Current Pharmaceutical Design - Volume 20, Issue 32, 2014

N-methyl-D-aspartate receptor (NMDAR) serves for both high cortical function and fundamental CNS mechanisms. NMDAR-mediated neurotransmission is the molecular engine for CNS development and plasticity; it is also the molecular underpin of learning, memory and cognition. Due to its critical role in CNS function, either over- or under-activation of NMDAR-mediated neurotransmission contributes significantly to the development of CNS disorders. In this issue of Current Pharmaceutical Design, the authors discuss the involvement of NMDARmediated neurotransmission in a variety of CNS disorders including schizophrenia [1], cognitive deficits in schizophrenia [2, 3], depression [4], aging [5], mild cognitive impairment and Alzheimer’s dementia [6], attention deficit hyperactivity disorder [7], frontal lobe synaptic plasticity [8] as well as autism spectrum disorder [9]. NMDAR distinguish itself in two ways: first, it is both ligand-gated and voltage-dependent; second, it requires co-activation by two ligands: glutamate or aspartate and either D-serine or glycine. The experience-dependent learning originates from these two critical coincidental mechanisms. First, the activation of non-NMDA glutamate receptor will relieve the magnesium blockade and allow the opening of NMDAR channel ionophore and calcium influx. This “coincidence rdquo; mechanism between NMDA and non-NMDA receptors provides a transduction and transformation of excitatory input from multiple modalities of stimulation through non-NMDARs into the molecular machinery of NMDAR that mediates complex CNS behaviors. In this regard, NMDAR serves as a high order integrator to summate the signals from the EPSP carried by the non-NMDARs. Second, D-serine and glycine, as obligatory co-agonists, provide another dimension of dynamics in the neocortex. D-serine and the racemic enzyme converting L-serine to D-serine are enriched in the corticolimbic regions [10]. D-serine plays a key role in NMDAR activation for high order cognitive functions, while glycine’s localization is much less specific, which is also enriched in the brain stem and spinal cord other than the forebrain. There are a variety of approaches to regulate NMDAR-mediated neurotransmission; not only by the electrophysiological and molecular coincidental mechanisms mentioned above, NMDAR-mediated neurotransmission also has multiple regulatory mechanisms. As in the aminergic or GABAergic system, the regulation can happen at the level of precursor and neurotransmitter synthesis and release, or termination of action by uptake or catabolism. Parallel to the aminergic or GABAergic systems (Table 1), administration of D-serine or glycine, can activation NMDAR to improve cognitive and psychotic symptoms as tryptophan loading can facilitate the synthesis of serotonin and improves the depressive symptoms. Blocking the high efficient uptake site of glycine transporter-1 (GlyT-1) in the forebrain [11] potentiates NMDA function similar to selective serotonin uptake inhibitor’s (SSRI’s) action to raise serotonin tone. However, D-serine appears not to have a high efficient uptake site; instead, there are low affinity exchangers alanine serine cysteine transporter-1 (ASC-1) and -2 which physiological role is unclear [12]. Therefore, D-serine regulation may provide a tone that slower in time scale than the high efficient mechanism like GlyT-1. The tonicclonic coordination between D-serine and glycine can provide another dimension of complexity, and thus possibilities of regulation.The occupation of the co-agonist site is obligatory for the activation of NMDAR. However, the presence of both glycine and D-serine is not essential since both co-agonists are full agonists with strong potency. These two co-agonists not only provide redundancy for the activation of NMDAR, it also provides an unique opportunities to regulate NMDAR [13]. Although glycine and D-serine have similar potency, the anatomic specificity favors D-serine. Other than their different anatomical localization at the gross regional level, their microanatomical and physiological functions are also different; synaptic NMDAR 2A subunit-containing and extrasynaptic 2B-containing NMDARs have different co-agonists: D-serine for synaptic NMDARs and glycine for extrasynaptic NMDARs [13]. In addition, it has been