C6 glioma model. Procedures. [18F]-FP-chlorotoxin was prepared from the reaction of chlorotoxin with [18F]-NFB (4-nitrophenyl 2-[18F]-fluoropropionate), which was synthesized from multistep reactions. Biodistribution was determined in 20 normal Kunming mice. Small-animal PET imaging with [18F]-FP-chlorotoxin was performed on the same rats bearing orthotopic C6 glioma at different time points (60 min, 90 min, and 120 min) after injection and compared with 2-deoxy-2-[18F] fluoro-D-glucose ([18F]-FDG). Results. [18F]-FP-Chlorotoxin was successfully synthesized in the radiochemical yield of 41% and the radiochemical purity of more than 98%. Among all the organs, the brain had the lowest and stable uptake of [18F]-FP-chlorotoxin, while the kidney showed the highest uptake. Compared with [18F]-FDG, a low uptake of [18F]-FP-chlorotoxin was detected in normal brain parenchyma and a high accumulation of [18F]-FP-chlorotoxin was found in the gliomas tissue. The glioma to normal brain uptake ratio of [18F]-FP-chlorotoxin was higher than that of [18F]-FDG. Furthermore, the uptake of [18F]-FP-chlorotoxin at 90 min after injection was better than that at 60 min after injection. Conclusions. Compared with [18F]-FDG, [18F]-FP-chlorotoxin has a low and stable uptake in normal brain parenchyma. [18F]-FP-Chlorotoxin seems to be a potential PET tracer with a good performance in diagnosis of the glioma.

scholarly journals 18F-FIMP: a LAT1-specific PET probe for discrimination between tumor tissue and inflammation

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Satoshi Nozaki ◽  
Yuka Nakatani ◽  
Aya Mawatari ◽  
Nina Shibata ◽  
William E. Hume ◽  
...  
Keyword(s):  
Pet Imaging ◽  
Early Phase ◽  
Liver Microsomes ◽  
Small Animal ◽  
Absorbed Dose ◽  
Biological Evaluation ◽  
Small Animal Pet ◽  
Positron Emission ◽  
Tumor Tissues

Abstract Positron emission tomography (PET) imaging can assist in the early-phase diagnostic and therapeutic evaluation of tumors. Here, we report the radiosynthesis, small animal PET imaging, and biological evaluation of a L-type amino acid transporter 1 (LAT1)-specific PET probe, 18F-FIMP. This probe demonstrates increased tumor specificity, compared to existing tumor-specific PET probes (18F-FET, 11C-MET, and 18F-FDG). Evaluation of probes by in vivo PET imaging, 18F-FIMP showed intense accumulation in LAT1-positive tumor tissues, but not in inflamed lesions, whereas intense accumulation of 18F-FDG was observed in both tumor tissues and in inflamed lesions. Metabolite analysis showed that 18F-FIMP was stable in liver microsomes, and mice tissues (plasma, urine, liver, pancreas, and tumor). Investigation of the protein incorporation of 18F-FIMP showed that it was not incorporated into protein. Furthermore, the expected mean absorbed dose of 18F-FIMP in humans was comparable or slightly higher than that of 18F-FDG and indicated that 18F-FIMP may be a safe PET probe for use in humans. 18F-FIMP may provide improved specificity for tumor diagnosis, compared to 18F-FDG, 18F-FET, and 11C-MET. This probe may be suitable for PET imaging for glioblastoma and the early-phase monitoring of cancer therapy outcomes.

scholarly journals 18F-Trifluoromethylated D-Cysteine as a Promising New PET Tracer for Glioma Imaging: Comparative Analysis With MRI and Histopathology in Orthotopic C6 Models

2021 ◽  
Vol 11 ◽  
Author(s):  
Hui Ma ◽  
Jing Zhao ◽  
Shaoyu Liu ◽  
Dingxiang Xie ◽  
Zhanwen Zhang ◽  
...  
Keyword(s):  
Pet Imaging ◽  
Tumor Volume ◽  
C6 Glioma ◽  
C6 Glioma Cells ◽  
Normal Brain ◽  
Sprague Dawley ◽  
Dce Mri ◽  
Pet Tracer ◽  
Contrast Enhanced ◽  
Tracer Accumulation

