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Purpose: Non-invasive imaging of metabotropic glutamate receptor 5 (mGlu5) in the brain using PET is of interest in e.g., anxiety, depression, and Parkinson’s disease. Widespread application of the most widely used mGlu5 tracer, [11C]ABP688, is limited by the short physical half-life of carbon-11. [18F]PSS232 is a fluorinated analog with promising preclinical properties and high selectivity and specificity for mGlu5. In this first-in-man study, we evaluated the brain uptake pattern and kinetics of [18F]PSS232 in healthy volunteers.Methods: [18F]PSS232 PET was performed with ten healthy male volunteers aged 20-40 years. Seven of the subjects received a bolus injection and the remainder a bolus/infusion protocol. Cerebral blood flow was determined in seven subjects using [15O]water PET. Arterial blood activity was measured using an online blood counter. Tracer kinetics were evaluated by compartment modeling and parametric maps were generated for both tracers.Results: At 90 min post-injection, 59.2 ± 11.1% of total radioactivity in plasma corresponded to intact tracer. The regional first pass extraction fraction of [18F]PSS232 ranged from 0.41 ± 0.06 to 0.55 ± 0.03 and brain distribution pattern matched that of [11C]ABP688. Uptake kinetics followed a simple two-tissue compartment model. The volume of distribution of total tracer (VT, ml/cm3) ranged from 1.18 ± 0.20 for white matter to 2.91 ± 0.51 for putamen. The respective mean distribution volume ratios (DVR) with cerebellum as the reference tissue were 0.88 ± 0.06 and 2.12 ± 0.10, respectively. The tissue/cerebellum ratios of a bolus/infusion protocol (30/70 dose ratio) were close to the DVR values.Conclusions: Brain uptake of [18F]PSS232 matched the distribution of mGlu5 and followed a two-tissue compartment model. The well-defined kinetics and the possibility to use reference tissue models, obviating the need for arterial blood sampling, make [18F]PSS232 a promising fluorine-18 labeled radioligand for measuring mGlu5 density in humans. [ABSTRACT FROM AUTHOR]

Amino acid transport is an attractive target for oncologic imaging. Despite a high demand of cancer cells for cationic amino acids, their potential as PET probes remains unexplored. Arginine, in particular, is involved in a number of biosynthetic pathways that significantly influence carcinogenesis and tumor biology. Cationic amino acids are transported by several cationic transport systems including, ATB (SLC6A14), which is upregulated in certain human cancers including cervical, colorectal and estrogen receptor-positive breast cancer. In this work, we report the synthesis and preliminary biological evaluation of a new cationic analog of the clinically used PET tumor imaging agent O-(2-[F]fluroethyl)- l-tyrosine ([F]FET), namely O-2((2-[F]fluoroethyl)methylamino)ethyltyrosine ([F]FEMAET). Reference compound and precursor were prepared by multi-step approaches. Radiosynthesis was achieved by no-carrier-added nucleophilic [F]fluorination in 16-20 % decay-corrected yields with radiochemical purity >99 %. The new tracer showed good stability in vitro and in vivo. Cell uptake assays demonstrated that FEMAET and [F]FEMAET accumulate in prostate cancer (PC-3) and small cell lung cancer cells (NCI-H69), with an energy-dependent mechanism. Small animal PET imaging with NCI-H69 xenograft-bearing mice revealed good tumor visualization comparable to [F]FET and low brain uptake, indicating negligible transport across the blood-brain barrier. In conclusion, the non-natural cationic amino acid PET probe [F]FEMAET accumulates in cancer cells in vitro and in vivo with possible involvement of ATB. [ABSTRACT FROM AUTHOR]

Purpose: The concentrative amino acid transporter ATB (SLC6A14) is under evaluation as a target for anticancer therapy. An ATB-selective positron emission tomography (PET) probe could advance preclinical drug development. We characterised the cationic tyrosine analogue O-2((2-[F]fluoroethyl)methyl-amino)ethyltyrosine ([F]FEMAET) as a PET probe for ATB activity. Procedures: Cell uptake was studied in vitro. ATB expression was quantified by real-time PCR. [F]FEMAET accumulation in xenografts was investigated by small animal PET with mice. Results: [F]FEMAET accumulated in PC-3 and NCI-H69 cancer cells in vitro. As expected for ATB transport, uptake was inhibited by LAT/ATB inhibitors and dibasic amino acids, and [F]FEMAET efflux was only moderately stimulated by extracellular amino acids. ATB was expressed in PC-3 and NCI-H69 but not MDA-MB-231 xenografts. PET revealed accumulation in PC-3 and NCI-H69 xenografts and significant reduction by ATB inhibition. Uptake was negligible in MDA-MB-231 xenografts. Conclusion: ATB activity can be imaged in vivo by PET with [F]FEMAET. [ABSTRACT FROM AUTHOR]

