Positron Emission Tomography Study of Changes in [11C]AZ14132516 Uptake Following Administration of AZD7798 to Healthy Participants and Patients With Crohn's Disease

Inclusion Criteria:

HEALTHY PARTICIPANTS:

1. Capable of giving signed informed consent as described in Appendix A which includescompliance with the requirements and restrictions listed in the ICF and in thisprotocol.

2. Able and willing to participate in all scheduled evaluations, abide by all studyrestrictions, and complete all required tests and procedures.

3. Participant must be ≥ 20 to 65 years of age inclusive, at the time of signing theinformed consent. Type of Participant and Disease Characteristics

4. Participants who are overtly healthy as determined by medical evaluation includingmedical history, physical examination, laboratory parameters, and cardiac monitoringbefore first administration of investigational product. Weight

5. Body weight within 50.0 to 100.0 kg and body mass index within the range 18.0 to 30.0 kg/m2 (inclusive).

6. Contraceptive use by males or females should be consistent with local regulationsregarding the methods of contraception for those participating in clinical studies.

(b) Male participants:

• Non-sterilised male participants who are sexually active with a female partnerof childbearing potential must use a condom with spermicide during the studyperiod and for at least 7 days following last radioligand administration and 4months following last dose of AZD7798, whichever is longer.

• It is strongly recommended that female partners of male participants also useat least one highly effective method of contraception throughout this period.

• Male participants must refrain from fathering a child or donating sperm duringthe study period and for at least 7 days following last radioligandadministration and 4 months following last dose of AZD7798, whichever islonger.

(c) Female participants: (i) Women of non-child bearing potential are defined asmeeting one of the following criteria at screening:

• Postmenopausal defined as amenorrhoea for at least 12 months followingcessation of all exogenous hormonal treatments and FSH levels in thepostmenopausal range.

• Documentation of irreversible surgical sterilisation by hysterectomy, bilateraloophorectomy, or bilateral salpingectomy but not tubal ligation.

(ii) WOCBP (ie, not meeting criteria above) must have a negative pregnancy test atscreening and before PET examination.

(iii) If sexually active with a non-sterilised male partner, WOCBP must use at leastone highly effective method of birth control during the study period and for atleast 7 days following last radioligand administration and 4 months following lastdose of AZD7798, whichever is longer.

(iv) It is strongly recommended that non-sterilised male partners of WOCBPparticipants use a male condom plus spermicide during the study period.

(v) WOCBP participants must not breastfeed and must not donate or retrieve ova fortheir own use during the study period and for at least 7 days following lastradioligand administration and 4 months following last dose of AZD7798, whichever islonger (d) Highly effective methods of birth control (i) Methods that can achieve afailure rate of less than 1% per year when used consistently and correctly areconsidered as highly effective birth control methods. Such methods include:

• Combined (oestrogen and progesterone containing) hormonal contraceptionassociated with inhibition of ovulation (oral, intravaginal or transdermal)

• Progesterone-only contraception associated with inhibition of ovulation (oral,injectable or implantable)

• Intrauterine device or hormone-releasing system

• Bilateral tubal occlusion

• Vasectomised partner (only acceptable if the partner is the sole sexual partnerof the participant and the vasectomised partner has received medical assessmentof surgical success)

• Sexual abstinence as defined by refraining from heterosexual intercourse duringthe entire period of risk associated with the study intervention. It is onlyacceptable if the preferred and usual lifestyle of the participant. PARTICIPANTS WITH CROHN'S DISEASE

1. As for Healthy Participants (IC#1) procedures.

2. Participant must be ≥ 20 to 65 years of age inclusive, at the time of signing theinformed consent.

3. Participants with confirmed Crohn's disease with small bowel involvement per studygastroenterologist (diagnosed via combination of clinical findings and at least oneof endoscopy and/or histology and/or imaging) with diagnosis made at least 3 monthsprior to screening.

4. Body weight within 50.0 to 100.0 kg and body mass index within the range 18.0 to 30.0 kg/m2 (inclusive).

5. As for Healthy Participants (IC#6).

Exclusion Criteria:

HEALTHY PARTICIPANTS:

1. Current significant major or unstable respiratory disease, heart disease,cerebrovascular disease, haematological disease, hepatic disease, renal disease,gastrointestinal disease, or other major disease.

2. History of cancer with the following exceptions

(a) Solid malignancy with curative therapy completed at least 5 years prior toscreening (b) Basal cell carcinoma or localised squamous cell carcinoma of the skinor in-situ carcinoma of the cervix, provided that curative therapy was completed atleast 12 months prior to screening

3. History of severe allergy/hypersensitivity or ongoing clinically importantallergy/hypersensitivity, as judged by the Investigator, or history ofhypersensitivity to biologic therapies.

