Sincalide

The synthetic sulfated C-terminal octapeptide of cholecystokinin (CCK-8), FDA approved since 1976 as Kinevac, an intravenous diagnostic agent that contracts the gallbladder and stimulates pancreatic secretion during hepatobiliary imaging and duodenal aspiration studies.

Also referenced as: Kinevac, CCK-8, CCK-OP, Cholecystokinin octapeptide, SQ 19844

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What is Sincalide?

Sincalide is the synthetic form of CCK-8, the C-terminal octapeptide of the gut hormone cholecystokinin: Asp-Tyr(SO3H)-Met-Gly-Trp-Met-Asp-Phe-NH2, with a molecular formula of C49H62N10O16S3 and a molecular weight of about 1,143 g/mol. The sulfated tyrosine is essential; it is the structural feature that gives the fragment full cholecystokinin activity at the gallbladder. The octapeptide was synthesized at Squibb around 1970, once sequencing of porcine cholecystokinin showed that the C-terminal fragment carried the hormone’s activity, and it was approved in the United States as Kinevac on July 21, 1976.

Sincalide is a diagnostic agent, not a therapy. It is given intravenously in a hospital or imaging department to make the gallbladder contract so that gallbladder emptying can be measured during hepatobiliary scintigraphy, to obtain concentrated bile or pancreatic fluid by duodenal aspiration, and to speed a barium meal through the small bowel. The same molecule, listed as sulfated CCK-8 or cholecystokinin octapeptide, appears in laboratory-supplier catalogs as a receptor-pharmacology reagent, which is the extent of its presence outside clinical use.

How it works

Sincalide reproduces the actions of endogenous cholecystokinin at the CCK1 receptor, a G protein-coupled receptor expressed on gallbladder smooth muscle, pancreatic tissue, enteric neurons, and vagal afferents.

• CCK1 receptor agonism on gallbladder smooth muscle. Radioligand binding on human donor gallbladders localized a single class of high-affinity CCK-8 sites to the smooth muscle layer, and strips contracted to CCK-8 at nanomolar concentrations; the desulfated octapeptide was about 150-fold less potent, which is why the sulfate group is retained in the drug (Tokunaga et al., Surgery, 1993, 113(2):155–162).
• Gq-coupled signaling and the receptor family. CCK1 and CCK2 receptors signal through phospholipase C and intracellular calcium to drive smooth-muscle contraction and pancreatic enzyme secretion; the receptor pharmacology, tissue distribution, and peripheral physiology are reviewed in Dufresne et al., Physiological Reviews, 2006, 86(3):805–847.
• Gallbladder emptying, sphincter relaxation, and transit. In mice lacking the CCK1 receptor, gallbladder volumes were larger, small-intestinal transit slowed, and cholesterol gallstones formed more readily on a lithogenic diet, demonstrating that CCK1 signaling through smooth muscle and enteric neurons governs gallbladder emptying and intestinal transit (Wang et al., Journal of Clinical Investigation, 2004, 114(4):521–528). The approved labeling describes the same pharmacology in humans: gallbladder contraction, pancreatic secretion that is synergistic with secretin, increased intestinal motility, pyloric contraction, and slowed gastric emptying.
• A rapid, short-lived response. After an intravenous bolus, the label reports maximal gallbladder contraction within 5 to 15 minutes, with radiographic gallbladder size falling by at least 40%. No pharmacokinetic section appears in either approved label. During review of the second application, the applicant pointed out that the frequently quoted 2.5- to 3-minute half-life came from a 1975 study that infused the natural porcine 33-amino-acid form of cholecystokinin rather than CCK-8 (Thompson et al., Annals of Surgery, 1975, 182(4):496–504); the FDA’s clinical pharmacology reviewers agreed, noted that the only CCK-8 figure in the literature (23 ± 16 minutes, in patients with sphincter of Oddi spasm) was of unclear relevance, and left half-life out of the label for lack of reliable data.

