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Abstract: The chemokine receptor CXCR4 is overexpressed in a variety of cancers including breast, prostate and lung cancer. Expression is also associated with invasion and metastasis. The possibility to image and quantify CXCR4 expression in vivo would be a valuable tool in the clinic to aid treatment regimens and to potentially understand the underlying biology of metastasis. Herein we describe the synthesis and the radiolabelling of an 18F-labelled cyclic pentapeptide, [18F]CCIC-0007 designed to bind to the extracellular domains of CXCR4. Radiolabelling was performed via conjugation of [18F]fluorobenzaldehyde with an aminooxy functionalised cyclopentapeptide. Typically, starting with 1.10GBq (30mCi) of aqueous [18F]fluoride, 105MBq (2.85mCi) of the formulated tracer was obtained within 2.5h (23±8% dc rcy, 8% EOS yield). Tissue pharmacokinetic studies in mice demonstrated rapid blood clearance, together with biliary and renal elimination. [Copyright &y& Elsevier]

Abstract: The epidermal growth factor receptor (EGFR/c-ErbB1/HER1) is overexpressed in many cancers including breast, ovarian, endometrial, and non-small cell lung cancer. An EGFR specific imaging agent could facilitate clinical evaluation of primary tumors and/or metastases. To achieve this goal we designed and synthesized a small array of fluorine containing compounds based on a 3-cyanoquinoline core. A lead compound, 16, incorporating 2′-fluoroethyl-1,2,3-triazole was selected for evaluation as a radioligand based on its high affinity for EGFR kinase (IC50 =1.81±0.18nM), good cellular potency (IC50 =21.97±9.06nM), low lipophilicity and good metabolic stability. ‘Click’ labeling afforded [18F]16 in 37.0±3.6% decay corrected radiochemical yield based on azide [18F]14 and 7% end of synthesis (EOS) yield from aqueous fluoride. Compound [18F]16 was obtained with >99% radiochemical purity in a total synthesis time of 3h. The compound showed good stability in vivo and a fourfold higher uptake in high EGFR expressing A431 tumor xenografts compared to low EGFR expressing HCT116 tumor xenografts. Furthermore, the radiotracer could be visualized in A431 tumor bearing mice by small animal PET imaging. Compound [18F]16 therefore constitutes a promising radiotracer for further evaluation for imaging of EGFR status. [Copyright &y& Elsevier]

Abstract: A general approach to 1,6,7-trihydroxyindolizidin-8-carboxylates is illustrated through the synthesis of a γ-lactone in an enantiopure form in seven steps starting from (3S)-3-t-butyloxy-1-pyrroline N-oxide and the acetonide of (2E,4S)-4,5-dihydroxy-2-pentenoic acid derived from (S)-malic acid and mannitol, respectively. The process was completely stereoselective and allowed the total control of the relative and absolute configuration of the five contiguous stereocentres of the product. [Copyright &y& Elsevier]

2,7-Dihydroxyhexahydropyrrolizine-1-carboxylic acid derivatives have been prepared in solid-phase by intermolecular 1,3-dipolar cycloaddition between an immobilised maleate or 4-hydroxycrotonate and an enantiopure 3-alkoxypyrroline N-oxide. [Copyright &y& Elsevier]