found that synaptic and extrasynaptic NMDARs have opposing effects in determining the fate of neurons; the mechanisms of cell destruction or cell survival in response to the activation of NMDAR depend in part on calcium and its route of entry, and more significantly on the subunit composition and localization of the NMDARs. Overall, the synaptic NMDAR activation is involved in neuroprotection, the stimulation of extrasynaptic NMDARs, triggers cell destruction pathways and may play a key role in the neurodegeneration associated with excitotoxicity. The multi-dimensional complexity of the physiology and pathology of NMDAR can be best exampled by these two co-agonists. Although the microscopic availability of the co-agonists matches the preferential affinity of synaptic NMDARs for D-serine and extrasynaptic NMDARs for glycine, this dichotomy is not universal. For example, long-term potentiation rely on synaptic NMDARs, but both glycine and D-serine can be involved [12]. Conversely, long-term depression requires both synaptic and extrasynaptic receptors. While the initial thought that Dserine originates from astrocytes, recent evidences indicate D-serine is also neuronal in origin [10]. Neuronal D-serine is required for NMDAR-dependent, long-term potentiation at the hippocampal CA1-CA3 synapses and proper synapse formation in the cerebral cortex. However, glycine is present on both forebrain and hindbrain, for both inhibitory and excitatory neurotransmission. Based upon the prediction that enhancement of NMDA function will improve the pathological state induced by NMDAR antagonists like phencyclidine and ketamine, glycine, a full agonist, was the first to be tested in schizophrenia [14]. However, glycine has poor efficacy and requires large amount of administration (>= 60 grams/day) to have a modest effect [15]. We first proposed D-cycloserine, a partial agonist, would be a better NMDA agent than glycine due to its CNS bioavailability. We found D-cycloserine offered an inverted-U dose-response curve consistent with its partial agonist activity in a dose-finding trial of schizophrenia [16]. To facilitate higher NMDA activation, we further conducted trials with full agonists, D-serine [17] and D-alanine [18]. As we predicted, the full agonists were able to elicit a higher level of NMDA activation and clinical improvement than the partial agonist. The dose-response of NMDA activation by the treatment of full agonist was later supported by an open-label trial, indicating 60 or 120 mg/kg D-serine has better efficacy than 30 mg/kg in symptom reduction and cognitive improvement [19]. We further hypothesized that the facilitation of NMDAR activation can be achieved by blocking the reuptake of the agonist, either glycine or D-serine. However, no high affinity uptake site for D-serine has been identified, therefore we focused on the GlyT-1 which is enriched in corticolimbic region, unlike GlyT-2 which is not present in the corticolimbic region. We also predicted, the competitive antagonist will elicit a safer pharmacological profile than the noncompetitive antagonist, for the concern that the high affinity blockade of the GlyT-1 may overactivate NMDAR, particularly when extrasynaptic NMDAR that mediates toxicity is involved. In addition, strong inhibition by noncompetitive antagonism can induce endocytosis [20]. The prototype GlyT-1 inhibitor we applied, sarcosine, is a naturally occurring amino acid, discovered at high concentration in tissues including CNS. Sarcocine’s efficacy had been proved in several small scale double blind, placebo controlled studies [21-25]. Supporting the advantage of competitive vs. noncompetitive GlyT-1 antagonist, all noncompetitive antagonists had failed the development so far, including bitopertin, which gave a weak signal at the Phase II study and did not meet its endpoints of the improvement of negative symptoms in two Phase III trials [26]. Infact, bitopertin provides a inverted-U dose-response, which also discourage the therapeutic approach of noncompetitive antagonism [27]. In addition to its efficacy in the main symptom domains of schizophrenia like positive, negative and cognitive symptoms, the depressive symptoms are also improved by NMDA enhancement treatments [23]. To determine whether the antidepressant effect is primary or secondary to the improvement of other symptom domains, we