Among the positron emitting isotopes, O-15 (T 1/2 = 2.037 minutes), N-13 (T 1/2 = 9.96 minutes), C-11 (T 1/2 = 20.34 minutes) and F-18 (T 1/2 = 109.77 minutes) are the common nuclei produced from cyclotron, reported for neuroimaging with PET. The conventional components of PET molecular imaging include production of radioisotopes, radiotracer synthesis, PET scanning and data interpretation.

Furthermore, PET biodistribution studies are able to confirm that the drug candidate/lead ligand reaches the target site and does not accumulate in non-target sites of potential toxicity. PET has been used for the quantification of neuroreceptor binding and release of neurotransmitters and measuring enzyme binding in disease pathology, early diagnosis, and evaluation of therapy effects.

The primary biological mechanisms that can be studied by PET imaging are specific binding to protein structures (eg: enzymes, transporters and receptors), metabolism, and blood regulation. PET uses positron-radiolabeled molecules in very low mass amounts to image and measure the function of biological processes with minimum disturbance. The rate of binding of 5-HT varies for 5-HTR subtypes, for example, 5HT 1ARs (K i = 0.2–400 nM), 5-HT 1BR (K i = 1–40 nM), 5-HT 7R (K i = 0.2–8 nM) and 5-HT 2AR (Ki = <10 nM) have the highest affinity for 5-HT. Among these receptors, 5-HT 3R is a ligand gated ion channel receptor (LGICR), whereas, others are coupled with G-protein coupled receptors (GPCR). Serotonin effects are mediated through seven 5-HT receptor subtypes, 5-HT 1 to 5HT 7 (5-HT 1A, 5-HT 1B, 5-HT 1D, 5-HT 1E, 5-HT 1F, 5-HT 2A, 5-HT 2B, 5-HT 2C, 5-HT 3, 5-HT 4, 5-HT 5A, 5-HT 5B, 5-HT 6, 5-HT 7A, 5-HT 7B,5-HT 7D) and serotonin transporter (SERT). The neurons project to most of the brain including hippocampus, midbrain, prefrontal, parietal and occipital cortical regions, cingulate cortex and cerebellum, whereas, 5-HT neurons in caudal raphe nuclei project to cerebellum and spinal cord. Serotonin neurons are confined to the brainstem and are located in the raphe nuclei. Serotonin is found in almost all brain regions and it is implicated in the pathophysiology of a variety of diseases, biological functions and biochemical pathways. Serotonin does not cross the blood brain barrier (BBB) the brain synthesizes all its serotonin from tryptophan (from diet) in two steps enzymatically with tryptophan hydroxylase (TPH) and tryptophan decarboxylase (TDC) respectively. Serotonin or 5-hydroxytryptamine (5-HT) is a neurotransmitter that is widely distributed in animals and plants. Herein we review the development and application of radioligands for PET imaging of 5-HTRs in living brain. Although research on PET imaging of 5-HTRs have been performed more than two decades, the successful radiotracers so far developed for human studies are limited to 5-HT 1AR, 5-HT 1BR, 5-HT 2AR, 5-HT 4R and 5-HT 6R. Positron emission tomography (PET) molecular imaging has the sensitivity to quantify binding of 5-HTRs in CNS disorders and to measure drug occupancy as part of a process of new drug development. Quantifying binding to 5-HTRs in vivo may permit assessment of physiologic and pathologic conditions, and monitoring disease progression, evaluating treatment response, and for investigating new treatment modalities. In the CNS, most of these receptors are expressed in high abundance in specific brain regions reflecting their role in brain functions. Serotonin receptors (5-HTRs) are implicated in the pathophysiology of a variety of neuropsychiatric and neurodegenerative disorders and are also targets for drug therapy.

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