Comparing MRI and histopathology, this study aims to comprehensively explore the potential application of 18F-trifluoromethylated D-cysteine (S-[18F]CF3-D-CYS) in evaluating glioma by using orthotopic C6 glioma models. Sprague–Dawley (SD) rats (n = 9) were implanted with C6 glioma cells. Tumor growth was monitored every week by multiparameter MRI [including dynamic contrast-enhanced MRI (DCE-MRI)], [18F]FDG, S-[18F]CF3-D-CYS, and [18F]FDOPA PET imaging. Repeated scans of the same rat with the two or three [18F]-labeled radiotracers were investigated. Initial regions of interest were manually delineated on T2WI and set on the same level of PET images, and tumor-to-normal brain uptake ratios (TNRs) were calculated to semiquantitatively assess the tracer accumulation in the tumor. The tumor volume in PET and histopathology was calculated. HE and Ki67 immunohistochemical staining were further performed. The correlations between the uptake of S-[18F]CF3-D-CYS and Ki67 were analyzed. Dynamic S-[18F]CF3-D-CYS PET imaging showed tumor uptake rapidly reached a peak, maintained plateau during 10–30 min after injection, then decreased slowly. Compared with [18F]FDG and [18F]FDOPA PET imaging, S-[18F]CF3-D-CYS PET demonstrated the highest TNRs (P < 0.05). There were no significant differences in the tumor volume measured on S-[18F]CF3-D-CYS PET or HE specimen. Furthermore, our results showed that the uptake of S-[18F]CF3-D-CYS was significantly positively correlated with tumor Ki67, and the poor accumulated S-[18F]CF3-D-CYS was consistent with tumor hemorrhage. There was no significant correlation between the S-[18F]CF3-D-CYS uptakes and the Ktrans values derived from DCE-MRI. In comparison with MRI and histopathology, S-[18F]CF3-D-CYS PET performs well in the diagnosis and evaluation of glioma. S-[18F]CF3-D-CYS PET may serve as a valuable tool in the clinical management of gliomas.

scholarly journals A novel PET tracer 18F-deoxy-thiamine: synthesis, metabolic kinetics, and evaluation on cerebral thiamine metabolism status

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Changpeng Wang ◽  
Siwei Zhang ◽  
Yuefei Zou ◽  
Hongzhao Ma ◽  
Donglang Jiang ◽  
...  
Keyword(s):  
High Performance ◽  
Specific Activity ◽  
High Accumulation ◽  
Metabolic Kinetics ◽  
Thiamine Metabolism ◽  
Pet Tracer ◽  
The Status ◽  
The Brain

Abstract Background Some neuropsychological diseases are associated with abnormal thiamine metabolism, including Korsakoff–Wernicke syndrome and Alzheimer’s disease. However, in vivo detection of the status of brain thiamine metabolism is still unavailable and needs to be developed. Methods A novel PET tracer of 18F-deoxy-thiamine was synthesized using an automated module via a two-step route. The main quality control parameters, such as specific activity and radiochemical purity, were evaluated by high-performance liquid chromatography (HPLC). Radiochemical concentration was determined by radioactivity calibrator. Metabolic kinetics and the level of 18F-deoxy-thiamine in brains of mice and marmosets were studied by micro-positron emission tomography/computed tomography (PET/CT). In vivo stability, renal excretion rate, and biodistribution of 18F-deoxy-thiamine in the mice were assayed using HPLC and γ-counter, respectively. Also, the correlation between the retention of cerebral 18F-deoxy-thiamine in 60 min after injection as represented by the area under the curve (AUC) and blood thiamine levels was investigated. Results The 18F-deoxy-thiamine was stable both in vitro and in vivo. The uptake and clearance of 18F-deoxy-thiamine were quick in the mice. It reached the max standard uptake value (SUVmax) of 4.61 ± 0.53 in the liver within 1 min, 18.67 ± 7.04 in the kidney within half a minute. The SUV dropped to 0.72 ± 0.05 and 0.77 ± 0.35 after 60 min of injection in the liver and kidney, respectively. After injection, kidney, liver, and pancreas exhibited high accumulation level of 18F-deoxy-thiamine, while brain, muscle, fat, and gonad showed low accumulation concentration, consistent with previous reports on thiamine distribution in mice. Within 90 min after injection, the level of 18F-deoxy-thiamine in the brain of C57BL/6 mice with thiamine deficiency (TD) was 1.9 times higher than that in control mice, and was 3.1 times higher in ICR mice with TD than that in control mice. The AUC of the tracer in the brain of marmosets within 60 min was 29.33 ± 5.15 and negatively correlated with blood thiamine diphosphate levels (r = − 0.985, p = 0.015). Conclusion The 18F-deoxy-thiamine meets the requirements for ideal PET tracer for in vivo detecting the status of cerebral thiamine metabolism.

