Interdisciplinary Initiatives Program Round 5 – 2010

Sandip Biswal, Radiology
Pankaj Jay Pasricha, no longer at Stanford
Frederick T. Chin, Radiology

Gastroparesis is a devastating disease affecting predominantly young women (females outnumber males by a ratio of 4:1); approximately a third of patients with longstanding diabetes; other cases are idiopathic. The disorder is clinically characterized by delayed gastric emptying, chronic nausea and vomiting, often accompanied by significant pain, discomfort, depression and anxiety. One key modulator of the pathophysiology in this syndrome is thought to be substance P (SP) and its receptor, neurokinin-1 (NK1) receptor. SP selective activation of NK1 and NK2 receptors delays gastric emptying. Centrally acting neurokinin receptor (NK1) antagonists have broad spectrum anti-emetic effects against both central (e.g. motion and opioids) and peripheral (vagal) afferent emetogenic pathways. The NK1 receptor may also play an important role in persistent visceral hyperalgesia, which is seen in about 50% of patients with gastroparesis. An NK1 receptor antagonist, aprepitant, is currently approved for the treatment of nausea and vomiting from chemotherapy and preliminary data from a pilot study in gastroparesis suggests that this drug may be beneficial in this condition as well. However, empiric administration of the drug may prove to be expensive and ineffective given the lengthy course needed to realize symptomatic resolution.

A clinical imaging study such as the one proposed below is needed to better predict beneficiaries of aprepitant therapy. Imaging of the NK1 receptor is now possible in human subjects using positron emission tomography-computed tomography (PET-CT) and a specific radioligand, [18F]-Labeled SP Antagonist–Receptor Quantifier ([18F]SPA-RQ) [2- fluoromethoxy-5-(5-trifluoromethyl-tetrazol-1-yl)benzyl]-[(2S,3S)-2-phenyl-piperidin-3- yl)amine], is a highly selective radiopharmaceutical with a sub-nanomolar affinity for the human NK1 receptor. By bringing together expertise in gastroparesis and molecular imaging, our goal is to develop a non-invasive clinical imaging method to determine a differential distribution of [18F]SPA-RQ uptake in the both the central nervous system (CNS) and enteric nervous systems (ENS) in human subjects with gastroparesis. Three aims of this project have been identified: In Aim 1, we install a customized Peltier reactor and optimize the synthesis of [18]SPA-RQ. In Aim 2, we perform dynamic [18F]SPA-RQ PET and Head MRIs in 7 normal healthy volunteers and 7 subjects suffering from gastroparesis to determine differential uptake patterns in the various CNS structures. In Aim 3, the exploratory and high-risk aspect of the proposal, we perform dynamic [18F]SPA-RQ PET-CT of the abdomen to establish, for the first time, NK1 receptor status in the ENS/gastrointestinal tract. Imaging patterns in the CNS and abdomen will be compared to controls and correlated with behavioral/physiologic measures of gastroparesis.

This proposal represents the first study to prospectively and quantitatively evaluate an important enteric nervous system and inflammatory/immune modulator of the gastrointestinal system in living human subjects using PET-CT. This effort, which is only possible through the proposed multidisciplinary alliance, will also be the first to describe the neuroanatomical and functional substrates of gastroparesis and chronic nausea in living human subjects. Ultimately, results from this study will help us objectify the NK1 receptor status of gastroparesis patients and will determine which gastroparetic patients will be ideal candidates for long-term therapy with NK1 receptor antagonists, such as aprepitant.