Anaplastic lymphoma kinase (ALK), an oncogenic receptor tyrosine kinase, is a therapeutic target in various cancers, including non-small cell lung cancer. Although several ALK inhibitors, including crizotinib, ceritinib, and alectinib, are approved for cancer treatment, their long-term benefit is often limited by the cancer's acquisition of resistance owing to secondary point mutations in ALK. Importantly, some ALK inhibitors cannot cross the blood-brain barrier (BBB) and thus have little or no efficacy against brain metastases. The introduction of a lipophilic moiety, such as a fluoroethyl group may improve the drug's BBB penetration. Herein, we report the synthesis of fluoroethyl analogues of crizotinib 1 , alectinib 4 , and ceritinib 9 , and their radiolabeling with 18F for pharmacokinetic studies. The fluoroethyl derivatives and their radioactive analogues were obtained in good yields with high purity and good molar activity. A cytotoxicity screen in ALK-expressing H2228 lung cancer cells showed that the analogues had up to nanomolar potency and the addition of the fluorinated moiety had minimal impact overall on the potency of the original drugs. Positron emission tomography in healthy mice showed that the analogues had enhanced BBB penetration, suggesting that they have therapeutic potential against central nervous system metastases. Image 1 • Anaplastic lymphoma kinase (ALK) is a therapeutic target in lung cancer. • Many ALK inhibitors are routinely used for therapy of lung cancer. • The blood-brain barrier remains a challenge for treatment of brain metastasis. • [19F/18F]Fluoroethyl analogues of ALK inhibitors have been developed and tested. • Preliminary in vitro and in vivo PET imaging pharmacokinetic results were encouraging, showing significant brain penetration. [ABSTRACT FROM AUTHOR]

Abstract: The solid-phase synthesis of two diastereomeric cyclic pseudopeptides containing the Arg-Gly-Asp sequence and the dipeptide isostere 2-amino-3-oxotetrahydro-1H-pyrrolizine-7a(5H)-carboxylic acid (GPTM) is described. Competition binding assays to purified αvβ3 and αvβ5 integrins with respect to [125I]echistatin showed a high inhibitory activity for the (2S,7aS)-GPTM derivative. Effects of the structural constraint induced by the two enantiomeric scaffolds (2R,7aR)-GPTM and (2S,7aS)-GPTM on the conformation of Arg-Gly-Asp sequence have been computationally investigated using as a reference the recently solved X-ray structure of cyclo(Arg-Gly-Asp-d-Phe-[N-Me]Val) in complex with the extracellular fragment of the αvβ3 receptor. The computational method disclosed the key role played by a bridging water molecule on differentiating the two ligands by a diverse stabilization of the ligand–protein complex. [Copyright &y& Elsevier]

Abstract: 1,3-Dipolar cycloaddition of acrylamide with the cyclic nitrone derived from proline tert-butyl ester has been employed in the synthesis of bicyclic Gly-(s-cis)Pro isosteres suitably protected for the Fmoc-based solid phase peptide synthesis. (R)-1-Phenylethylamine was introduced as chiral auxiliary to resolve racemic intermediates and obtain enantiopure compounds. Using methacrylamide as dipolarophile, the analogous Ala-Pro mimetics have been prepared in racemic form, whereas the same strategy applied to methyl itaconate failed to give the corresponding Asp-Pro mimetic. [Copyright &y& Elsevier]

Abstract: Molecular imaging is an ideal platform for non-invasive detection and assessment of cancer. In recent years, the targeted imaging of CXCR4, a chemokine receptor that has been associated with tumour metastasis, has become an area of intensive research. In our pursuit of a CXCR4-specific radiotracer, we designed and synthesised a novel derivative of the CXCR4 peptidic antagonist TN14003, CCIC16, which is amenable to radiolabelling by chelation with a range of PET and SPECT radiometals, such as 68Ga, 64Cu and 111In as well as 18F (Al18F). Potent in vitro binding affinity and inhibition of signalling-dependent cell migration by unlabelled CCIC16 were confirmed by a threefold uptake in CXCR4-over-expressing cells compared to their isogenic counterparts. Furthermore, in vivo experiments demonstrated the favourable pharmacokinetic properties of the 68Ga-labelled tracer 68 Ga–CCIC16, along with its CXCR4-specific accumulation in tissues with desirable contrast (tumour-to-muscle ratio: 9.5). The specificity of our tracer was confirmed by blocking experiments. Taking into account the attractive intrinsic PET imaging properties of 68Ga, the comprehensive preclinical evaluation presented here suggests that 68 Ga–CCIC16 is a promising PET tracer for the specific imaging of CXCR4-expressing tumours. [Copyright &y& Elsevier]