Research status

Sincalide’s literature is that of a diagnostic tool. The questions studied are how to give it reproducibly and what the resulting gallbladder ejection fraction means, not whether it treats anything.

Infusion methodology and normal values. The original label called for a 30- to 60-second injection, and many departments later used 3- to 5-minute infusions. In 20 healthy subjects, a 3-minute infusion produced gallbladder ejection fractions too variable to define a normal range (six of 20 fell below 35%), whereas a 60-minute infusion of the same dose yielded a usable lower limit of normal (Ziessman et al., Radiology, 2001, 221(2):404–410). The definitive study, a randomized crossover in 60 healthy volunteers enrolled at four institutions (NCT00685477), compared 15-, 30-, and 60-minute infusions of 0.02 mcg/kg; the coefficient of variation of the ejection fraction was 52%, 35%, and 19% respectively, and the 60-minute infusion gave a lower limit of normal of 38% (Ziessman et al., Journal of Nuclear Medicine, 2010, 51(2):277–281). That method and threshold were adopted by the SNM practice guideline for hepatobiliary scintigraphy (Tulchinsky et al., Journal of Nuclear Medicine Technology, 2010, 38(4):210–218) and by an interdisciplinary consensus panel (DiBaise et al., Clinical Gastroenterology and Hepatology, 2011, 9(5):376–384). Both approved labels still list the 30- to 60-second bolus first but offer a 30- or 50-minute infusion as the alternative that reduces nausea and cramping.

What the test is used for, and the unsettled part. A reduced ejection fraction on cholecystokinin-cholescintigraphy, together with biliary pain and a normal ultrasound, defines biliary dyskinesia, now the leading indication for cholecystectomy in children. A pilot randomized trial of laparoscopic cholecystectomy versus nonoperative therapy enrolled 30 adults; 14 of 15 patients randomized to the nonoperative arm crossed over, 13 of them to surgery, and all 26 operated patients reported pain relief at a median follow-up of 12 months, but the trial mainly showed that a definitive randomized comparison is hard to run (Richmond et al., Journal of the American College of Surgeons, 2016, 222(6):1156–1163). A 2024 review concluded that most supporting data are retrospective with short follow-up, that scan protocols still vary between institutions despite the guideline, and that the evidence for operating on children and on the “hyperkinetic” gallbladder is insufficient (Richmond, JAMA Surgery, 2024, 159(9):1079–1084). The reproducibility problems are in the test’s use and interpretation, not in whether sincalide contracts the gallbladder.

The therapeutic trial that failed. The one attempt to use sincalide as a treatment was in neonates on parenteral nutrition, where the hypothesis was that regular gallbladder emptying would prevent cholestasis. A multicenter, double-blind, placebo-controlled trial (NCT00004414, enrolling from 1996 to 2001) randomized 243 very-low-birth-weight and surgical neonates to twice-daily CCK-8 or placebo; conjugated bilirubin did not differ (1.76 versus 1.93 mg/dL), nor did sepsis, time to enteral feeding, length of stay, or mortality, and the authors concluded it should not be recommended for this purpose (Teitelbaum et al., Pediatrics, 2005, 115(5):1332–1340). Follow-up ultrasound 2 to 4 years later in 38 of the children found it had not prevented gallstone formation either (Tsai et al., Journal of Pediatric Surgery, 2005, 40(1):263–267). No later therapeutic trial is registered.