has conducted both rodent behavior studies and a trial of sarcosine treatment in major depression. In which, sarcosine treatment not only elicits an antidepressant-like behavior profile in both acute and chronic stress model of depression, but also reach a much higher remission rate than a standard SSRI treatment in major depression [28]. It had been well known that magnesium infusion can quickly relieve migraine and eclampsia, likely due to its blockade of NMDAR. Given the recent findings that NMDAR antagonists can improve the symptoms of depression, the mechanistic question was raised why both NMDA enhancement and blockade can improve the symptoms of depression [4]. It is possible that both treatments share a final common target, like m-TOR or BDNF, through some unidentified intermediate mechanism. However, NMDAR agonist and antagonist have different time scales in improving the depressive symptoms; NMDAR antagonist elicits an almost immediate effect, which is much faster than agonist treatment. At the same time, the underline molecular mechanism of NMDAR antagonists is unclear given that the proposed BDNF activation and synaptogenesis will take days to weeks to develop, while ketamine’s effect is immediate. The efficacy of NMDA treatment is not limited to schizophrenia and depression. The efficacy had been shown in improving the symptoms of dementia and obsessive compulsive disorder (OCD) by sarcosine treatment [29], which is consistent with the involvement of glutamatergic neurotransmission in dementia and memory and the circuitry of OCD. NMDA neurotransmission is ubiquitous and involved in many fundamental function of CNS including psychosis, cognition, rewarding, motor, etc. Its modulation can certainly offer beneficial outcome in the symptoms involving these circuitries. In the hindsight, though NMDA-enhancement treatment is particularly relevant to schizophrenia given that the NMDAR antagonists generate “schizophrenia-like” symptoms, it is not surprising that the treatment is also beneficial for a variety of CNS disorders. While looking back the development of aminergic and GABAergic treatments, I saw the history of glutamatergic treatments, developed in the past two to three decades, could follow a similar path. All three lines of treatments can involve neurotransmitter and its precursor (chloroziapoxide, tryptophan), agonist/antagonist (L-dopa, chlopromazine), uptake blocker (imipramine, fluoxetine, bupropion), catabolism inhibitor (iproniazid, selegiline) (Table 1). In analogy to the aminergic and GABAergic treatments, I saw the missing NMDA treatment options of: first, the neurotransmitter uptake inhibition by GlyT-1 inhibitor; second, NMDAR antagonists; third, the inhibition of the D-amino acid oxidase (DAAO), which metabolize D-serine [30]. The treatment of DAAO inhibition is analogous to monoamin oxidase inhibitors (MAOI), which upregulates monoamine for CNS disorders like depression and Parkinson disease. In another word, DAAO inhibitors are similar to MAOI in raising the tone of neurotransmitter of interest, by inhibiting the catabolism enzyme. The legendary biochemist, Sir Hans Adolf Krebs discovered D-amino acid deaminase and considered the enzyme ldquo;in search of function” [31]. Almost eighty years later, the enzyme, now known as DAAO, has gained attention as a critical regulator of CNS neurotransmission. Its main substrate, D-serine is a critically important co-agonist of the NMDAR. We recently demonstrated that sodium benzoate, as a DAAO inhibitor, can substantially improve the symptoms and neurocognition of schizophrenia, presumably enhance NMDA function by raising D-serine level [32]. In mild cognitive impairment (MCI), sodium benzoate also improves the cognition and function [33]. In late 19 century, the planet Neptune was mathematically predicted before it was directly observed; working from Le Verrier's calculations, telescopic observations of Neptune was confirming afterwards. In developing the NMDA treatment for CNS disorder, we predicted DAAO inhibition could be the last missing approach in regulating the grand regulator of CNS, NMDAR-mediated neurotransmission. To search for novel DAAO inhibitors, one of the articles in this issue discuss an innovative informatics method to determine the potential activity of DAAO inhibitors in this new frontier of CNS drug development [34].

