Translocator protein (TSPO) ligands for the diagnosis or treatment of neurodegenerative diseases: a patent review (2010 – 2015; part 2)

Introduction: The 18-kDa translocator protein (TSPO) has been highlighted as a potential drug target in diverse neurodegenerative diseases because the up-regulation of TSPO in the CNS is related to neuroinflammation. Diverse TSPO ligands are currently in clinical trials or are under development at the preclinical stage for the treatment and/or diagnosis of neurodegenerative processes. These TSPO ligands may shed light on novel therapeutics for neurodegenerative diseases in the near future.

Areas covered: This review describes TSPO ligands that have been patented from 2010 to 2015. Numerous indole-derived TSPO ligands will be analyzed on the basis of their TSPO affinities. Furthermore, cholesterol-like compounds and miscellaneous TSPO ligands will be summarized along with their pharmaceutical uses.

Expert opinion: Diverse TSPO ligands have demonstrated their biological efficacies in experimental models of neurodegenerative diseases, and some of them are now in clinical trials. The indole-derived TSPO ligands can be highlighted as efficient diagnostic agents because they have high selectivity and affinity for TSPO. Moreover, one potent cholesterol-like TSPO ligand has been described as a neuroprotective compound. Therefore, additional preclinical and clinical studies for highly potent TSPO ligands are recommended for the successful pharmacological application of TSPO ligands.     

Effects of different doses and schedules of diazepam treatment on lymphocyte parameters in rats

Benzodiazepines (BZD) are widely used for the treatment of anxiety. They enhance GABA-ergic neurotransmission through the binding on specific BDZ recognition sites, within the GABA_A receptor-ion channel complex. However, recent studies showed that BZD also act on peripheral benzodiazepine receptor sites (PBR) or translocator protein 18 kDa (TSPO). Evidence for a direct immunomodulatory action for BZD emerged from studies that demonstrated the presence of TSPO on immune/inflammatory cells. The present study was designed to analyze the effects of diazepam on rat lymphocyte parameters, specifically on phenotype, cell proliferation and cell death. The effects of both acute and long-term (21 days) diazepam (1 and 10 mg/kg/day) administrations were evaluated. Results showed that diazepam (1 mg/kg) treatment did not change the immune parameters analyzed. However, both diazepam (10 mg/kg) acute and long-term treatments decreased the number of apoptotic cells; they also increased the percentage of T cytotoxic cells; decreased the percentage of B cells and increased the corticosterone serum levels. The induction of functional tolerance was suggested for the highest dose of diazepam (10 mg/kg), but not for the smaller dose (1 mg/kg) used, at least for diazepam effects on corticosterone serum levels. Diazepam effects were discussed as being related to the number of TSPO sites present on immune cells and/or to the increased levels of serum corticosterone observed after the treatments used.     

Translocator protein (TSPO) ligands for the diagnosis or treatment of neurodegenerative diseases: a patent review (2010–2015; part 1)

Introduction: The translocator protein (TSPO) is an emerging target in diverse neurodegenerative diseases. Up-regulated TSPO in the central nervous system (CNS) appears to be involved in neuroinflammatory processes; therefore, the development of potent TSPO ligands is a promising method for alleviating or imaging patients with neurodegenerative diseases.

Areas covered: This review will provide an overview of recently developed TSPO ligands patented from 2010 to 2015. Part 1 will present a summary focusing on TSPO ligands other than indole-based or cholesterol-like compounds, which will be discussed in part 2. Part 1 covers diverse benzodiazepine-derived analogues such as isoquinoline carboxamides and aryloxyanilides. Moreover, bicyclic ring structures such as imidazopyridine, pyrazolopyrimidine, and phenylpurine will be highlighted as promising scaffolds for TSPO ligands. A brief analysis of currently reported TSPO structures will also be covered in part 1.

Expert opinion: Although the underlying pharmacological mechanism of TSPO remains to be elucidated, several TSPO ligands have shown therapeutic efficacy in experimental animal models of neurodegenerative diseases. In addition, radioactive TSPO ligands have been extensively studied for the diagnosis of neurodegenerative processes. Thus, further studies on both the basic and applied mechanisms of TSPO are warranted in the pursuit of successful pharmacological applications of TSPO ligands.     

[F]DPA-714, [F]PBR111 and [F]FEDAA1106—Selective radioligands for imaging TSPO 18 kDa with PET: Automated radiosynthesis on a TRACERLAb FX-FN synthesizer and quality controls

Imaging of TSPO 18 kDa with PET is more and more considered as a relevant biomarker of inflammation in numerous diseases. Development of new radiotracers for TSPO 18 kDa has seen acceleration in the last years and the challenge today is to make available large amounts of such a radiotracer in compliance with GMP standards for application in humans. We present in this technical note automated productions of [¹⁸F]DPA-714, [¹⁸F]PBR111 and [¹⁸F]FEDAA1106, three promising radiotracers for TSPO 18 kDa imaging, using a TRACERlab FX-FN synthesizer. This note also includes the quality control data of the validation batches for the manufacturing qualification of clinical production of [¹⁸F]DPA-714.     

