Design, synthesis, and evaluation of a novel PET imaging agent targeting lipofuscin in senescent cells.

Promoting a senescent phenotype to suppress tumour progression may present an alternative strategy for treating cancer and encourages the development of positron emission tomography (PET) imaging biomarkers for assessing response to treatment. The accumulation of lipofuscin deposits in senescent cells is visualised using the pathology stain Sudan Black B (SBB) which is an emerging biomarker of senescence. We describe the design, synthesis and evaluation of [F]fluoroethyltriazole-SBB ([F]FET-SBB), a fluorine-18 radiolabelled derivative of SBB.

Synthesis and evaluation of 3'-[F]fluorothymidine-5'-squaryl as a bioisostere of 3'-[F]fluorothymidine-5'-monophosphate.

The squaryl moiety has emerged as an important phosphate bioisostere with reportedly greater cell permeability. It has been used in the synthesis of several therapeutic drug molecules including nucleoside and nucleotide analogues but is yet to be evaluated in the context of positron emission tomography (PET) imaging. We have designed, synthesised and evaluated 3'-[F]fluorothymidine-5'-squaryl ([F]SqFLT) as a bioisostere to 3'-[F]fluorothymidine-5'-monophosphate ([F]FLTMP) for imaging thymidylate kinase (TMPK) activity.

Consideration of Metabolite Efflux in Radiolabelled Choline Kinetics.

Hypoxia is a complex microenvironmental condition known to regulate choline kinase α (CHKA) activity and choline transport through transcription factor hypoxia-inducible factor-1α (HIF-1α) and, therefore, may confound the uptake of choline radiotracer [F]fluoromethyl-[1,2-H]-choline ([F]-D4-FCH). The aim of this study was to investigate how hypoxia affects the choline radiotracer dynamics. Three underlying mechanisms by which hypoxia could potentially alter the uptake of the choline radiotracer, [F]-D4-FCH, were investigated: F-D4-FCH import, CHKA phosphorylation activity, and the efflux of [F]-D4-FCH and its phosphorylated product [F]-D4-FCHP.

Novel Non-Congeneric Derivatives of the Choline Kinase Alpha Inhibitor ICL-CCIC-0019.

Choline kinase alpha (CHKA) is a promising target for the development of cancer therapeutics. We have previously reported ICL-CCIC-0019, a potent CHKA inhibitor with high cellular activity but with some unfavorable pharmacological properties. In this work, we present an active analogue of ICL-CCIC-0019 bearing a piperazine handle (CK146) to facilitate further structural elaboration of the pharmacophore and thus improve the biological profile.

Effective Detection and Monitoring of Glioma Using [F]FPIA PET Imaging.

Background: Reprogrammed cellular metabolism is a cancer hallmark. In addition to increased glycolysis, the oxidation of acetate in the citric acid cycle is another common metabolic phenotype. We have recently developed a novel fluorine-18-labelled trimethylacetate-based radiotracer, [F]fluoro-pivalic acid ([F]FPIA), for imaging the transcellular flux of short-chain fatty acids, and investigated whether this radiotracer can be used for the detection of glioma growth.