18F-RB390: innovative ligand for imaging the T877A androgen receptor mutant in prostate cancer via positron emission tomography (PET).

BACKGROUND Detecting prostate cancer before spreading or predicting a favorable therapy are challenging issues for impacting patient's survival. Presently, 2-[(18) F]-fluoro-2-deoxy-D-glucose ((18) F-FDG) and/or (18) F-fluorocholine ((18) F-FCH) are the generally used PET-tracers in oncology yet do not emphasize the T877A androgen receptor (AR) mutation being exclusively present in cancerous tissue and escaping androgen deprivation treatment. METHODS We designed and synthesized fluorinated 5α-dihydrotestosterone (DHT) derivatives to target T877A-AR. We performed binding assays to select suitable candidates using COS-7 cells transfected with wild-type or T877A AR (WT-AR, T877A-AR) expressing plasmids and investigated cellular uptake of candidate (18) F-RB390. Stability, biodistribution analyses and PET-Imaging were assessed by injecting (18) F-RB390 (10MBq), with and without co-injection of an excess of unlabeled DHT in C4-2 and PC-3 tumor bearing male SCID mice (n = 12). RESULTS RB390 presented a higher relative binding affinity (RBA) (28.1%, IC50  = 32 nM) for T877A-AR than for WT-AR (1.7%, IC50  = 357 nM) related to DHT (RBA = 100%). A small fraction of (18) F-RB390 was metabolized when incubated with murine liver homogenate or human blood for 3 hr. The metabolite of RB390, 3-hydroxysteroid RB448, presented similar binding characteristics as RB390. (18) F-RB390 but not (18) F-FDG or (18) F-FCH accumulated 2.5× more in COS-7 cells transfected with pSG5AR-T877A than with control plasmid. Accumulation was reduced with an excess of DHT. PET/CT imaging and biodistribution studies revealed a significantly higher uptake of (18) F-RB390 in T877A mutation positive xenografts compared to PC-3 control tumors. This effect was blunted with DHT. CONCLUSION Given the differential binding capacity and the favorable radioactivity pattern, (18) F-RB390 represents the portrayal of the first imaging ligand with predictive potential for mutant T877A-AR in prostate cancer for guiding therapy. Prostate 75:348-359, 2015. © 2014 Wiley Periodicals, Inc.

Serial [18F]-fluoromisonidazole PET during radiochemotherapy for locally advanced head and neck cancer and its correlation with outcome.

PURPOSE The aim was to assess changes of tumour hypoxia during primary radiochemotherapy (RCT) for head and neck cancer (HNC) and to evaluate their relationship with treatment outcome. MATERIAL AND METHODS Hypoxia was assessed by FMISO-PET in weeks 0, 2 and 5 of RCT. The tumour volume (TV) was determined using FDG-PET/MRI/CT co-registered images. The level of hypoxia was quantified on FMISO-PET as TBRmax (SUVmaxTV/SUVmean background). The hypoxic subvolume (HSV) was defined as TV that showed FMISO uptake ⩾1.4 times blood pool activity. RESULTS Sixteen consecutive patients (T3-4, N+, M0) were included (mean follow-up 31, median 44months). Mean TBRmax decreased significantly (p<0.05) from 1.94 to 1.57 (week 2) and 1.27 (week 5). Mean HSV in week 2 and week 5 (HSV2=5.8ml, HSV3=0.3ml) were significantly (p<0.05) smaller than at baseline (HSV1=15.8ml). Kaplan-Meier plots of local recurrence free survival stratified at the median TBRmax showed superior local control for less hypoxic tumours, the difference being significant at baseline and after 2weeks (p=0.031, p=0.016). CONCLUSIONS FMISO-PET documented that in most HNC reoxygenation starts early during RCT and is correlated with better outcome.

Changes in [18F]Fluoro-2-deoxy-D-glucose incorporation induced by doxorubicin and anti-HER antibodies by breast cancer cells modulated by co-treatment with metformin and its effects on intracellular signalling

Peer reviewed

A two-step fluorinase enzyme mediated 18F labelling of an RGD peptide for positron emission tomography

Peer reviewed

Changes in [18F]Fluoro-2-deoxy-D-glucose incorporation induced by doxorubicin and anti-HER antibodies by breast cancer cells modulated by co-treatment with metformin and its effects on intracellular signalling

Peer reviewed

A two-step fluorinase enzyme mediated 18F labelling of an RGD peptide for positron emission tomography

Peer reviewed

Last-step enzymatic [18F]-fluorination of cysteine-tethered RGD peptides using modified Barbas linkers

Acknowledgements We thank the Engineering and Physical Sciences Research Council, UK, for a research grant. Funded by Engineering and Physical Sciences Research Council, UK

Changes in [18F]Fluoro-2-deoxy-D-glucose incorporation induced by doxorubicin and anti-HER antibodies by breast cancer cells modulated by co-treatment with metformin and its effects on intracellular signalling

Peer reviewed

A two-step fluorinase enzyme mediated 18F labelling of an RGD peptide for positron emission tomography

Peer reviewed

Cerebrotendinous xanthomatosis with bradyphrenia and psychiatric disorders: a case with 18F-FDG PET imaging and a literature review