scholarly journals An in vivo multimodal feasibility study in a rat brain tumour model using flexible multinuclear MR and PET systems

2020 ◽  
Author(s):  
Chang-Hoon Choi ◽  
Carina Stegmayr ◽  
Aliaksandra Shymanskaya ◽  
Wieland A. Worthoff ◽  
Nuno A da Silva ◽  
...  
Keyword(s):  
Brain Tumour ◽  
Small Animal ◽  
Optimal Combination ◽  
Small Animal Pet ◽  
Molecular Profile ◽  
Genetic Profile ◽  
Normal Brain ◽  
Valuable Insight ◽  
Wide Range

Abstract Background : In addition to the structural information afforded by 1 H MRI, the use of X-nuclei, such as sodium-23 ( 23 Na) or phosphorus-31 ( 31 P), offers important complementary information concerning physiological and biochemical parameters. By then combining this technique with PET, which provides valuable insight into a wide range of metabolic and molecular processes by using of a variety of radioactive tracers, the scope of medical imaging and diagnostics can be significantly increased. While the use of multimodal imaging is undoubtedly advantageous, identifying the optimal combination of these parameters to diagnose a specific dysfunction is very important and is advanced by the use of sophisticated imaging techniques in specific animal models.Methods : In this pilot study, rats with intracerebral 9L gliosarcomas were used to explore a combination of sequential multinuclear MRI using a sophisticated switchable coil set in a small animal 9.4 T MRI scanner and, subsequently, a small animal PET with the tumour tracer O-(2-[ 18 F]-fluoroethyl)-L-tyrosine ( 18 F-FET). This enabled in vivo multinuclear MR-PET experiments to be conducted without compromising the performance of either multinuclear MR or PET.Results : High-quality in vivo images and spectra including high-resolution 1 H imaging, 23 Na-weighted imaging, detection of 31 P metabolites and 18 F-FET uptake were obtained, allowing the characterisation of tumour tissues in comparison to a normal brain. These parameters have been shown to be useful in the identification of the genetic profile of gliomas, particularly concerning the mutation of the isocitrate hydrogenase gene, which is highly relevant for treatment strategy.Conclusions : The combination of multinuclear MR and PET in, for example, brain tumour models with specific genetic mutations will enable the physiological background of signal alterations to be explored and the identification of the optimal combination of imaging parameters for the non-invasive characterisation of the molecular profile of tumours.

2-[18F]Fluorophenylalanine: Synthesis by Nucleophilic 18F-Fluorination and Preliminary Biological Evaluation

Synthesis ◽  
2019 ◽  
Vol 51 (03) ◽  
pp. 664-676 ◽  
Author(s):  
Bernd Neumaier ◽  
Daniel Modemann ◽  
Boris Zlatopolskiy ◽  
Elizaveta Urusova ◽  
Johannes Zischler ◽  
...  
Keyword(s):  
Amino Acids ◽  
Schiff Base ◽  
Biological Evaluation ◽  
Schiff Base Complexes ◽  
Biological Study ◽  
Automated Synthesis ◽  
Pet Tracer ◽  
Iodonium Salt ◽  
Acidic Conditions

