PB183, a sigma receptor ligand, as a potential PET probe for the imaging of prostate adenocarcinoma Nicola Antonio Colabufo, * Carmen Abate, Marialessandra Contino, Carmela Inglese, Mauro Niso, Francesco Berardi and Roberto Perrone Dipartimento Farmacochimico, Universita ` degli Studi di Bari, via Orabona 4, 70125 Bari, Italy Received 21 December 2007; revised 25 January 2008; accepted 29 January 2008 Available online 2 February 2008 Abstract—PB183, a non-selective sigma receptor ligand displaying high sigma-1 and sigma-2 receptor affinity, was evaluated in pros- tate tumour cell lines for its suitability as PET radiotracer. The pharmacodynamic and pharmacokinetic properties suggested PB183 as a potential PET radiotracer to visualize prostate adenocarcinoma. Ó 2008 Elsevier Ltd. All rights reserved. Sigma receptors, classified into sigma-1 and sigma-2 subtypes, are a distinct class of receptors. 1 Sigma-1 sub- type has been cloned 2 and characterized as a mamma- lian homologue of the yeast sterol isomerase 3 though devoid of enzymatic activity. Sigma-2 receptor has not been cloned yet, but recently an attempt to characterize it led to hypothesize sigma-2 subtype as a class of his- tones receptor family. 4 These receptors, present in many normal tissues, 5 are overexpressed in several human and rodent tumour cell lines, 6 so that they are considered potential biomarkers 7 for the evaluation of the proliferative status of tumour. Tumour grade and stage could be monitored by non invasive imaging techniques such as PET and SPECT. 8–12 In the last years, we have been developing several cyclohexylpiperazine derivatives as potent sig- ma-2 receptor ligands, and among them PB28 (Fig. 1) displayed a potent agonist activity 13 and a moderate selectivity towards sigma-1 subtype (sigma-1/sigma-2 ratio = 40). 14 Starting from these results, PB28 was radiolabelled as [ 11 C]PB28 by Kassiou et al. 8 and its biodistribution was evaluated in mice brain in absence and in presence of unlabelled PB28.[ 11 C]PB28 showed a good uptake, but when its specific binding was determined in the pres- ence of unlabelled PB28 or DTG or haloperidol, high non-specific binding was found. Moreover, we studied another sigma-2 ligand, PB167 (Fig. 1), suggesting it as a probe for PET studies in the same implanted tu- mour animal model. 15 Although [ 11 C]PB167 displayed a good uptake in EMT- 6 implanted cells, unfortunately its uptake in CNS was remarkable. On the other hand, PB167 in CNS 0960-894X/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved. doi:10.1016/j.bmcl.2008.01.109 Keywords: PB183; Cyclohexylpiperazine derivative; PB28; TRAMP cells; Prostate adenocarcinoma; PET. * Corresponding author. E-mail: colabufo@farmchim.uniba.it O O N N R PB28 R n 3 PB167 5 PB183 3 (CH 2 ) n Figure 1. Cyclohexylpiperazine derivatives structures. Available online at www.sciencedirect.com Bioorganic & Medicinal Chemistry Letters 18 (2008) 1990–1993