Background and Objectives: Cerebrotendinous xanthomatosis (CTX) is a rare autosomal recessive lipid-storage disease caused by mutations in the CYP27A1. The purpose of this study is to determine the clinical characteristics, neuroimaging and mutation detect in a family with CTX systematically. Methods: Collecting history materials and detecting the routine clinical biochemical tests and imaging examination, and for the first time taking the whole body positron emission tomography (PET)-CT examination for probed in the world to research abnormal metabolism activities in CTX. To observe the effect of treatment with chenodeoxycholic acid (CDCA) and stains before and after the intervention, using serum lipid level detection and neuropsychological evaluation. Genetic testing was carried out to screen the nine exons and exon-intron boundaries about 200-300bq of CYP27A1. Results: A 37-year-old woman with typical clinical characteristics of CTX. Magnetic resonance imaging (MRI) of brain showed bilateral lesions in the dentate nucleus of the cerebellum, then, PET images revealed multiple abnormal hypermetabolism areas at distal tendon, and multifocal areas of hypometabolism in bilateral sides of cerebellar hemispheres, the frontal lobe and temporal lobe. Histopathology reveals accumulation of xanthoma cells and dispersed lipid crystal clefts in xanthomas. In genetic analysis, it shown an insertion of cytosine (77-78insC) located in the first exon of CYP27A1 in the proband. Conclusions: We found that a Chinese patient presented a typical clinical feature of CTX along with clear correlation on both structural and functional imaging had a novel mutation in the CYP27A1 gene.

16α-[18F]-fluoro-17ß-oestradiol ([18F]FES): A biomarker for imaging oestrogen receptor expression with positron emission tomography (PET)

International audience

Estudo combinado de PET com [11C]PiB e [18F]FDG na avaliação de doença de Alzheimer

A doença de Alzheimer (DA) têm-se constituído, nos últimos anos, num sério problema de saúde pública nas sociedades ocidentais, um reflexo de uma população cada vez mais envelhecida fruto da melhoria geral da assistência médica e das mudanças demográficas daí decorrentes. Tratando-se uma doença neurodegenerativa a DA conduz à perda de diversas faculdades cognitivas e carateriza-se pela redução progressiva de tamanho e número das células cerebrais, a par da formação de emaranhados neurofibrilares (NFTs) no seu interior e placas de β-amilóide (Aβ) no espaço exterior. Na última década, o diagnóstico da DA ganhou um importante aliado com a possibilidade de realização de Tomografia por Emissão de Positrões (PET) com o radiofármaco [11C]PiB que apresenta afinidade pelas placas de Aβ. Recentemente, foi também possível aumentar a confiança deste diagnóstico complementando-o com a avaliação do metabolismo cerebral da glicose através da sua conjugação, no mesmo protocolo PET com a [18F]FDG. No que concerne à realidade portuguesa, o ICNAS, uma unidade orgânica de investigação da Universidade de Coimbra focada na Utilização Biomédica das Ciências Nucleares, que inclui na sua estrutura uma unidade de produção radiofarmacêutica com ciclotrão, é um local privilegiado para a realização de PET cerebral com [11C]PiB. Desde Abril de 2012 até Julho de 2014 foram já realizados 107 estudos com [11C]PiB, dos quais 37 fizeram parte de estudos sequenciais onde o mesmo doente realizou o estudo combinado com [11C]PiB e [18F]FDG.

Exposição à radiação em exames de corpo inteiro de 18F-FDG PET-TC

O sistema de PET-TC resulta da combinação de duas modalidades de imagem médica: a Tomografia Computorizada (TC), que permite obter imagens anatómicas precisas, e a Tomografia por Emissão de Positrões (PET), que oferece imagens moleculares do corpo humano. Num exame hibrido de PET-TC, para além da exposição interna, o doente é também submetido a uma exposição externa devida à irradiação do mesmo por uma fonte externa, referente à aquisição dos dados de TC. Como tal, o exame de PET-TC tem associado um aumento da exposição para o doente [Huang, 2009], pelo que normalmente os scans de TC são adquiridos com baixa dose [Nunes,2011]. Pretende-se com este trabalho, estabelecer um método capaz de estimar a dose efetiva em exames de corpo inteiro de 18F-FDG PET-TC, uma vez que existem diversos métodos para realizar análise dosimétrica dos exames individuais de PET e de TC, e comparar os valores obtidos com os valores utilizados em outros países. Foram recolhidos dados de 24 pacientes que efetuaram exames de corpo inteiro de PET-TC com 18F-FDG no ICNAS, por questões de saúde e por necessidade própria, com o intuito de estimar a dose efetiva associada a esses exames. Para estimar a dose efetiva referente ao exame de TC recorreu-se ao valor de DLP, fornecido pelo equipamento de TC com controlo de qualidade em dia, e ao método dos coeficicientes de dose efetiva normalizados, proposto pela CE, obtendo-se um valor de dose de 4.75 mSv. A dose efetiva do exame de PET foi calculada com base nos valores da atividade no momento de aquisição das imagens e em coeficientes de dose para a PET, obtendo-se um valor de dose de 4.77 mSv. Concluiu-se que para os pacientes sujeitos ao exame de corpo inteiro de 18F-FDG PET-TC, foi registado um valor de dose de 9.47 mSv de dose efetiva. Este valor de dose efetiva para os exames de PET-TC é significativamente mais baixo comparativamente aos valores registados em vários estudos internacionais (13.65 mSv, 14.3 mSv, 18.85 mSv, 24.8 mSv, 25 mSv, 32.18 mSv), dos quais apenas no estudo de Brix um dos hospitais estudados regista um valor ligeiramente inferior, de 8.5 mSv. Com este estudo foi possível determinar o valor de exposição à radiação a que os pacientes do ICNAS se encontram sujeitos em exames de corpo inteiro de 18F-FDG PET-TC considerando as duas modalidades de imagem médica.