2-[18F]Fluorophenylalanine (2-[18F]FPhe), a promising PET tracer for imaging of cerebral infarction and tumors, was efficiently prepared from an easily accessible iodonium salt precursor using Cu-mediated radiofluorination under ‘low base’ or ‘minimalist’ conditions. Whereas significant racemization was initially observed if the ‘minimalist’ protocol was applied for radiolabeling, it was completely suppressed by the careful adjustment of 18F– preprocessing. The initial biological study revealed a higher uptake of 2-[18F]FPhe in different tumor cells in comparison to that of [18F]FET. In contrast to 4-[18F]FPhe, which suffered from rapid defluorination in vivo, 2-[18F]FPhe demonstrated a sufficient in vivo stability. Conclusively, 2-[18F]FPhe is a promising PET probe that is now readily available using Cu-mediated radiofluorination under ‘minimalist’ or ‘low base’ conditions. The simplicity of the translation of the proposed procedures to automated synthesis modules allows a broad biological evaluation of 2-[18F]FPhe. Notably, a novel protocol for the preparation of N-Boc protected amino acids from the respective Ni-Schiff base complexes was developed that avoided application of strongly acidic conditions.

scholarly journals Evaluation of [68Ga]Ga-NODAGA-RGD for PET Imaging of Rat Autoimmune Myocarditis

2021 ◽  
Vol 8 ◽  
Author(s):  
Arghavan Jahandideh ◽  
Mia Ståhle ◽  
Jenni Virta ◽  
Xiang-Guo Li ◽  
Heidi Liljenbäck ◽  
...  
Keyword(s):  
Pet Imaging ◽  
Ex Vivo ◽  
Cell Surface Receptor ◽  
Myocardial Inflammation ◽  
Autoimmune Myocarditis ◽  
Inflammatory Lesions ◽  
Pet Tracer ◽  
Freund’S Adjuvant ◽  
Freund's Adjuvant

The 68Gallium-labeled 1,4,7-triazacyclononane-1-glutaric acid-4,7-diacetic acid conjugated radiolabelled arginine-glycine-aspartic acid peptide ([68Ga]Ga-NODAGA-RGD) is a positron emission tomography (PET) tracer binding to cell surface receptor αvβ3 integrin that is upregulated during angiogenesis and inflammation. We studied whether αvβ3 targeting PET imaging can detect myocardial inflammation in a rat model of autoimmune myocarditis. To induce myocarditis, rats (n = 8) were immunized with porcine cardiac myosin in complete Freund's adjuvant on days 0 and 7. Control rats (n = 8) received Freund's adjuvant alone. On day 21, in vivo PET/CT imaging with [68Ga]Ga-NODAGA-RGD followed by ex vivo autoradiography and immunohistochemistry were carried out. Inflammatory lesions were detected histologically in the myocardium of 7 out of 8 immunized rats. In vivo PET images showed higher [68Ga]Ga-NODAGA-RGD accumulation in the myocardium of rats with inflammation than the non-inflamed myocardium of control rats (SUVmean 0.4 ± 0.1 vs. 0.1 ± 0.02; P = 0.00006). Ex vivo autoradiography and histology confirmed that [68Ga]Ga-NODAGA-RGD uptake co-localized with inflammatory lesions containing αvβ3 integrin-positive capillary-like structures. A non-specific [68Ga]Ga-DOTA-(RGE)2 tracer showed 76% lower uptake than [68Ga]Ga-NODAGA-RGD in the inflamed myocardium. Our results indicate that αvβ3 integrin-targeting [68Ga]Ga-NODAGA-RGD is a potential PET tracer for the specific detection of active inflammatory lesions in autoimmune myocarditis.

scholarly journals A Semi Rigid Novel Hydroxamate AMPED-Based Ligand for 89Zr PET Imaging

Molecules ◽  
2021 ◽  
Vol 26 (19) ◽  
pp. 5819
Author(s):  
Lisa Russelli ◽  
Francesco De Rose ◽  
Loredana Leone ◽  
Sybille Reder ◽  
Markus Schwaiger ◽  
...  
Keyword(s):  
Pet Imaging ◽  
Ex Vivo ◽  
Small Animal ◽  
Biologically Active ◽  
Small Animal Pet ◽  
Organ Distribution ◽  
Complexing Agent ◽  
Distribution Studies