Schizophrenia, a multifactorial mental disorder with polygenic inheritance as well as environmental influences, encompasses a characteristic group of symptoms. Negative and cognitive symptoms which respond poorly to currently available antipsychotics remain a great clinical challenge. Aggressive studies are ongoing to explore the etiological mechanisms of this disease. Among them, one of the primary causal factors is dysfunction of the N-methyl-D-aspartate (NMDA)-type glutamate receptors. This article reviews the clinical manifestations of the disease, limitations of current antipsychotics and reconceptualization of the nature of disease and treatment modalities based on the evidence provided by drug models, genetic studies, and clinical trials. The NMDA receptor (NMDAR) model plays a critical role in the revolution of pharmaceutical industry as a new set of drug targets is proposed. Investigations on the modulation of glutamatergic system, particularly the intrinsic NMDA glycine modulatory site, exhibit encouraging results. A group of “NMDA-enhancing agents” either acts directly or indirectly on the glycine modulatory site, showing therapeutic efficacy in preclinical and early clinical trials. A new generation of therapeutic agents targeting the NMDAR shows promise as the next wave of drug development for schizophrenia.

Schizophrenia is a serious neuropsychiatric disease characterized by positive symptoms, negative symptoms and cognitive impairment. Evidence have shown that cognitive impairment sustains in every clinical stage, may relate with the liability, may predict functional outcome in schizophrenia and could be the core symptom of schizophrenia. The treatment of cognitive impairment in schizophrenia could alleviate the burden of the illness and has become the subject of intensive research. In this review, we synthesize current advances of assessing strategies, pharmacological and non-pharmacological treatments of cognitive impairment in schizophrenia. According to the registered records of ClinicalTrials.gov, the most widely studied strategies have aimed at modifying neurochemical mechanisms of dopamine metabolism, glutamate metabolism, γ-aminobutyric acid (GABA) metabolism, serotonin metabolism, acetylcholine metabolism, and oxytocin. Despite preclinical data for putative pro-cognitive drugs, their clinical benefits for schizophrenia patients have been limited. The small sample sizes and the short treatment duration could be related with the suboptimal results. Evidence supported the short-term benefits of cognitive remediation therapy on cognitive domains with small to moderate effects; however, the small sample sizes and the characteristics of subjects limited the generalization of the positive results and the long-term functional outcome is not clear. Combination therapy is promising, by integrating pro-cognitive agents and cognitive rehabilitation programs or combining two kinds of pro-cognitive agents via different mechanisms. Future studies should investigate the pro-cognitive drugs’ long-term efficacy, rebound deterioration in psychosis/cognition following discontinuation, and related biomarkers of functional outcome.

Schizophrenia and other psychiatric disorders are generally diagnosed based on a collection of symptoms defined by a combination of an individual’s feelings, perceptions, and behaviors. Many of these disorders are characterized by specific cognitive and social deficits. Although it is nearly impossible to recapitulate the full phenotypic spectrum of schizophrenia in mice, mouse models play an indispensable role in understanding the pathogenesis of this disorder and the development of new therapeutics. Genetic mouse models of schizophrenia and mouse behavioral tests provide a feasible approach for elucidating causal relationships between susceptibility gene(s) and schizophrenia-related symptoms. There has been a proliferation of studies characterizing basic behavioral phenotypes in mice. Since there is no way to completely model human psychiatric symptoms in mice, the major role of behavioral tests is to provide insights into underlying affected circuitry and pathophysiology. Given that the recovery of cognitive and social abilities significantly benefits functional outcomes, there has been an increasing interest in characterizing cognitive and social functions in mutant mice; however, these functions are not easy to measure. In this review, a selection of conventional behavioral tasks was briefly described and three specific behavioral tasks aimed at characterizing social communication, attentional function, and choice behavior in mice were highlighted. The choice of specific behavioral tasks during experimental planning should take into consideration a variety of factors, including their validity, reliability, sensitivity, utility, and specificity. Based upon the hypothetical hypofunction of N-methyl-D-aspartate receptor (NMDAR)-mediated signaling pathways in the involvement of cognitive and social impairments in schizophrenia, three NMDAR-related compounds/drugs, D-serine, sarcosine, and D-cycloserine, are discussed as an example.

Major depressive disorder (MDD) is a common, recurrent mental illness that affects millions of people worldwide. Accumulating evidence suggests that the N-methyl-D-aspartate (NMDA) receptor, a subtype of glutamate receptors, plays an important role in the neurobiology and treatment of this disease. Currently, the non-competitive NMDA receptor antagonist ketamine is considered as one of the most attractive candidate drugs in therapy of treatment-resistant depression. A recent study demonstrated ketamine's rapid antidepressant activity in patients with treatment-resistant MDD and bipolar disorder. The response rate for ketamine ranged from 25% to 85% at 24 hours post-infusion and from 14% to 70% at 72 hours post-infusion, with generally mild adverse effects. Based on the role of the NMDA receptor in depression, a number of therapeutic drugs which interact with this receptor have been developed. In this article, we reviewed recent findings concerning the role of glutamatergic signaling in the neurobiology of MDD and potential, novel therapeutic drugs, such as ketamine, memantine, AZD6765, traxoprodil, MK-0657, GLYX-13, NRX-1047, D-cycloserine, sarcosine, all of which target this system.

The world population is growing older and age-related cognitive decline is becoming a burden of societal importance. D-serine is an endogenous amino acid that activates the co-agonist site of the NMDA-glutamate receptor, which is related to cognitive functions, such as learning and memory. Studies in aged rodents have shown a marked decrease in the levels of D-serine in brain regions such as the hippocampus, a key region for encoding memory. Exogenous administration of D-serine in rodents has demonstrated pro-cognitive effects in several brain functions, including memory and executive function. Further to animal studies, our group has observed an agerelated decrease in D-serine in the blood of healthy adults and elderly. The oral administration of D-serine induced significant improvement in executive function and spatial problem solving in elderly, some of the key cognitive domains affected by aging. In this review we propose the activation of the co-agonist site of NMDA receptors as a target to remediate features of the age-related cognitive decline. The cognitive effects of other agents targeting the co-agonist site of NMDA receptors are also discussed.

