[11c]mk-6884 positron emission tomography (pet) tracer validation trial (mk-6884-001)

Conditions: Alzheimer's Disease

Summary: the purpose of this open-label, 3-part study is to investigate the safety and efficacy of \[11c\]mk-6884 as a positron emission tomography (pet) imaging agent for quantifying muscarinic 4 (m4) positive allosteric modulator (pam) receptor density in brain regions of interest. the study will enroll healthy participants (parts 1 and 2) and participants with alzheimer's disease (ad) (part 3). the primary efficacy hypothesis is that the average intra-subject test-retest (t-rt) variability of tracer uptake in brain regions of interest is ≤20%.


Eligibility criteria:
inclusion criteria: part 1, 2 and 3: * male, or non-pregnant and non-breast feeding female of 18 to 55 years of age (part 1) or 55 to 85 years of age (parts 2 and 3); in addition: * male participant who is sexually active with females of childbearing potential must be willing to use a condom from the first dose of study drug until 3 months post the last dose of study drug * female participant with reproductive potential must have serum β-human chorionic gonadotropin (β-hcg) test result consistent with non-pregnant state at screening and agree to use two acceptable methods of birth control beginning at screening visit, during study and until 2 weeks after the last dose of study drug * female participant of non-childbearing potential must be post-menopausal female (participant has been without menses for at least 1 year and has a follicle stimulating hormone \[fsh\] level in the postmenopausal range at screening), or surgically sterile female (status post hysterectomy, oophorectomy, or tubal ligation) * body mass index (bmi) ≤35 kg/m\^2, with height ≤195 cm and weight ≤136 kg * in good health (part 1) or generally healthy (parts 2 and 3) based on medical history, physical examination, vital sign measurements and electrocardiogram (ecg) * nonsmoker and/or has not used nicotine or nicotine-containing products for at least approximately 3 months part 2 only: * willing to allow placement of an arterial catheter in the radial artery * mini mental status examination (mmse) score ≥27 * no history of subjective memory or other cognitive complaints * no objective evidence of memory or cognitive impairment part 3 only: * moderate to severe ad as defined by: * mmse score ≤20 * meets national institute of neurological and communicative diseases and stroke/alzheimer's disease and related disorders association (nincds-adrda) criteria for probable ad * meets diagnostic and statistical manual of mental disorders, 5th edition (dsm-v) criteria for ad * rosen-modified hachinski score ≤4 * screening magnetic resonance imaging (mri) scan consistent with a diagnosis of ad * clear history of cognitive and functional decline over ≥1 year * on a stable dose of one of protocol-defined acetylcholinesterase inhibitors (acheis) (i.e., donepezil and rivastigmine) for symptomatic treatment of ad. dose must be stable for at least the last 4 weeks before screening * has a reliable trial partner/caregiver who is able to accompany the participant to all clinic visits, if needed, and able to provide information to study investigator/staff via telephone contact exclusion criteria: part 1, 2, and 3: * mentally or legally incapacitated, has significant emotional problems at the time of screening visit or expected during the conduct of the trial or has a history of clinically significant psychiatric disorder of the last 5 years, except (for part 3 only) for psychiatric disorders associated with ad * history of clinically significant endocrine, gastrointestinal, cardiovascular, hematological, hepatic, immunological, renal, respiratory, genitourinary or major neurological abnormalities or diseases, unless (for part 2 and 3 only) adequately controlled through a stable medication regimen * history of cancer * history of significant multiple and/or severe allergies or has had an anaphylactic reaction or significant intolerability to prescription or non-prescription drugs or food. for part 2, this includes any known allergy to lidocaine which may be used as an anesthetic for the placement of the arterial catheter * has positive test result for hepatitis b surface antigen, hepatitis c antibodies or human immunodeficiency virus (hiv) * has had major surgery or donated or lost 1 unit of blood (approximately 500 ml) within 4 weeks prior to screening * has participated in another investigational trial within 4 weeks of screening * corrected qt (qtc) interval ≥470 msec (for males) or ≥480 msec (for females) * is unable to refrain from or anticipates the use of any medication, including prescription and non-prescription drugs or herbal remedies, beginning approximately 2 weeks prior to administration of the initial dose of study drug and throughout the study. * consumes \>3 servings of alcohol a day * consumes \>6 caffeine servings a day * is currently a regular or recreational user of cannabis, any illicit drugs or has a history of drug (including alcohol) abuse within approximately 3 months * has participated in a pet research study or other study involving administration of a radioactive substance or ionizing radiation within 12 months prior to screening or has undergone an extensive radiological examination within this period * suffers from claustrophobia or an inability to tolerate confinement in small places and would be unable to undergo mri or pet scanning part 2 only: - has been administered an achei within the prior 3 months or will require administration of an achei during study part 3 only: * has been administered galantamine within the prior 7 days or will require administration of galantamine during study * history within 2 years prior to screening, or current evidence of any neurological or neurodegenerative disorder other than ad that is associated with transient or sustained alterations in cognition * history within 2 years prior to screening, or current evidence of a psychotic disorder or a major depressive disorder part 2 and 3 only: - has or is suspected to have implanted or embedded metal objects, or fragments in the head or body that would present a risk during the mri scanning procedure