Synthesis,Characterization, and in Vitro Evaluation of a New TSPO-Selective Bifunctional Chelate Ligand

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Brain translocator protein occupancy by ONO‐2952 in healthy adults: A Phase 1 PET study using [11C]PBR28

ONO‐2952, a novel antagonist of translocator protein 18 kDa (TSPO), binds with high affinity to TSPO in rat brain and human tumor cell line membrane preparations. This study used the TSPO‐specific PET radioligand [¹¹ C]PBR28 to confirm binding of ONO‐2952 to brain TSPO in human subjects, and evaluate brain TSPO occupancy and its relationship with ONO‐2952 plasma concentration. Sixteen healthy subjects received a single oral dose of 200, 60, 20, or 6 mg ONO‐2952 (n = 4 per dose). Two PET scans with [¹¹ C]PBR28 were conducted ≤7 days apart: at baseline and 24 h after ONO‐2952 administration. [¹¹ C]PBR28 regional distribution volume (V_T) was derived with kinetic modeling using the arterial input function and a two tissue compartment model. Nonspecific binding (V_ND) was obtained on an individual basis for each subject using linear regression as the x‐intercept of the Lassen plot. The binding potential relative to V_ND (BP_ND) was derived as the difference between V_T in the ROI (V_T ROI) and V_ND, normalized to V_ND; BP_ND = (V_T ROI – V_ND)/V_ND. TSPO occupancy was calculated as the change in BP_ND (ΔBP_ND) from individual's baseline scan to the on‐medication scan to the baseline BP_ND value. TSPO occupancy by ONO‐2952 was dose dependent between 20–200 mg, approaching saturation at 200 mg both in the whole brain and in 15 anatomic regions of interest (ROI). Estimated K_i values ranged from 24.1 to 72.2 nM. This open‐label, single‐center, single‐dose study demonstrated engagement of ONO‐2952 to brain TSPO. The relationship between pharmacokinetics and TSPO occupancy observed in this study support the hypothesis that ONO‐2952 could potentially modulate neurosteroid production by binding to brain TSPO.     

Identification, characterization and potent antitumor activity of ECO-4601, a novel peripheral benzodiazepine receptor ligand

Purpose

ECO-4601 is a structurally novel farnesylated dibenzodiazepinone discovered through DECIPHER^® technology, Thallion’s proprietary drug discovery platform. The compound was shown to have a broad cytotoxic activity in the low micromolar range when tested in the NCI 60 cell line panel. In the work presented here, ECO-4601 was further evaluated against brain tumor cell lines. Preliminary mechanistic studies as well as in vivo antitumor evaluation were performed.

Methods

Since ECO-4601 has a benzodiazepinone moiety, we first investigated if it binds the central and/or peripheral benzodiazepine receptors. ECO-4601 was tested in radioligand binding assays on benzodiazepine receptors obtained from rat hearts. The ability of ECO-4601 to inhibit the growth of CNS cancers was evaluated on a panel of mouse, rat and human glioma cell lines using a standard MTT assay. Antitumor efficacy studies were performed on gliomas (rat and human), human breast and human prostate mouse tumor xenografts. Antitumor activity and pharmacokinetic analysis of ECO-4601 was evaluated following intravenous (IV), subcutaneous (SC), and intraperitoneal (IP) bolus administrations.

Results

ECO-4601 was shown to bind the peripheral but not the central benzodiazepine receptor and inhibited the growth of CNS tumor cell lines. Bolus SC and IP administration gave rise to low but sustained drug exposure, and resulted in moderate to significant antitumor activity at doses that were well tolerated. In a rat glioma (C6) xenograft model, ECO-4601 produced up to 70% tumor growth inhibition (TGI) while in a human glioma (U-87MG) xenograft, TGI was 34%. Antitumor activity was highly significant in both human hormone-independent breast (MDA-MB-231) and prostate (PC-3) xenografts, resulting in TGI of 72 and 100%, respectively. On the other hand, IV dosing was followed by rapid elimination of the drug and was ineffective.

Conclusions

Antitumor efficacy of ECO-4601 appears to be associated with the exposure parameter AUC and/or sustained drug levels rather than C _max. These in vivo data constitute a rationale for clinical studies testing prolonged continuous administration of ECO-4601.