The prevalence of Alzheimer’s disease (AD) in the elderly is growing rapidly worldwide, and the deteriorating clinical course of AD places a heavy burden on both the patients and their families. Early detection and intervention of mild cognitive impairment in the early phase of AD is vital for the purpose of improving the cognitive performance of patients and preventing the existing deficits from worsening. However, the main compounds currently used to treat early AD, acetylcholinesterase inhibitors (AChEIs), are unsatisfactory in efficacy and safety. Moreover, evidence indicates that AChEIs are ineffective in treating AD at extremely early stages, which implies that mechanisms other than those targeted by AChEIs underlie the pathogenesis of AD. Dysfunctional glutamatergic neurotransmission, particularly that mediated by the N-methyl-D-aspartate (NMDA) receptor, has been reported to play a role in the pathophysiology of AD. The NMDA receptor (NMDAR) regulates synaptic plasticity, memory, and cognition, and the attenuation of NMDAR-mediated neurotransmission can result in impaired neuroplasticity and cognitive deficits in the aging brain. Furthermore, NMDARs also interact with amyloid beta peptide/amyloid precursor protein and tau protein, whose production represents the main manifestations of AD. In this paper, we review the evidence supporting NMDA dysfunction in both animal models of AD and patients afflicted with AD, and we also review the literature that suggests that NMDA-enhancing agents such as glycine and D-cycloserine can improve cognitive functions. The benefits and limitations of NMDAR antagonists that can diminish the excitatory neurotoxicity triggered by glutamate are also addressed in relation to AD. We propose that enhancing glutamatergic neurotransmission by activating the NMDAR may be effective in treating the cognitive decline that occurs in AD. Prospective studies on AD in which NMDA-enhancing agents are used are required to verify this hypothesis and confirm the long-term efficacy and safety of the treatment agents.

Attention deficit hyperactivity disorder (ADHD) is a long recognized and common childhood disorder. ADHD adolescents tend to encounter more difficulties in school and peer relationships, whereas ADHD adults have more occupational and interpersonal difficulties. However, with the treatment of central nervous system (CNS) stimulants, 10-20 % of the patients still remain poor responders to treatment. Among hypotheses for ADHD, dysfunction of N-methyl-D-aspartate (NMDA)-type glutamate receptors has recently been suggested by accumulating genetic and animal studies. This article systemically reviews evidence supporting NMDA dysfunction as a potential ADHD pathogenesis from perspectives of neurodevelopment, attentional circuitry, and impulse inhibition. The review also addresses the development of novel treatments for ADHD via modulation of glutamatergic system, particularly the NMDA/glycine site. These so-called NMDA enhancers may provide a new treatment option for patients with ADHD.

Autism spectrum disorders (ASD) are developmental disorders that are characterized by deficits in reciprocal social interactions and communication, as well as by the presence of impairing repetitive behaviors and restricted interests. Prior work examining human pathology, and model systems and genetic studies have all led to the current conceptualization of ASD as a disorder of synaptic formation and functioning (a “synapsopathy”). In this regard, glutamate, the major excitatory neurotransmitter in central nervous system synaptic transmission, with roles in learning, memory and synaptic plasticity, is hypothesized to play an important role in the pathophysiology of ASD. Molecules targeting glutamate signaling have been suggested to possess therapeutic potential for ASD treatment. This review focuses on the role of the structure and function of glutamate receptors, describes synaptic cell-adhesion molecule pathways related to glutamate and/or ASD, introduces a rare disease approach in the development of novel drugs for ASD treatment, and reports on glutamate- related clinical trials. We will also present promising new techniques using human-induced pluripotent stem cells, which may afford researchers the ability to study the relationships between clinical phenotypes, cellular responses and glutamate involvement in ASD.

