Roberto Perrone

The serotonin 7 (5-HT₇) receptor was the last serotonin receptor subtype to be discovered in 1993. This receptor system has been implicated in several central nervous system (CNS) functions, including circadian rhythm, rapid eye movement sleep, thermoregulation, nociception, memory and neuropsychiatric symptoms and pathologies, such as anxiety, depression and schizophrenia. In 1999, medicinal chemistry efforts led to the identification of SB-269970, which became the gold standard selective 5-HT₇ receptor antagonist, and later of various selective agonists such as AS-19, LP-44, LP-12, LP-211 and E-55888. In this review, we summarize the preclinical pharmacological studies performed using these agonists, highlighting their strengths and weaknesses. The data indicate that 5-HT₇ receptor agonists can have neuroprotective effects against N-methyl-d-aspartate-induced toxicity, modulate neuronal plasticity in rats, enhance morphine-induced antinociception and alleviate hyperalgesia consecutive to nerve lesion in neuropathic animals.

We report the synthesis of compounds structurally related to the high‐affinity dopamine D₄receptor ligandN‐{2‐[4‐(3‐cyanopyridin‐2‐yl)piperazin‐1‐yl]ethyl}‐3‐methoxybenzamide (1e). All compounds were specifically designed as potential PET radioligands for brain D₄receptor visualization, having lipophilicity within a range for brain uptake and weak non‐specific binding (0.75P100‐fold), but its D₄receptor affinity was suboptimal for imaging of brain D₄receptors (K_i=30 nM).

PET radiotracer development to target in vivo P‐glycoprotein (P‐gp) could be an important strategy for the early diagnosis of neurodegenerative disorders such as Alzheimer’s disease (AD). Indeed, as a dysfunction of P‐gp is responsible for the accumulation of β‐amyloid plaques (a hallmark of AD) in brain parenchyma, P‐gp is the cause of AD onset. P‐gp substrates and inhibitors are useful for imaging the activity or expression of this protein, respectively; herein we discuss the in vivo evaluation of some¹¹C radiotracers with P‐gp‐inhibitory activity, such as [¹¹C]MC18 and [¹¹C]MC113, as well as P‐gp substrates [¹¹C]MC266 and [¹¹C]MC80. Moreover, the radiosynthesis of all these P‐gp probes is reported.

With the aim of contributing to the development of novel antitumor agents, high‐affinity σ₂receptor agonists were developed, with 6,7‐dimethoxy‐2‐[4‐[1‐(4‐fluorophenyl)‐1H‐indol‐3‐yl]butyl]‐1,2,3,4‐tetrahydroisoquinoline (15) and 9‐[4‐(6,7‐dimethoxy‐1,2,3,4‐tetrahydroisoquinolin‐2‐yl)butyl]‐9H‐carbazole (25) showing exceptional selectivity for the σ₂subtype. Most of the compounds displayed notable antiproliferative activity in human MCF7 breast adenocarcinoma cells, with similar activity in the corresponding doxorubicin‐resistant MCF7adr cell line. Surprisingly, a few compounds, including25, displayed enhanced activity in MCF7adr cells over parent cells, recalling the phenomenon of collateral sensitivity, which is under study for the treatment of drug‐resistant tumors. All of the compounds showed interaction with P‐glycoprotein (P‐gp), and15and25, with the greatest activity, were able to revert P‐gp‐mediated resistance and reestablish the antitumor effect of doxorubicin in MCF7adr cells. We therefore identified a series of σ₂receptor agonists endowed with intriguing antitumor properties; these compounds deserve further investigation for the development of alternate strategies against multidrug‐ resistant cancers.