In this work, we designed, developed, characterized, and investigated a new chelator and its bifunctional derivative for 89Zr labeling and PET-imaging. In a preliminary study, we synthesized two hexadentate chelators named AAZTHAS and AAZTHAG, based on the seven-membered heterocycle AMPED (6-amino-6-methylperhydro-1,4-diazepine) with the aim to increase the rigidity of the 89Zr complex by using N-methyl-N-(hydroxy)succinamide or N-methyl-N-(hydroxy)glutaramide pendant arms attached to the cyclic structure. N-methylhydroxamate groups are the donor groups chosen to efficiently coordinate 89Zr. After in vitro stability tests, we selected the chelator with longer arms, AAZTHAG, as the best complexing agent for 89Zr presenting a stability of 86.4 ± 5.5% in human serum (HS) for at least 72 h. Small animal PET/CT static scans acquired at different time points (up to 24 h) and ex vivo organ distribution studies were then carried out in healthy nude mice (n = 3) to investigate the stability and biodistribution in vivo of this new 89Zr-based complex. High stability in vivo, with low accumulation of free 89Zr in bones and kidneys, was measured. Furthermore, an activated ester functionalized version of AAZTHAG was synthesized to allow the conjugation with biomolecules such as antibodies. The bifunctional chelator was then conjugated to the human anti-HER2 monoclonal antibody Trastuzumab (Tz) as a proof of principle test of conjugation to biologically active molecules. The final 89Zr labeled compound was characterized via radio-HPLC and SDS-PAGE followed by autoradiography, and its stability in different solutions was assessed for at least 4 days.

scholarly journals Maximizing the use of batch production of 18F-FDOPA for imaging of brain tumors to increase availability of hybrid PET/MR imaging in clinical setting

2020 ◽  
Author(s):  
M S Aboian ◽  
R Barajas ◽  
J Shatalov ◽  
V Ravanfar ◽  
E Bahroos ◽  
...  
Keyword(s):  
Clinical Practice ◽  
Amino Acid ◽  
Brain Tumors ◽  
Pet Imaging ◽  
Critical Role ◽  
Normal Brain ◽  
Mri Imaging ◽  
Pet Tracer ◽  
Amino Acid Pet ◽  
The Cost

Abstract Background Amino acid PET imaging of brain tumors has been shown to play an important role in predicting tumor grade, delineation of tumor margins, and differentiating tumor recurrence from the background of post-radiation changes, but is not commonly used in clinical practice due to high cost. We propose that PET/MRI imaging of patients grouped to the day of tracer radiosynthesis will significantly decrease the cost of PET imaging, which will improve patient access to PET. Methods Seventeen patients with either primary brain tumors or metastatic brain tumors were recruited for imaging on 3T PET/MRI and were scanned on 4 separate days in groups of 3-5 patients. The first group of consecutively imaged patients contained three patients, followed by two groups of 5 patients, and last group of 4 patients. Results For each of the patients, standard of care gadolinium enhanced MRI and dynamic PET imaging with 18F-FDOPA amino acid tracer was obtained. The total cost savings of scanning 17 patients in batches of 4 as opposed to individual radiosynthesis was 48.5% ($28,321). Semiquantitative analysis of tracer uptake in normal brain were performed with appropriate accumulation and expected subsequent washout. Conclusion Amino acid PET tracers have been shown to play a critical role in characterization of brain tumors but their adaptation to clinical practice has been limited due to high cost of PET. Scheduling patient imaging to maximally utilize the radiosynthesis of imaging tracer significantly reduces the cost of PET and results in increased availability of PET tracer use in neuro-oncology.

scholarly journals A novel PET tracer 18F-deoxy-thiamine: synthesis, metabolic kinetics, and evaluation on cerebral thiamine metabolism status

2020 ◽  
Author(s):  
Changpeng Wang ◽  
Siwei Zhang ◽  
Yuefei Zou ◽  
Hongzhao Ma ◽  
Donglang Jiang ◽  
...  
Keyword(s):  
High Performance ◽  
Specific Activity ◽  
High Accumulation ◽  
Metabolic Kinetics ◽  
Thiamine Metabolism ◽  
Pet Tracer ◽  
The Status ◽  
The Brain