Synaptic plasticity is now known to occur at glutamate synapses throughout the brain, including the neocortex, and to play a role in neurodevelopment as well as in a broad spectrum of adult neural functions. Here the hypothesis that synaptic plasticity, specifically long term depression, is the neural substrate that mediates adolescent synaptic pruning is re-examined in the context of its ramifications for neuropsychiatric illnesses. Stress, which in part is mediated by dopamine acting via the D1 receptor, may disrupt normal synaptic plasticity in adolescence resulting in excessive synaptic elimination. In this manner elevated dopamine levels due to stress could contribute to deficits in gray matter volume and reduced neural connectivity in diseases such as major depressive disorder and schizophrenia. Attention deficit hyperactivity disorder, another developmental illness associated with cortical gray matter volume deficits, may represent a state of diminished dopamine stimulation that is equally disruptive to normal mechanisms of synaptic plasticity. In post-traumatic stress disorder, long term potentiation necessary for conditioned fear extinction, is thought to be impaired. Recent evidence suggests that genotypes related to dopamine neurotransmission confer vulnerability to post-traumatic stress disorder, perhaps indicating that low dopamine levels are less permissive of the synaptic plasticity that underlies consolidation and retention of fear extinction. Further understanding of the role that dopamine-modulated synaptic plasticity plays in development and, when disrupted, in precipitating neuropsychiatric illness could lead to novel drug treatments, and ultimately to preventative pharmacotherapeutic interventions, for these disorders.

In silico prediction of the new drug-target interactions from existing databases is of important value for the drug discovery process. Currently, the amount of protein targets that have been identified experimentally is still very small compared with the entire human proteins. In order to predict protein-ligand interactions in an accurate manner, we have developed a support vector machine (SVM) model based on the chemical-protein interactions from STITCH. New features from ligand chemical space and interaction networks have been selected and encoded as the feature vectors for SVM analysis. Both the 5-fold cross validation and independent test show high predictive accuracy that outperforms the state-of-the-art method based on ligand similarity. Moreover, 91 distinct pairs of features have been selected to rebuild a simplifier model, which still maintains the same performance as that based on all 332 features. Then, this refined model is used to search for the potential D-amino acid oxidase inhibitors from STITCH database and the predicted results are finally validated by our wet experiments. Out of 10 candidates obtained, seven D-amino acid oxidase inhibitors have been verified, in which four are newly found in the present study, and one may have a new application in therapy of psychiatric disorders other than being an antineoplastic agent. Clearly, our model is capable of predicting potential new drugs or targets on a large scale with high efficiency.

Glimepiride sulfonamide (GS) is a drug intermediate to synthesize glimepiride (antidiabetic drug). We hypothesized that GS exerts gluco-regulatory effect because GS is comprised of the structural components of dipeptidyl peptidase-IV (DPP-IV) inhibitors sitagliptin and DPP-728and glimepiride (sulfonylurea based antidiabetic drug).We analyzed the drug-likeness and docking efficiency of GS with DPP-IV using in silico tools. Also DPP-IV inhibition assays were conducted in vitro. Gluco-regulatory potential and parameters of drug safety were evaluated on normal euglycemic and streptozotocin (STZ) induced diabetic rats. We observed strong drug-likeness and DPP-IV binding efficiency of GS. Similarly, profound DPP-IV inhibition was also observed in vitro. Studies on euglycemic and STZ induced diabetic rats revealed antidiabetic potential for GS without significant change in the studied toxicological parameters. Glimepiride sulfonamide has antidiabetic potential mainly through DPP-IV inhibition, but also through insulin stimulation and alpha-amylase inhibition.

Many tumors express one or more proteins that are either absent or hardly present in normal tissues, and which can be targeted by radiopharmaceuticals for either visualization of tumor cells or for targeted therapy. Radiopharmaceuticals can consist of a radionuclide and a carrier molecule that interacts with the tumor target and as such guides the attached radionuclide to the right spot. Radiopharmaceuticals hold great promise for the future of oncology by providing early, precise diagnosis and better, personalized treatment. Most advanced developments with marketed products are based on whole antibodies or antibody fragments as carrier molecules. However, a substantial number of (pre)clinical studies indicate that radiopharmaceuticals based on other carrier molecules, such as peptides, nonimmunoglobulin scaffolds, or nucleic acids may be valuable alternatives. In this review, we discuss the biological molecules that can deliver radionuclide payloads to tumor cells in terms of their structure, the selection procedure, their (pre)clinical status, and advantages or obstacles to their use in a radiopharmaceutical design. We also consider the plethora of molecular targets existing on cancer cells that can be targeted by radiopharmaceuticals, as well as how to select a radionuclide for a given diagnostic or therapeutic product.