In vivo imaging method of mood disorders

#The present invention concerns in vivo imaging and in particular in vivo imaging of the peripheral benzodiazepine receptor (PBR). A method useful for the diagnosis of certain mood disorders in a subject is provided comprising use of an indole-based in vivo imaging agent.

#The peripheral benzodiazepine receptor (PBR, also known as translocator protein (TSPO)) is a mitochondrial protein involved in cell proliferation. PBR is known to be mainly localised in peripheral tissues and glial cells but its physiological function remains to be clearly elucidated. Subcellularly, PBR is known to localise on the outer mitochondrial membrane, indicating a potential role in the modulation of mitochondrial function and in the immune system. It has furthermore been postulated that PBR is involved in cell proliferation, steriodogenesis, calcium flow and cellular respiration. Perturbed PBR expression has been linked with a number of mood disorders, as now discussed.

#Using the known PBR imaging agent [11C]PK11195 to image 7 schizophrenia patients and 8 age-matched healthy volunteers, Doorduin et al (J Nucl Med 2009; 50: 1801-7) showed a significantly higher binding potential of the PBR ligand in the hippocampus of schizophrenic patients than in healthy volunteers. These data have been confirmed and extended by van Berkel et al (Biol Psychiatry 2008; 64: 820-2) who showed, by [11C]PK11195 imaging, that microglia activation is present in patients at, the onset of schizophrenia. Furthermore, Ritsner et al (J Psychiatric Res 2003; 37(6): 549-556) demonstrated decreased platelet PBR in persistently violent schizophrenia patients using 3H-PK11195 binding to platelet membranes. Nakamura et al (Am. J Med Genetics 2006; 141B(3): 222-226) demonstrated that variation in the PBR gene influences susceptibility to panic disorder. Furthermore, reduction of PBR was found in patients with panic disorder in a study carried out by Chelli et al (Eur Neuropsychopharmacol 2008; 18: 249-254). Johnson et al (Biol Psychiatry 1998 Feb. 15; 43(4):306-9) noted that patients with generalised social phobia had a significantly lower density of PBR as compared with normal control subjects. Decreased expression of PBR has been noted in patients with anxiety and post-traumatic stress disorder (Gavish et al Pharm Rev 1999; 51: 629-650; Dell'Osso et al Psychiatry Res 2010; 177(1-2): 139-143). The picture of PBR expression in depressive disorders is somewhat mixed. Weizman et al (J Affective Dis 1995; 33(4): 257-261) demonstrated that major depression, in contrast to stress and some anxiety disorders, is not associated with alteration of PBR However, decreased PBR expression where depressed patients are also suicidal has been reported by Soreni et al (Biol Psychiatry 1999; 46(4): 484-488). Also, Giubertoni et al (Biol Psychiatry 1997; 42(1): 252S) have demonstrated that patients with untreated dysthymic disorder have significantly increased PBR density compared with normal controls. Increased PBR has been, shown in patients with bipolar disorder (Marazziti et al Life Sci 2005; 77: 3268-3275). In addition, separation anxiety disorder in depressed patients was linked to a reduction in PBR expression in a study by Abelli et al (Neuropsychobiol 2010; 62(2): 98-103). Obsessive compulsive disorder may also be associated with PBR, as discussed by Rocca et al Eur Neuropsychopharm 2000; 10(5): 337-340.

#FIG. 1 shows co-elution of imaging agent 5 (prepared according to Example 1) and non-radioactive imaging agent 5 (prepared according to Example 2).

#FIG. 2 shows co-elution of imaging agent 6 (prepared according to Example 3) and non-radioactive imaging agent 6 (prepared according to Example 4).

#FIG. 3 shows co-elution of imaging agent 7 (prepared according to Example 5) and non-radioactive imaging agent 7 (prepared according to Example 6).

#In one aspect, the present invention provides a method for the diagnosis and/or monitoring in a subject of a mood disorder wherein said mood disorder is characterised by abnormal expression of peripheral benzodiazepine receptors (PBR), and wherein said method comprises the following steps: (a) administering to said subject an in vivo imaging agent of Formula I:

#wherein: R1 is C1-3 alkyl or C1-3 fluoroalkyl; R2 is hydrogen, hydroxyl, halo, cyano, C1-3 alkyl, C1-3 alkoxy, C1-3 fluoroalkyl, or C1-3 fluoroalkoxy; R3 and R4 are independently C1-3 alkyl, C7-10 aralkyl, or R3 and R4, together with the nitrogen to which they are attached, form a nitrogen-containing C4-6 aliphatic ring optionally comprising 1 further heteroatom selected from nitrogen, oxygen and sulfur; Y1 is O, S, SO, SO2 or CH2; and, Y2 is CH2, CH2—CH2, CH(CH3)—CH2 or CH2—CH2—CH2; and wherein Formula I as defined comprises an atom which is a radioisotope suitable for in vivo imaging; (b) allowing said administered in vivo imaging agent of step (a) to bind to PBR expressed in said subject; (c) detecting signals emitted by the radioisotope of said bound in vivo imaging agent of step (b) using a suitable in vivo imaging procedure; (d) generating an image representative of the distribution and/or extent of said signals detected in step (c); and, (e) determining the distribution and/or extent of PBR expression in said subject wherein said expression is directly correlated with the distribution and/or extent of said signals as represented in said image generated in step (d); (f) using the distribution and extent of PBR expression as determined in step (e) in the diagnosis and/or monitoring of said mood disorder.

#The term “useful in” should be taken to mean that the method of the invention can be used as a means to diagnose a disease, or is used in conjunction with other methods in order to reach a diagnosis. Preferably, the method of the invention is to be considered as an in vivo imaging method that provides information that is used in conjunction with information derived from, clinical examination in order to reach a diagnosis.