Abstract Background: Some neuropsychological diseases are associated with abnormal thiamine metabolism, including Korsakoff-Wernicke syndrome and Alzheimer’s disease. However, in vivo detection of the status of brain thiamine metabolism is still unavailable and needs to be developed. Methods: A novel PET tracer of 18F-deoxy-thiamine was synthesized using an automated module via a two-step route. The main quality control parameters, such as specific activity, radiochemical purity, radiochemical concentration, were evaluated by high performance liquid chromatography (HPLC). Metabolic kinetics and brain level of 18F-deoxy-thiamine in mice and marmosets were studied by micro-positron emission tomography/computed tomography (PET/CT). In vivo stability, renal excretion rate, biodistribution of 18F-deoxy-thiamine in the mice were assayed using HPLC and γ-counter. Also, the correlation between the retention of cerebral 18F-deoxy-thiamine in 60 minutes after injection as represented by the area under the curve (AUC) and blood thiamine levels were investigated. Results: The 18F-deoxy-thiamine was stable both in vitro and in vivo. The uptake and clearance of 18F-deoxy-thiamine were quick in the mice. It reached the max standard uptake value (SUVmax) of 4.61±0.53 in the liver within 1 minute, 18.67±7.04 in the kidney within half a minute. The SUV dropped to 0.72±0.05 and 0.77±0.35 after 60 minutes of injection in the liver and kidney, respectively. After injection, kidney, liver, and pancreas exhibited high accumulation level of 18F-deoxy-thiamine, while brain, muscle, fat, and gonad showed low accumulation concentration, consistent with previous reports on thiamine distribution in mice. Within 90 minutes after injection, the level of 18F-deoxy-thiamine in the brain of C57BL/6 mice with thiamine deficiency by thiamine-deprived diet (TD) was 1.9 times higher than that in control mice, and was 3.1 times higher in ICR mice with TD than that in control mice. The AUC of the tracer in the brain of marmosets within 60 minutes was 29.33 ± 5.15 and negatively correlated with blood thiamine diphosphate levels (r = -0.985, p = 0.015).Conclusion: The 18F-deoxy-thiamine meets the requirements for ideal PET tracer for in vivo detecting the status of cerebral thiamine metabolism.

Development and validation of an immuno-PET tracer for patient stratification and therapy monitoring of antibody-drug conjugate therapy.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 11006-11006
Author(s):  
Ohad Ilovich ◽  
Arutselvan Natarajan ◽  
Ataya Sathirachinda ◽  
Richard Kimura ◽  
Ananth Srinivasan ◽  
...  
Keyword(s):  
Therapy Monitoring ◽  
Small Animal Pet ◽  
Patient Stratification ◽  
Phase I Clinical Trials ◽  
Serum Stability ◽  
Pet Tracer ◽  
Biodistribution Studies ◽  
Companion Diagnostic ◽  
Antibody Drug

11006 Background: SAR566658 is an antibody-drug immunoconjugate consisting of a humanized monoclonal antibody (huDS6) against the tumor-associated MUC1-sialoglycotope, CA6, conjugated to a cytotoxic maytansinoid (DM4). SAR566658 is currently undergoing phase I clinical trials in patients with CA6-positive solid tumors. A companion diagnostic based on huDS6 may facilitate patient stratification and early evaluation of therapeutic efficacy. The present study describes the development and preclinical evaluation of three novel Copper-64 (t½= 12.7h) labeled antibody fragments (two Fabs and a diabody) derived from the huDS6 antibody. One fragment was chosen based on imaging figures of merit for further specificity evaluations. Methods: The affinity of all fragments and their DOTA conjugates to CA6 was validated using flow cytometry. The DOTA conjugates were labeled with Copper-64 and evaluated in human serum stability studies, in vivo small animal PET imaging and 24-hour biodistribution studies in nude mice bearing either CA6 positive (WISH) or CA6 negative (A2780) subcutaneous tumors. The specificity of the lead tracer was evaluated in vivo via blocking studies and isotype controls. Results: All fragments and their DOTA conjugates had high affinity (Kd = 4-20 nM) for WISH cells. 64Cu-DOTA-B-Fab gave superior results in radio-synthesis (RCY - 60%, SA - 55 GBq/µmole, >99% purity), serum stability (94±5%, n=3) and biodistribution profile. Its two isotype controls gave statistically significant (P<0.05) uptake values in WISH but not A2780 tumors (see table). Blocking with B-Fab or huDS6 prior to tracer administration afforded a 23% (p<0.05, n=8) and 26% (p<0.05, n=7) decrease in WISH tumor uptake, respectively. Conclusions: These preclinical studies suggest that 64Cu-DOTA-B-Fab may be a suitable companion diagnostic for SAR566658 in cancer patients and requires further investigation.[Table: see text]

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