Introduction Both subtypes of sigma (σ) receptors, σ 1 and σ 2 , are over-expressed in many cancers with σ 2 proposed as a biomarker of tumor proliferation. We are interested in developing a high affinity selective σ 2 radioligand for in vivo monitoring of proliferative status of solid tumors and response to anti-cancer therapies. 1-Cyclohexyl-4-[3-(5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)propyl]piperazine (PB28) represents one of the lead candidates in the development of σ receptor ligands for therapeutic and diagnostic applications. However, the utility of PB28 is limited due to its relatively high lipophilicity. Methods A more hydrophilic analogue (–)-( S )- 1 was radiolabeled with 11 C via standard O -alkylation. In vitro autoradiography with [ 11 C](–)-( S )- 1 was done using rat brain slices. PET imaging was performed in mice bearing EMT6, C6 or PC-3 tumors after i.v. injection of [ 11 C](–)-( S )- 1 . Results [ 11 C](–)-( S )- 1 was produced in 53% ± 7% isolated decay-corrected yield with radiochemical and chemical purity over 99% and specific activity greater than 100 GBq/μmol. In vitro autoradiography with [ 11 C(–)-( S )- 1 resulted in a heterogeneous binding of the tracer in the rat brain with the highest radioactivity signals in the cortex region followed by cerebellum. This binding was successfully blocked by 10 μM of either haloperidol, (+)-( R )- 1 or PB28. For C6 xenografts low target-to-nontarget ratio and high non-specific binding did not allow clear tumor visualization. No accumulation was visible in EMT6 tumor or in PC-3 tumor. Rat and mouse brain uptake was low and homogeneous while stronger signal was detected in the spinal cord. High accumulation of radioactivity was observed in liver and intestine suggesting hepatobiliary clearance. Conclusions Despite excellent in vitro properties, [ 11 C](–)-( S )- 1 did not provide high enough specific binding in vivo and is, therefore, not a useful PET tracer for imaging σ 2 expression in tumors. [ABSTRACT FROM AUTHOR]

Abstract: In the search for an efficient, fluorine-18 labeled amino acid based radiotracer for tumor imaging with positron emission tomography (PET), two new tryptophan analogs were synthesized and characterized in vitro and in vivo. Both are tryptophan alkyl-derivatives, namely 2-(3-[18F]fluoropropyl)-dl-tryptophan ([18F]2-FPTRP) and 5-(3-[18F]fluoro-propyl)-dl-tryptophan ([18F]5-FPTRP). Standard reference compounds and precursors were prepared by multi step approaches. Radiosynthesis was achieved by no-carrier-added nucleophilic [18F]fluorination in 29–34% decay corrected yields with radiochemical purity over 99%. In vitro cell uptake assays showed that both compounds are substrates for amino acid transport and enter small cell lung cancer cells (NCI-H69) most probably almost exclusively via large neutral amino acids transporter(s) (LAT). Small animal PET imaging with xenograft bearing mice revealed high tumor/background ratios for [18F]2-FPTRP comparable to the well established tyrosine analog O-(2-[18F]fluroethyl)-l-tyrosine ([18F]FET). Radiometabolite studies showed no evidence of involvement of a biotransformation step in tumor accumulation. [Copyright &y& Elsevier]

Abstract: σ2 Receptors are promising biomarkers for cancer diagnosis given the relationship between the proliferative status of tumors and their density. With the aim of contributing to the research of σ2 receptor Positron Emission Tomography (PET) probes, we developed 2-[3-[6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl]propyl]-3,4-dihydroisoquinolin-1(2H)-one (3), with optimal σ2 pharmacological properties and appropriate lipophilicity. Hence, 3 served as the lead compound for the development of a series of dihydroisoquinolinones amenable to radiolabeling. Radiosynthesis for compound 26, which displayed the most appropriate σ2 profile, was developed and σ2 specific binding for the corresponding [18F]-26 was confirmed by in vitro autoradiography on rat brain slices. Despite the excellent in vitro properties, [18F]-26 could not successfully image σ2 receptors in the rat brain in vivo, maybe because of its interaction with P-gp. Nevertheless, [18F]-26 may still be worthy of further investigation for the imaging of σ2 receptors in peripheral tumors devoid of P-gp overexpression. [Copyright &y& Elsevier]

Abstract: Introduction: We report on the synthesis, radiolabeling, in vitro and in vivo characterization of N-Me-[18F]FHBT (6-(3-[18F]fluoro-2-(hydroxymethyl)propyl)-1,5-dimethylpyrimidin-2,4(1H,3H)-dione), a C-6-substituted N-1-methylated pyrimidine derivative as a reporter probe for imaging herpes simplex virus type 1 thymidine kinase (HSV1-TK) expression. Methods: N-Me-[18F]FHBT was synthesized via a standard nucleophilic substitution reaction followed by acidic cleavage of the methoxytrityl protecting group. Cell uptake was studied in vitro with control HEK293 (human embryonic kidney cells) and HEK293 cells stably transfected with nonmutant HSV1-tk (HEK293TK+ cells). Positron emission tomography (PET) imaging and biodistribution studies of N-Me-[18F]FHBT or [18F]FHBG were performed in nude mice bearing xenografts of HEK293 control and TK+ cells. Results: N-Me-[18F]FHBT was obtained in a two-step reaction in an overall maximal radiochemical yield (decay-corrected) of 5% and a radiochemical purity >96%. The tracer uptake in HSV1-TK containing HEK293TK+ cells was 14.5 times (at 30 min) and 55.4 times (at 240 min) higher than in control HEK293 cells. In mice, N-Me-[18F]FHBT and [18F]FHBG accumulated significantly and exhibited similar radioactivity levels in the HEK293TK+ xenografts; however, standardized uptake values ratios between HEK293TK+ and HEK293 control xenografts were higher for [18F]FHBG than for N-Me-[18F]FHBT. Both tracers showed high gall bladder and abdominal activity. Conclusion: The biological evaluations demonstrated the feasibility of using N-methylated C-6-substituted pyrimidine derivative N-Me-[18F]FHBT as a PET radiotracer for monitoring HSV1-TK expression in vivo. [Copyright &y& Elsevier]