GCPII is mainly expressed in four tissues of the body, including prostate epithelium, the proximal tubules of the kidney, the jejunal brush border of the small intestine and ganglia of the nervous system.

[6][9][10] Indeed, the initial cloning of the cDNA encoding the gene expressing PSMA was accomplished with RNA from a prostate tumor cell line, LNCaP.

[11][12] PSMA shares homology with the transferrin receptor and undergoes endocytosis but the ligand for inducing internalization has not been identified.

[13] It was found that PSMA was the same as the membrane protein in the small intestine responsible for removal of gamma-linked glutamates from polygammaglutamate folate.

[16] The FOLH1 gene has multiple potential start sites and splice forms, giving rise to differences in membrane protein structure, localization, and carboxypeptidase activity based on the parent tissue.

[18] Human PSMA is highly expressed in the prostate, roughly a hundred times greater than in most other tissues.

[20] In human prostate cancer, the higher expressing tumors are associated with quicker time to progression and a greater percentage of patients suffering relapse.

[24][25][26][27] This uses a radiolabelled small molecule that binds with high affinity to the extra-cellular domain of the PSMA receptor.

Previously, an antibody targeting the intracellular domain (indium-111 capromabpentide, marketed as Prostascint) was used,[28] although detection rate was low.

In 2020, the results of a randomised phase 3 trial ("ProPSMA study")[29] was published comparing Gallium-68 PSMA PET/CT to standard imaging (CT and bone scan).

The study concludes that PSMA PET/CT is a suitable replacement for conventional imaging, providing superior accuracy, to the combined findings of CT and bone scanning.

[33] A prospective phase II study demonstrated a response (as defined by reduction in PSA of 50% or more) in 64% of men.

[37] Research has also shown that small-molecule-based NP inhibitors are beneficial in animal models that are relevant to neurodegenerative diseases.

[37] Some specific applications of this research include neuropathic and inflammatory pain, traumatic brain injury, ischemic stroke, schizophrenia, diabetic neuropathy, amyotrophic lateral sclerosis, as well as drug addiction.

[37] Previous research has found that drugs that are able to reduce glutamate transmission can relieve the neuropathic pain, although the resultant side-effects have limited a great deal of their clinical applications.

[38] Therefore, it appears that, since GCPII is exclusively recruited for the purpose of providing a glutamate source in hyperglutamatergic and excitotoxic conditions, this could be an alternative to avert these side-effects.

[39] One major hurdle with using many of the potent GCPII inhibitors that have been prepared to date are typically highly polar compounds, which causes problems because they do not then penetrate the blood–brain barrier easily.

[40] Glutamate is the “primary excitatory neurotransmitter in the human nervous system”,[37] participating in a multitude of brain functions.

Since its promise for possible neurological disease therapy and specific drug targeting, NAAG peptidase inhibitors have been widely created and studied.

A few small molecule examples are those that follow:[37] Pain cause by injury to CNS or PNS has been associated with increase glutamate concentration.

[43] Following initial impact, glutamate levels rise and cause excitotoxic damage in a process that has been well characterized.

[37] With its ability to reduce glutamate levels, NAAG inhibition has shown promise in preventing neurological damage associated with SHI and TBI.