4. Participants with unstable hypertension (as judged by the Investigator) orsymptomatic hypotension, history of pre-syncope or syncope due to orthostatichypotension and/or induced by change of posture (orthostatic hypotension defined as 25 mmHg decrease in systolic and/or 15 mmHg).

5. Significant abnormalities on clinical examination, including neurological andphysical examination, vital signs and ECG.

6. Chemistry, haematology, or urine analysis results that may interfere with the studyor present a safety risk to the participant.

7. Leukocyte, lymphocyte or neutrophil counts below the LLN. A re-test is allowedduring screening in cases of mild leukopenia clinically suspected to be transient.

8. Abnormal vital signs, after 10 minutes of supine rest as judged by the investigator.As a guide, any readings outside the following should be considered in theevaluation:

9. systolic BP ≥ 150 mmHg

10. diastolic BP ≥ 90 mmHg

11. heart rate ≤ 35 bpm or ≥ 100 bpm The inclusion of participants meeting theabove criteria may be decided on a case-by case basis by the PrincipalInvestigator.

12. Any clinically important abnormalities in rhythm, conduction or morphology ofresting ECG that may interfere with the interpretation of QTc interval changes. Thismay include participants with any of the following:

(a) PR (PQ) interval prolongation of clinical significance as judged by theInvestigator (b) Intermittent second or third-degree AV block (AV block II Mobitztype 1, Wenchebach, while asleep or in deep rest is not disqualifying) (c)Incomplete, full, or intermittent bundle branch block (QRS ≤ 110 ms with normal QRSand T wave morphology is acceptable if there is no evidence of left ventricularhypertrophy) (d) Abnormal T wave morphology (e) Prolonged QTcF ≥ 470 ms or shortenedQTcF ≤ 340 ms or a family history of long QT syndrome The inclusion of participantsmeeting the above criteria may be decided on a case-by case basis by the PrincipalInvestigator.

10. Positive hepatitis B, hepatitis C or HIV serology as defined by:

(a) HBsAg or anti-HBc Ab positivity (b) Anti-HCV Ab positivity (c) Anti-HIV Abpositivity Prior/Concomitant Therapy

11. Participants must abstain from taking prescription or non-prescription drugs (including vitamins, recreational drugs, and dietary or herbal supplements) within 7days or 5 halflives (whichever is longer) before the start of study interventionuntil completion of the follow-up visit, unless, in the opinion of the investigatorand sponsor, the medication will not interfere with the study.

12. Current drug abuse or dependence or positive screen for drugs of abuse at screeningvisit.

13. Involvement in the planning and/or conduct of the study (applies to both AstraZenecastaff and/or staff at the study site).

14. Suffers from claustrophobia that limits the ability to undergo the scanningprocedure.

15. Positive SARS-CoV-2 rapid antigen test at screening.

16. Any other reason that, in the study PI opinion, prohibits the inclusion of theparticipants into the study.

17. Judgement by the investigator that the participant should not participate in thestudy if the participant is unlikely to comply with study procedures, restrictions,and requirements.

18. Live or attenuated vaccine within 4 weeks of Screening and until the end of thefollow-up period and until 12 weeks after the end of the follow-up period (1 yearfor BCG vaccination).

19. An active infection, or history of serious infection within the preceding 28 days.

20. Use of antibiotics within 28 days prior to the first administration of IMP, unless,in the opinion of the investigator, the medication will not interfere with thestudy.

21. History of symptomatic herpes simplex (excluding cold sores) or herpes zosterinfection within 3 months prior to screening.

22. Positive or indeterminate tuberculosis (TB) QuantiFERON test.

23. Has received another new chemical entity (defined as a compound which has not beenapproved for marketing) within 30 days/5 half-lives, whichever is longer, of thefirst administration of IMP in this study. The period of exclusion begins 30 days/5half-lives, whichever is longer, after the final dose.

24. Participation in a PET imaging research study within last year.

PARTICIPANTS WITH CROHN'S DISEASE

1. Current diagnosis of ulcerative colitis, indeterminate colitis, inflammatory boweldisease unclassified, infectious colitis, or ischaemic colitis.

2. History of CMV colitis within 12 months prior to screening.

3. Complications of Crohn's Disease including short bowel syndrome, strictures/stenoseswith symptomatic obstruction or pre-stenotic dilation, or other conditions wheresurgery may be anticipated during the study period.

4. Planned bowel or perianal surgery for Crohn's disease prior to end of study followup visit.

5. Recent bowel resection surgery within 6 months of screening.

6. Participants with undrained fistula or abscess, including active perianal disease.

7. Positive C. difficile toxin test during screening.

8. Current significant major or unstable respiratory disease, heart disease,cerebrovascular disease, haematological disease, hepatic disease, renal disease,gastrointestinal disease, or other major diseases other than active Crohn's disease.