Sincalide as a research probe. Because it reliably empties the gallbladder, CCK-8 infusion is used as a tool in physiology studies: a GSK crossover study measured whether a single dose of albiglutide blunted Kinevac-induced gallbladder emptying in 20 healthy subjects (NCT02496221, completed October 13, 2015), Danish investigators have used exogenous cholecystokinin infusions to show that GLP-2 abolishes the hormone’s gallbladder-contracting effect in 15 healthy men (Lange et al., Journal of Clinical Endocrinology & Metabolism, 2024, 110(1):123–129), and a University of Copenhagen study of gut hormones and splanchnic blood flow in postural orthostatic tachycardia syndrome lists continuous CCK-8 infusion among its interventions (NCT07019519, recruiting, estimated completion September 30, 2026). A comparison of the approved product with pharmacy-compounded CCK-8 in 20 patients during an earlier supply gap found similar though not identical gallbladder responses (Krishnamurthy et al., Journal of Nuclear Medicine, 2003, 44(4):499–504), and a bench study found little chemical degradation for 8 days after reconstitution, against a labeled 8-hour hold time, while noting that microbial testing had not been done (Belanger et al., Journal of Nuclear Medicine Technology, 2020, 48(2):174–176).

Supply history and the second approval. Kinevac originated at Squibb and is held today by Bracco Diagnostics under NDA 017697. After a 2001 supply warning the product was reformulated with a stabilized excipient system in 2002; it was then listed in the FDA Drug Shortages Database from June 2013 until December 2015 and again from March 2017, and departments fell back on compounded sincalide or fatty meals during the gaps (Ponto, Journal of Nuclear Medicine Technology, 2015, 43(2):117–121). MAIA Pharmaceuticals’ 505(b)(2) application (NDA 210850), which relied on the FDA’s findings for Kinevac and ran no new clinical trial, received priority review because of the recurrent shortages, was tentatively approved on February 23, 2018, and received final approval on November 22, 2022 once a Bracco patent had expired. The MAIA product is also marketed under the Fosun Pharma USA label, and Fresenius Kabi lists an authorized generic of Kinevac under Bracco’s NDA. In November 2026, Drugs@FDA lists only these two applications for sincalide, and Kinevac’s entry in the FDA Drug Shortages Database still reads “currently in shortage.”

Common dosage forms

• Approved products. Every US sincalide product is a sterile lyophilized powder containing 5 mcg of sincalide per single-dose vial, for intravenous use only, supplied by Bracco Diagnostics (Kinevac), Fresenius Kabi (an authorized generic of Kinevac), MAIA Pharmaceuticals and Fosun Pharma USA.
• Who handles it. A hospital and imaging-department product used by nuclear medicine, radiology, and gastroenterology staff; there is no take-home, oral, pen, or self-administered presentation.
• Compounded sincalide. During past shortages, compounding pharmacies supplied non-FDA-approved sincalide vials to imaging departments; these are outside the approved supply chain.
• Research supply. Sulfated CCK-8 is sold by laboratory suppliers as a lyophilized research-grade peptide, typically as the ammonium or sodium salt in milligram quantities, for receptor and physiology experiments. It has little presence in the research-peptide vial market.

Key considerations

• Regulatory status. The FDA Approved status reflects the July 21, 1976 approval of Kinevac under NDA 017697 and the November 22, 2022 approval of a second sincalide product under NDA 210850. The approval covers three diagnostic indications in adults, and sincalide is not approved to treat any condition.
• Serious hypersensitivity is the labeled safety signal. Anaphylaxis and anaphylactic shock have been reported during and within an hour of administration, and the label also warns that stimulated contraction can move small gallstones into the bile ducts and that sincalide may cause preterm labor or spontaneous abortion.
• The test is only as reproducible as its protocol. Slow infusion is the reference method, yet protocols still differ between institutions, and the clinical value of operating on a low ejection fraction remains contested.
• Supply has been unreliable for two decades. Recurrent shortages drove departments to compounded product and fatty-meal alternatives, each with its own reference values, and the second NDA and the authorized generic were the regulatory response.
• Naming confusions. “CCK-8” is also the abbreviation for Cell Counting Kit-8, a colorimetric proliferation assay, so literature searches on the abbreviation return mostly unrelated cell-biology papers, and “CCK-OP” is the older clinical abbreviation. Sincalide is the sulfated octapeptide specifically, and non-sulfated catalog material is not pharmacologically equivalent.