The integrin a v b 3 receptor is upregulated on tumor cells and endothelium and plays important roles in angiogenesis and metastasis. Arg-Gly-Asp (RGD) peptide ligands have high affinity for these integrins and can be radiolabeled for PET imaging of angiogenesis or tumor development. We have assessed the safety, stability, and tumor distribution kinetics of a novel radiolabeled RGD-based integrin peptide-polymer conjugate, 18 F-AH111585, and its feasibility to detect tumors in metastatic breast cancer patients using PET. Methods: The biodistribution of 18 F-AH111585 was assessed in 18 tumor lesions from 7 patients with metastatic breast cancer by PET, and the PET data were compared with CT results. The metabolic stability of 18 F-AH111585 was assessed by chromatography of plasma samples. Regions of interest (ROIs) defined over tumor and normal tissues of the PET images were used to determine the kinetics of radioligand binding in tissues. Results: The radiopharmaceutical and PET procedures were well tolerated in all patients. All 18 tumors detected by CT were visible on the 18 F-AH111585 PET images, either as distinct increases in uptake compared with the surrounding normal tissue or, in the case of liver metastases, as regions of deficit uptake because of the high background activity in normal liver tissue. 18 F-AH111585 was either homogeneously distributed in the tumors or appeared within the tumor rim, consistent with the pattern of viable peripheral tumor and central necrosis often seen in association with angiogenesis. Increased uptake compared with background (P 5 0.002) was demonstrated in metastases in lung, pleura, bone, lymph node, and primary tumor. Conclusion: 18 F-AH111585 designed to bind the a v b 3 integrin is safe, metabolically stable, and retained in tumor tissues and detects breast cancer lesions by PET in most anatomic sites.

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ABSTRACT:The NC100668 consists of a 13-amino acid peptide, N-terminally blocked with an acetyl group containing an iodinated tyrosine and coupled to a Tc-chelator (NC100194) via the C-terminal glycine. Using the common three-letter abbreviations for amino acids, the structure of NC100668 is Acetyl-Asn-Gln-Glu-Gln-Val-Ser-ProTyr(3-iodo)-Thr-Leu-Leu-Lys-Gly-NC100194, where NC100194 is represented by the chemical formula -NH-CH 2 -CH 2 -N(CH 2 -CH 2 -NH-C(CH 3 ) 2 -C(CH 3 )ϭN-OH) 2 . The detailed structure is shown in Fig. 1.99m Tc-NC100668 is being developed as a diagnostic radiopharmaceutical for imaging of venous thromboembolism, which is a major health problem with an estimated average annual incidence in the United States exceeding 1 per 1000 (Silverstein et al., 1998). The peptide moiety of NC100668 is similar to part of the N-terminal sequence in ␣ 2 -antiplasmin (Moroi and Aoki, 1976;Lijnen et al., 1987). The mechanism of action is by covalent linking between a glutamine in ␣ 2 -antiplasmin (corresponding to Gln-2 in NC100668) and a lysine in fibrin mediated by enzymatic action of blood coagulation factor XIIIa (Ichinose et al., 1983;Lee et al., 2001;Jaffer et al., 2004).Diagnostic radiopharmaceuticals are radioactive substances that are administered to patients. Many of these agents are labeled with the ␥-emitter 99m Tc, which has a half-life of 6.02 h (Liu et al., 1997). Due to the short half-life, the 99m Tc-based agents are distributed to hospitals in a Tc-free form as a freeze-dried product ready for labeling with technetium. On the day of the imaging procedure, the 99m Tc is added to the product as the pertechnetate anion TcO 4 Ϫ eluted from a 99 Mo/ 99m Tc generator with saline. The freeze-dried substances are then solubilized in saline in the presence of a reducing agent, which converts the pertechnetate to a lower oxidation state, facilitating coordination to the chelate component of the agent. There is a vast excess of the agent compared with the added Tc as typically less than 1% of the injected agent is in the form of the Tc complex. Hence, the unlabeled agent makes up almost the entire amount of the chemical entity injected, whereas there is only the very small amount of the 99m Tc-labeled agent, which is visualized during the diagnostic imaging procedure. The Tc-free substance is therefore in focus when Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.doi:10.1124/dmd.105.006239.ABBREVIATIONS: NC100668, Acetyl-Asn-Gln-Glu-Gln-Val-Ser-Pro-Tyr(3-iodo)-Thr-Leu-Leu-Lys-Gly-NC100194; NC100194, -NH-CH 2 -CH 2 -N(CH 2 -CH 2 -NH-C(CH 3 ) 2 -C(CH 3 )ϭN-OH) 2 ; Fmoc, 9-fluorenyloxycarbonyl; Boc, butyl oxy carbonyl; PyBOP, benzotriazole-1-yl-oxy-tris-pyrrolidinophosphonium hexafluorophosphate; DMF, dimethylformamide; TFA, trifluoroacetic acid; MS, mass spectrometry; HPLC, high-performance liquid chromatography; QWBA, quantitative whole-body autoradiography; SAC, self-absorption coefficient; % ID, percentage of injected dose; LC-MS, liquid chromatography-mass...

Developing racemic radiotracers, as for racemic therapeutics, is a considerable challenge due to differences of the enantiomers in pharmacokinetics, efficacy and potential toxicity. We have shown that the enantiomers of the promising racemic PET ligand [(18)F]GE-180 do not share identical performance, with S-[(18)F]GE-180 demonstrating higher TSPO affinity, higher brain uptake and better retention to the high TSPO-expressing lungs. Furthermore, S-[(18)F]GE-180 has also been shown to be enantiomerically stable in vivo, with no observed conversation of the eutomer to the distomer. As a single enantiomer, S-[(18)F]GE-180 retains the beneficial characteristics of the racemate and is a promising imaging agent for imaging neuroinflammation in vivo.

Targeted protein biomarker determination by immunocapture LC-MS/MS: comparison of peptide and protein capture using anti-protein antibodies.

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