9. History of cancer with the following exceptions (a) Solid malignancy with curativetherapy completed at least 5 years prior to screening (b) Basal cell carcinoma orlocalised squamous cell carcinoma of the skin or in-situ carcinoma of the cervix,provided that curative therapy was completed at least 12 months prior to screening

10. History of severe allergy/hypersensitivity or ongoing clinically importantallergy/hypersensitivity, as judged by the Investigator, or history ofhypersensitivity to biologic therapies.

11. Participants with unstable hypertension (as judged by the Investigator) orsymptomatic hypotension, history of pre-syncope or syncope due to orthostatichypotension and/or induced by change of posture (orthostatic hypotension defined as 25 mmHg decrease in systolic and/or 15 mmHg).

12. Significant abnormalities on clinical examination, including neurological andphysical examination, vital signs and ECG other than signs of Crohn's disease.

13. Chemistry, haematology, or urine analysis results that may interfere with the studyor present a safety risk to the participant.

14. Abnormal vital signs, after 10 minutes of supine rest as judged by the investigator.As a guide, any readings outside the following should be considered in theevaluation:

(a) systolic blood pressure (BP) ≥ 150 mmHg (b) diastolic BP ≥ 90 mmHg (c) heartrate ≤ 35 bpm or ≥100 bpm The inclusion of participants meeting the above criteriamay be decided on a case-by case basis by the Principal Investigator.

15. Any clinically important abnormalities in rhythm, conduction or morphology ofresting ECG that may interfere with the interpretation of QTc interval changes. Thismay include participants with any of the following:

16. PR (PQ) interval prolongation of clinical significance as judged by theInvestigator

17. Intermittent second or third-degree AV block (AV block II Mobitz type 1,Wenchebach, while asleep or in deep rest is not disqualifying)

18. Incomplete, full, or intermittent bundle branch block (QRS ≤ 110 ms with normalQRS and T wave morphology is acceptable if there is no evidence of leftventricular hypertrophy)

19. Abnormal T wave morphology

20. Prolonged QTcF ≥ 470 ms or shortened QTcF ≤ 340 ms or a family history of longQT syndrome. The inclusion of participants meeting the above criteria may be decided on a case-bycase basis by the Principal Investigator.

21. Positive hepatitis B, hepatitis C or HIV serology as defined by:

22. HBsAg or anti-HBc Ab positivity

23. Anti-HCV Ab positivity and HCV RNA positivity

24. Anti-HIV Ab positivity Prior/Concomitant Therapy

25. Treatment with an anti-TNF biologic within 8 weeks of first dose and throughout thestudy period, unless therapeutic drug monitoring is performed and drugconcentrations are undetectable.

26. Treatment with any biologic, other than an anti-TNF (including vedolizumab andustekinumab) within 12 weeks prior to first dose and throughout the study period,unless therapeutic drug monitoring is performed and drug concentrations areundetectable.

27. Treatment with rituximab within 12 months prior to first dose and throughout thestudy period.

28. Treatment with Sphingosine-1-phosphate receptor modulators within 12 weeks prior tofirst dose and throughout the study period.

29. Treatment with Janus Kinase inhibitors within 2 weeks prior to first dose andthroughout the study period

30. Treatment with apheresis (eg, Adacolumn, Cellsorba) within 2 weeks prior to firstdose and throughout the study period.

31. Treatment with corticosteroids at a total daily dose of greater than 20 mgprednisone or equivalent.

32. Involvement in the planning and/or conduct of the study (applies to both AstraZenecastaff and/or staff at the study site).

33. Suffers from claustrophobia that limits the ability to undergo the scanningprocedure.

34. Positive SARS-CoV-2 rapid antigen test at screening.

35. Any other reason that, in the study PI opinion, prohibits the inclusion of theparticipants into the study.

36. Judgement by the investigator that the participant should not participate in thestudy if the participant is unlikely to comply with study procedures, restrictions,and requirements.

37. Live or attenuated vaccine within 4 weeks of Screening and until 12 weeks after theend of the follow-up period (1 year for Bacillus Calmette-Guerin vaccination).

38. An active infection, or history of serious infection within the preceding 28 days.

39. History of symptomatic herpes simplex (excluding cold sores) or herpes zosterinfection within 3 months prior to screening.

40. Positive or indeterminate TB QuantiFERON test performed within 1 year of screening (without known interval exposure to TB) or during screening period unless evidenceof completion of full treatment course for latent TB with no clinical symptoms orsigns indicative of re-activation.

41. Chest x-ray with signs of malignancy or latent or active TB infection performedwithin 1 year of screening (without known interval exposure to TB) or duringscreening period.

42. Has received another new chemical entity (defined as a compound which has not beenapproved for marketing) within 30 days/5 half-lives, whichever is longer, of thefirst administration of IMP in this study. The period of exclusion begins 30 days/5half-lives, whichever is longer, after the final dose.